Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][CH:18]1[CH2:20][O:19]1>ClCCl>[OH:10][CH2:9][C:7]1[N:6]([CH2:17][CH:18]([OH:19])[CH3:20])[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Reactant: CC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(O)Cn1nc([N+](=O)[O-])cc1CO
Temperature: 30 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with (3-nitro-1H-pyrazol-5-yl)methanol (0.57 g, 4.0 mmol), Cs2CO3 (261 mg, 0.8 mmol), and 2-methyloxirane (20 mL). The mixture was stirred at 30° C. for 2 days. The mixture was cooled to room temperature and diluted with dichloromethane (100 mL). The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 250a (0.40 g, 50%) as a white solid. MS-ESI: [M+H]+ 202.3
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])[S:14][N:13]=1)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH:35]1[CH2:38][CH:37]([C:39]([O:41]C)=[O:40])[CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:14][N:13]=[C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:35]4[CH2:36][CH:37]([C:39]([OH:41])=[O:40])[CH2:38]4)[CH:7]=[CH:6][CH:5]=3)[N:16]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile (D55) (150 mg) in dichloromethane (DCM) (7.5 mL) was added sodium acetate (31.4 mg), hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (58.1 mg) and 5 drops of acetic acid. After stirring for 30 min, sodium triacetoxyborohydride (122 mg) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated. The residue was dissolved in isopropanol/water (10 mL, 1:1), 0.5M sodium hydroxide (3.83 mL) was added, the reaction solution was heated to 90° C. for 1 h. The solvent was removed in vacuo and the residue was acidified to pH=3-4. The resulting solution was extracted with ethyl acetate (2*15 mL), and the combined organic phases were dried over sodium sulphate, concentrated and purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid (E26) (31 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.05 (3H, t), 1.31 (6H, d), 2.84 (4H, m), 3.35 (2H, m), 3.57 (1H, m), 4.20 (4H, m), 4.90 (1H, m), 7.28 (1H, t), 7.37 (1H, d), 7.44 (1H, d), 7.68 (1H, dd), 8.26 (1H, dd), 8.41 (1H, d). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C26H28N4O3S requires 476. found 477.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=2)O1.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.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].O.CCOC(C)=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][CH2:32][NH:31][C:29]([C:26]1[N:27]=[CH:28][C:23]([C:2]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:24][CH:25]=1)=[O:30])[CH3:38]
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)O)cn1
Reaction time: 3 h

Procedure:
2-bromo-4-(trifluoromethyl)benzoic acid (538 mg, 2.0 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (1.0 g, 3.0 mmol), Pd(dppf)Cl2 (163 mg, 0.2 mmol), and K2CO3 (1.1 g, 8.0 mmol) were dissolved in 1,4-dioxane (12 mL) and water (4 mL) and heated to 90° C. After 3 h the resulting mixture was diluted EtOAc and water and 2N aqueous HCl was added until the pH of the aqueous layer was ca. 3-4. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3C=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].CC1N=C(N2CCN(CCCCC)C2=O)SC=1C(OCC)=O>>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]2=[O:23])[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: CCCCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Product: CCCCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Yield: 65 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-pentylimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 65% yield: MS (ES+) m/z 298.3 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:45](C#N)=[CH:44][S:43][CH:42]=4)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C([NH:51][C:52]1[C:53]2SC=[C:58](C3C=CC(O)=CC=3)[C:54]=2[N:55]=[CH:56][N:57]=1)(C)C>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]4[C:45]5[N:51]=[CH:52][N:57]=[C:56]([NH:55][CH:54]([CH3:58])[CH3:53])[C:44]=5[S:43][CH:42]=4)=[CH:39][CH:40]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: CC(C)Nc1ncnc2c(-c3ccc(O)cc3)csc12
Product: CC(C)Nc1ncnc2c(-c3ccc(OCCCc4sc(N5CCc6cccc(C(=O)Nc7nc8ccccc8s7)c6C5)nc4C(=O)O)cc3)csc12

Procedure:
The title compound 69 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 69B: 1H NMR (DMSO-d6): δ 8.59 (s, 1H), 8.25 (s, 1H), 8.00 (d, J=7.67 Hz, 1H), 7.66-7.79 (m, 4H), 7.32-7.48 (m, 4H), 7.03 (d, J=8.59 Hz, 2H), 4.84 (s, 2H), 4.41-4.47 (m, 1H), 4.05 (t, J=6.14 Hz, 2H), 3.72-3.75 (m, 2H), 3.19-3.22 (m, 2H), 3.03 (t, J=5.98 Hz, 2H), 2.00-2.08 (m, 2H), 1.28 (d, J=6.44 Hz, 6H). ESI (+)/MS: 762 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[F:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCCl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[F:29])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: O=C(O)c1ccccc1F
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1c(NC(=O)c2ccccc2F)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Yield: 41.9 %

Procedure:
6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (8 mg, 0.02 mmol), 2-fluorobenzoic acid (4.2 mg, 0.03 mmol), PyBOP (16 mg, 0.03 mmol) and DIEA (6.5 mg, 0.05 mmol) in 1,2-dichloroethane (0.5 ml) were stirred at RT for 16 hrs. The reaction mixture was concentrated and purified by silica gel flash chromatography to isolate 374 as a white solid (4 mg, 42%). [M+H]+=478.
Reaction SMILES: [CH3:1]C(C[AlH]CC(C)C)C.[C:10]([Si:16]1([CH3:20])[CH2:19][CH2:18][CH2:17]1)#[C:11][CH2:12][CH2:13][CH2:14][CH3:15].[F-].[Na+].O>CCCCCC.CCOCC.C(Cl)Cl>[CH:10](/[Si:16]1([CH3:20])[CH2:17][CH2:18][CH2:19]1)=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:1]
Reactant: CCCCC#C[Si]1(C)CCC1
Reactant: CC(C)C[AlH]CC(C)C
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCC/C=C\[Si]1(C)CCC1
Temperature: 0 °C
Reaction time: 9 h

Procedure:
Neat DIBAL-H (1.93 mL, 1.52 g, d=0.789, 10.7 mmol, 1.2 equiv) was added to a solution of 1-(1-hexynyl)-1-methylsilacyclobutane (1.62 g, 9,0 mmol) in hexane (14 mL) and Et2O (9 mL) at 0° C. The mixture was stirred for 3 h at 0° C., 9 h at rt, and then was diluted with CH2Cl2 (40 mL). Solid NaF (3.21 g, 76.4 mmol, 8.5 equiv) was added, followed by H2O (2.9 mL, 161 mmol, 17.8 equiv) and the suspension was stirred for 3 h, then was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, pentane) and Kugelrohr distillation to afford 1.35 g (82%) of (Z)-1 as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)(=[O:22])=[O:21])[C@@H:14]([C:16]([O:18]C)=[O:17])[CH3:15].O.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)(=[O:22])=[O:21])[C@@H:14]([C:16]([OH:18])=[O:17])[CH3:15]
Reactant: COC(=O)[C@@H](C)N(c1c(Cc2c(F)cccc2F)cccc1OC)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(c2c(Cc3c(F)cccc3F)cccc2OC)[C@H](C)C(=O)O)cc1OC
Reaction time: 48 h
Yield: 50.1 %

Procedure:
To 0.164 g of methyl N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]-(R)-alaninate dissolved in 8 ml of a 1,4-dioxane/water mixture (4/1) is added, at room temperature, 0.015 g of lithium hydroxide monohydrate. The mixture is left at room temperature for 48 hours. The reaction medium is washed with 1M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/ethanol mixture to give 0.08 g of the expected product.
Reaction SMILES: C(S)C.[H-].[Na+].[H][H].C[O:9][C:10]1[CH:24]=[CH:23][C:13]2[CH:14]=[CH:15][N:16]3[CH:22]=[CH:21][CH:20]=[C:17]3[C:18](=[O:19])[C:12]=2[CH:11]=1.Cl>CN(C)C=O>[OH:9][C:10]1[CH:24]=[CH:23][C:13]2[CH:14]=[CH:15][N:16]3[CH:22]=[CH:21][CH:20]=[C:17]3[C:18](=[O:19])[C:12]=2[CH:11]=1
Reactant: COc1ccc2ccn3cccc3c(=O)c2c1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: O=c1c2cc(O)ccc2ccn2cccc12

Procedure:
Ethanethiol (0.62 g., 10 mmoles), dissolved in dimethyl formamide (10 ml.) is added to a suspension of sodium hydride (0.5 g. of 50% oil dispersion) in dry dimethyl formamide (5 ml.). The mixture is stirred until all hydrogen has evolved and 9-methoxy-11H-pyrrolo[2,1-b][3]benzazepin-11-one (2.26 g., 10 mmoles) is added. The solution is refluxed for a period of 3 hours. The cooled reaction mixture is acidified with 0.2N HCl and extracted with chloroform. The organic layer is washed with water, dried over sodium sulfate and concentrated to yield 9-hydroxy-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: C[O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21]([OH:23])=[O:22])=[N:12]3)=[C:7]2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21]([OH:23])=[O:22])=[N:12]3)=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methoxy-benzo[a]phenazine-11-carboxylic acid (II.1, see Reference Example 1A) (441 mg) in dichloromethane (30 mL) cooled to 0° C. was added a 1.0M solution of boron tribromide in dichloromethane (7.25 mL). The reaction mixture was allowed to warm to room temperature and then stirred for 16 hours. The mixture was then poured onto ice/water yielding 4-hydroxy-benzo[a]phenazine-11-carboxylic acid as a red/brown solid which was collected by filtration and air dried (230 mg).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([C@@H:36]3[C@@H:39]([CH2:40][CH2:41][C@@H:42]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[OH:43])[C:38](=[O:51])[N:37]3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)(=O)C.C(N(CC)CC)C.O>CO>[F:50][C:47]1[CH:48]=[CH:49][C:44]([C@@H:42]([OH:43])[CH2:41][CH2:40][C@H:39]2[C:38](=[O:51])[N:37]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C@@H:36]2[C:33]2[CH:32]=[CH:31][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([C@@H:6]4[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]4[OH:4])[CH:25]=3)=[CH:35][CH:34]=2)=[CH:45][CH:46]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccccc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c3)cc2)N1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol (10.5 mg, 0.013 mmol) was dissolved in 0.30 mL of methanol and 0.30 mL of triethylamine followed by drop-wise addition of water (0.80 mL). The yellowish mixture stirred at room temperature overnight. LCMS of the solution confirmed complete consumption of the starting material and formation of the fully deprotected material. The mixture was concentrated in vacuo, and purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford 2.8 mg (35%) of the desired (1S)-1,5-anhydro-1-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a white powder; 1H NMR (300 MHz, CD3OD) δ 7.65 (d, J=11.1 Hz, 2H), 7.54-7.23 (m, 10H), 7.05-6.89 (m, 3H), 4.61 (t, J=6.3 Hz, 1H), 4.19 (d, J=9.0 Hz, 1H), 3.87 (d, J=10.7 Hz, 1H), 3.73-3.63 (m, 1H), 3.49-3.36 (m, 3H) 3.22-3.18 (m, 2H), 1.89 (m, 4H) ppm; MS [M−OH]+ 596.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31](O)=[O:32].CO>O1CCCC1>[F:29][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:7]=[C:2]([F:1])[C:3]=1[CH2:30][CH2:31][OH:32]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cnc(N2CCC([C@H]3C[C@@H]3CCOc3cc(F)c(CCO)c(F)c3)CC2)nc1
Temperature: 50 °C

Procedure:
To a solution of {2,6-difluoro-4-[2-((1R,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid (72.0 mg, 0.125 mmol) in 1 ml anhydrous tetrahydrofuran at 0° C. was added 1 M borane-tetrahydrofuran complex (0.375 ml, 0.375 mmol) dropwise. The reaction mixture was stirred at 50° C. for an hour. The mixture was diluted by addition of 1 ml of methanol, concentrated under reduced pressure, and the residue purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 25-95% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. LC/MS (m/z): 448.4 (M+H)+. Human EC50: 7.2 nM
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:26]=1.[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH2:30].P.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH:30][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:26]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C1c2ccc(Cl)cc2CCc2c(OCCN3CCOCC3)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2c(OCCN3CCOCC3)cccc21

Procedure:
For the synthesis of the title compound, 0.48 g (0.0013 mol) of 8-chloro-1-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.17 g (0.0013 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)2, 0.14 g of phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10 ml of toluene and 2 ml of tert-BuOH are reacted by method O. Purification is carried out by column chromatography (flash; SiO2; hexane 60%/ethyl acetate 40%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]3[C:26]([NH:27][C:28]([CH3:32])([CH3:31])[CH2:29][CH3:30])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]1)=[O:14])=[CH:7]2)([O-])=O>CN(C)C=O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]3[C:26]([NH:27][C:28]([CH3:31])([CH3:32])[CH2:29][CH3:30])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]1)=[O:14])=[CH:7]2
Reactant: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Reaction time: 4 h

Procedure:
To a solution of 1-[5-nitroindole-2-carbonyl]-4-[3-(1,1-dimethylpropylamino)-2-pyridinyl]piperazine (PREPARATION 67, 1.00 g) in dimethylformamide/methanol (200 ml, 50/50) under nitrogen is added palladium on carbon (10%, 250 mg). The mixture is put under hydrogen (balloon) for 4 hr and nitrogen for 17 hr, filtered through a pad of celite, and concentrated under reduced pressure to give the title compound, NMR (CDCl3) 9.25, 7.66, 7.24, 7.06, 6.88, 6.76, 6.63, 4.58, 4.05, 3.35, 3.14, 1.73, 1.35 and 0.91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22](O)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[CH:12][C:11]([C:22]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=[O:23])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 75A in analogy to the synthesis of the compound of Example 1. 23 mg (39% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:22][NH2:23].C1COCC1>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]([S:12]([NH:23][CH3:22])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CNS(=O)(=O)c1cccc(C(=O)OC)c1Cl
Yield: 72 %

Procedure:
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added a 2M solution of methylamine in THF (5.6 mL, 11.2 mmol). Purification of the product (2:1 hex:EtOAc) provided methyl 2-chloro-3-[(methylamino)sulfonyl]benzoate (430 mg, 72%) as a solid. 1H NMR (400 MHz, CDCl3), δ 8.23 (dd, 1H, J=7.9, 1.7 Hz), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.48 (t, 1H, J=7.9 Hz), 5.16 (q, 1H, J=5.2 Hz), 3.94 (s, 3H), 2.62 (d, 3H, J=5.3 Hz); ESI-MS 264 (M+H). Methyl 2-chloro-3-[(methylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(methylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 250 (M+H), 272 (M+Na).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH2:36]OS(C)(=O)=O)[CH:33]=[C:32]([O:42][CH2:43][CH3:44])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16]>C1COCC1>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH2:36][N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:33]=[C:32]([O:42][CH2:43][CH3:44])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16]
Reactant: C1CCNC1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(COS(C)(=O)=O)cc(OCC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CN2CCCC2)cc(OCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
N-Ethyldiisopropylamine (132 mg, 1.02 mmol) and pyrrolidine (145 mg, 2.04 mmol) were added to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-methanesulphonyloxymethyl-phenyl)-acetate (221 mg, 0.511 mmol) obtained in Example 234.3 in THF (2 ml) and the mixture was stirred for 1 h. at room temperature. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2/MeOH 99:1). There were obtained 153 mg (73%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-pyrrolidin-1-ylmethyl-phenyl)-acetate as a yellowish foam; MS: 408 ([M+H]+).
Reaction SMILES: C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:15][CH:16]([C:18]#[C:19][C:20]12[O:32][C:21]1([CH3:31])[CH2:22][CH:23]([O:27]C(=O)C)[C:24]2([CH3:26])[CH3:25])[CH3:17])(=O)C.[OH-].[Na+]>O>[OH:32][C:21]1([CH3:31])[CH2:22][CH:23]([OH:27])[C:24]([CH3:25])([CH3:26])[C:20]1=[C:19]=[CH:18][CH:16]([OH:15])[CH3:17]
Reactant: CC(=O)OC(C)C#CC12OC1(C)CC(OC(C)=O)C2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C=C=C1C(C)(O)CC(O)C1(C)C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To 30 ml of an anhydrous THF suspension containing 808 mg of lithium aluminum hydride was slowly added 35 ml of an anhydrous THF solution containing 2.0 g of 2-acetoxy-4-(4-acetoxy-1,2-epoxy-2,5,5-trimethylcyclopentyl)but-3-yn under ice-cooling in a nitrogen atmosphere over 10 minutes. After the addition, the mixture was placed under refluxing conditions and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled, and 0.8 ml of water, 0.8 ml of a 15% sodium hydroxide aqueous solution, and 2.4 ml of water were carefully added thereto in this order, followed by vigorously stirring for 20 minutes. Any insoluble matter was removed by filtration with suction, and the filtrate was concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to obtain 902 mg (yield: 60%) of 4-(2,4-dihydroxy-2,5,5-trimethylcyclopentylidene)but-3-en-2-ol.