Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@:9]1([C:42]([F:45])([F:44])[F:43])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][S:36]2(=[O:41])=[O:40])[CH2:11][CH2:10]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([N:23]2[C:24]3[CH:25]=[C:17]4[CH2:16][CH2:15][CH2:14][C@@H:13]5[CH2:33][C@@:9]([OH:8])([C:42]([F:45])([F:43])[F:44])[CH2:10][CH2:11][C@@:12]5([CH2:34][N:35]5[CH2:39][CH2:38][CH2:37][S:36]5(=[O:40])=[O:41])[C:18]4=[CH:19][C:20]=3[CH:21]=[N:22]2)=[CH:31][CH:30]=1
Reactant: O=S1(=O)CCCN1C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S1(=O)CCCN1C[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)isothiazolidine 1,1-dioxide (35, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rg=Benzyl) (63 mg, 0.10 mmol) in DCM (3 mL) was cooled to about 0° C. and treated with BBr3 (0.40 mL, 0.40 mmol). The mixture was stirred for about 30 min, then the reaction was quenched by dropwise addition of MeOH (5 mL) and warmed to rt. The reaction was concentrated under reduced pressure, then dissolved in MeOH (5 mL) and stirred at 35° C. for about 15 min. DCM (5 mL) was added and the mixture was concentrated onto silica gel (1 g). The residue was purified on silica gel column (4 g) using a gradient of 30-100% EtOAc in DCM. Product fractions were combined and concentrated. The residue was dissolved in MeOH (5 mL) and water (3 mL), then concentrate under reduced pressure to about (3 mL) volume. The product was filtered off and dried under reduced pressure to yield 2-(((3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)isothiazolidine 1,1-dioxide (11, R1=4-Fluorophenyl, R2=1,1-dioxidoisothiazolidin-2-yl)methyl, R3=Trifluoromethyl) (22 mg, 41%) as an off-white solid; LC/MS, method 2, Rt=2.59 min, MS m/z 552 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 7.90 (s, 1H), 7.85-7.76 (m, 2H), 7.62 (s, 1H), 7.45-7.37 (m, 2H), 5.98 (s, 1H), 3.65 (q, J=14.6 Hz, 2H), 3.41-3.32 (m, 1H), 3.14-2.99 (m, 2H), 2.96-2.86 (m, 1H), 2.36-2.25 (m, 1H), 2.20-2.08 (m, 1H), 2.08-1.55 (m, 12H), 1.49-1.35 (m, 1H). (Example 75)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.Cl>O.[Fe].C(O)C>[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(I)cnc1Cl
Yield: 92.3 %

Procedure:
5-iodo-3-nitro-2-chloropyridine (230 mg, 0.809 mmol), ethanol (1 mL), water (6 drops), and concentrated HCl (0.020 mL) were stirred at room temperature for 10 min. Iron (500 mg, 8.95 mmol) was then added in small portions and the reaction round bottom flask was placed into a 100° C. oil bath for 20 min. The iron was removed by filtration, washed with ethanol, then the combined ethanol layers were concentrated under reduced pressure. The crude residue was purified by flash chromatography using 9:1 hexane:ethyl acetate to give 5-iodo-3-amino-2-chloropyridine (190 mg, 92%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCC1
Reactant: Sc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccccc1SC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a sealed tube fitted with a septum to allow for the contents to be placed under an argon atmosphere is placed 2-chloro-benzenethiol (20 mmol) and N,N-dimethylformamide (15 mL). To this solution under argon is then added in small portions sodium hydride (1.1 equiv.). After addition is complete the reaction mixture is stirred for another 20 min at 25° C. To this solution is then added cyclopentyl bromide (1.1 equiv) and the reaction is then sealed and the tube placed in an oil bath and heated to 100° C. for 20 h. After such time the reaction mixture is cooled to 25° C. and then poured onto crushed ice and extracted with diethyl ether. The combined organic layers are then washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The resulting liquid is then distilled to yield 1-chloro-2-cyclopentylsulfanyl-benzene.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Cl:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: N#C[S-]
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 2-bromo-1-(3-chlorophenyl)ethanone (7.55 g, 32.3 mmol) and potassium thiocyanate (3.14 g, 32.3 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture. Crystals were collected by filtration and washed with water to give 4.92 g (69.8%) of the desired product as a solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[C:28]([C:29]#[N:30])=[C:27]([CH3:31])[N:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C.CCOC(C)=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[C:28]([C:29]#[N:30])=[C:27]([CH3:31])[N:26]=[CH:25][CH:24]=3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Cc1nccc(Cl)c1C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccc(N[C@@H](C)c2nc3ccc(F)cc3n2-c2ccccc2)c1C#N
Reaction time: 86 h
Yield: 24.6 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.083 g, 0.25 mmol), 4-chloro-2-methylnicotinonitrile (0.035 g, 0.23 mmol) and diisopropylethylamine (0.160 mL, 0.92 mmol) in isopropanol (1 mL) was heated to 80° C. in a sealed tube under argon for 2 h then at 75° C. for 86 h. The reaction mixture was cooled, diluted with EtOAc (20 mL) and washed with water (10 mL). The organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-8% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated and freeze dried to give 340 as a pale brown solid, (21 mg, 24%). LCMS (Method C): RT 3.11 min [M+H]+ 372.08. 1H NMR δ (ppm DMSO-d6): 7.98 (1H, d, J=6.15 Hz), 7.77 (1H, dd, J=8.82, 4.86 Hz), 7.52-7.50 (5H, m), 7.12-7.11 (2H, m), 6.85 (1H, dd, J=8.91, 2.51 Hz), 6.40 (1H, d, J=6.24 Hz), 5.11 (1H, dq, J=7.04 Hz), 2.41 (3H, s), 1.56 (3H, d, J=6.64 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].Br[CH2:33][C:34]1([CH2:37]Br)[CH2:36][CH2:35]1.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:37][C:34]3([CH2:36][CH2:35]3)[CH2:33]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: BrCC1(CBr)CC1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CC2(CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.6 g, 1.36 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.136 g, 3.4 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,1-bis(bromomethyl)cyclopropane (0.482 g, 1.4 mmol, for preparation see J. Org. Chem. 1993, 58, 4122-26) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 5-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-spiro[2,3]hexane-5-carboxylate (150 mg) as a low melting solid.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([CH3:21])[CH:11]=1)(=O)C.[ClH:22]>CO>[ClH:22].[CH3:21][C:12]1[CH:11]=[C:10]([NH:9][C:5]2[NH:6][CH2:7][CH2:8][N:4]=2)[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(-c2ccccc2)n1

Procedure:
1-Acetyl-2-(3-methyl-1-phenyl-5-pyrazolyl) amino-2-imidazoline (35.0 g.) was treated with HCl in methanol as described in Example II to give 28.7 g. product as the hydrochloride. mp 182°-184°
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([S:64](Cl)(=[O:66])=[O:65])=[C:61]([CH3:63])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:64]([C:60]1[S:59][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[N:62][C:61]=1[CH3:63])(=[O:65])=[O:66])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (510 mg) was reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to yield (S)-2-({(3S,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (526 mg) according to General Procedure E. The title compound (32 mg) was prepared by the hydrolysis of (S)-2-({(3S,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LCMS m/z=968) (40 mg) according to General Procedure B. LCMS (m/z): 952.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: CC(C)(C)c1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-tert-butylphenyl borate (0.47 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 16 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:1) and recrystallized from ethyl acetate/diisopropylether to give colorless crystals of methyl 7-(4-tert-butylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (793.6 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1[C:10]([CH:20]=[O:21])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:22]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[C:10]([CH2:20][OH:21])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)Nc1cccc(N(Cc2ccccc2)Cc2ccccc2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc(N(Cc2ccccc2)Cc2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
The product from Example 42A (0.017 g, 0.043 mmoles) in ethanol (2 mL) was treated with sodium borohydride (0.002 g, 0.053 mmoles). After stirring two hours at room temperature, the reaction mixture was quenched with saturated ammonium chloride and extracted with chloroform. The extracts were combined, dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate/hexanes) to provide the title compound (0.015 g, 88%). 1H NMR (300 MHz, CDCl3) δ7.63 (s, 1H), 7.12-7.38 (m, 13H), 4.67 (s, 2H), 4.06 (s, 4H), 2.85 (s, 3H); MS (ESI+) m/z 397 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][O:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[O:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:25][CH:24]=1
Reactant: Cc1c(OCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(COc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
To a solution 2-[4-(4-hydroxy-butyl)-benzyloxy]-3-methyl-chromen-4-one (101 mg, 0.30 mmol) dissolved in anhydrous dichloromethane (3.0 mL) was added TsCl (68 mg, 0.36 mmol), DMAP (55 mg, 0.45 mmol) and TEA (0.050 mL, 0.36 mmol). The reaction mixture continued stirring at room temperature. After 20 h, the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to yield toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-chromen-2-yloxymethyl)-phenyl]-butyl ester (75.2 mg, 0.15 mmol) in moderate yield (51%). 1H (CDCl3, 600 MHz): δ 8.21 (1H, dd, J=8.2,1.5 Hz), 7.77 (2H, d, J=8.3 Hz). 7.60 (1H, m), 7.33 (2H, d, J=8.0 Hz), 7.36 (2H, d, J=8.0 Hz), 7.39 (2H, d, J=8.2 Hz), 7.33 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=7.9 Hz), 5.43 (2H, s), 4.04 (2H, t, J=5.9 Hz), 2.59 (2H, t, J=7.3 Hz), 2.44 (3H, s), 1.99 (3H, s), 1.68 (4H, m);); 13C (CDCl3, 150 MHz): δ 178.2, 161.8, 152.2, 144.2, 141.9, 132.7, 132.2, 131.9, 129.3, 128.3, 127.7, 127.4, 125.6, 127.7, 122.1, 116.1, 70.1, 69.8, 34.3, 27.9, 26.5, 21.1, 6.7. HRMS calcd for C28H28O6S: 545.1498. found. 515.1493.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][C:8]=2[F:24])=[N:4][N:3]=1.N1([CH:34]=[O:35])C2C=CC=CC=2N=N1>C1COCC1>[F:24][C:8]1[CH:9]=[C:10]([N:13]2[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]2=[O:23])[CH:11]=[CH:12][C:7]=1[C:5]1[S:6][C:2]([NH:1][CH:34]=[O:35])=[N:3][N:4]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3nnc(N)s3)c(F)c2)C(=O)O1
Reactant: O=Cn1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3nnc(NC=O)s3)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
To a stirred suspension of the compound of Example 30 (184 mg) in dry THF (5 mL) is added 1H-benzotriazole-1-carboxaldehyde (168 mg). The reaction mixture is heated at reflux for 48 hours, cooled and concentrated. The residue is dissolved in EtOH/CH3CN, absorbed onto silica gel and purified by flash chromatography using 7% MeOH in CH2Cl2 as the eluent to yield 155 mg of the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:20][CH2:19]3)=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>CO>[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]([N:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23]3)=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CN1CCN(C2=Nc3ccccc3Cc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCN(C2=Nc3ccccc3Cc3ccccc32)CC1
Yield: 63.1 %

Procedure:
2N Aqueous sodium hydroxide solution (5 ml) was added to a solution of 1.82 g of ethyl 4-(11H-dibenz[b,e]azepin-6-yl)-1-piperazineacetate in 18 ml of methanol. The solution was refluxed for 30 min and then concentrated. The residue was dissolved in hot water and the solution was neutralized with 0.5N hydrochloric acid. The precipitates were collected by filtration to give 1.06 g of colorless crystals, which were recrystallized from ethanol to give colorless granules, mp 181°-183° C. (decomp.).
Reaction SMILES: [CH:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=O.C(OC(=O)C)(=O)C>C(O)(=O)CC.C(NCCCC)CCC>[CH:1]([C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][C:9]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: COC(=O)C=O
Reactant: CCCCCCC=O
Solvent: CCC(=O)O
Solvent: CCCCNCCCC
Solvent: CC(=O)OC(C)=O
Product: CCCCCC(C=O)=CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 57 g (0.5 mol) of n-heptanal and 44 g (0.5 mol) of methyl glyoxylate was added dropwise to a mixture of 1.85 g (0.025 mol) of propionic acid and 3.22 g (0.025 mol) of di-n-butylamine in such a way that the temperature did not exceed 80° C. After the addition was complete the mixture was stirred at 80° C. for 30 min, then 102 g (1 mol) of acetic anhydride were added and the mixture was heated to boiling. Acetic acid slowly distilled out, 51 g being obtained in 2 hours. Fractional distillation of the bottom product yielded 59 g of methyl 3-formyl-3-pentylacrylate with a boiling point of 82°-85° C./1 mbar, corresponding to a yield of 64% of theory. The trans/cis isomer ratio was 78/22.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH:21]([CH3:23])[CH3:22])[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=4)[NH:12][C:11]3=[O:20])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31](I)[CH:30]=[C:29]([Br:34])[CH:28]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC>C(#N)C.[Cu]I>[CH3:24][O:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([N:12]2[C:13]3[C:18](=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C@:10]3([CH2:9][C@:8]3([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:21]([CH3:23])[CH3:22])[C:11]2=[O:20])[CH:30]=[C:29]([Br:34])[CH:28]=1
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: CC(C)[C@]1(c2ccc(Cl)cc2)C[C@]12C(=O)Nc1ccc(F)cc12
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N2C(=O)[C@@]3(C[C@]3(c3ccc(Cl)cc3)C(C)C)c3cc(F)ccc32)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 82 %

Procedure:
(1R,2R) and (1S,2S)-2-(4-chlorophenyl)-5′-fluoro-2-isopropylspiro[cyclopropane-1,3′-indolin]-2′-one prepared according to Scheme 2 (0.33 g, 1 mmol), and the 3-bromo-5-iodo-benzoic acid methyl ester (0.409 g, 1.2 mmol), CuI (20 mg), K2CO3 (0.276 g, 2 mmol) were placed in a Schlenk tube under argon atmosphere and dissolved in dry acetonitrile. The N,N′-dimethyl-1,2-ethanediamine (21 μL) was added into the mixture. The mixture was stirred at 80° C. for 14 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography to give the title compound as white powder (0.444 g, 82%). LC/MS m/e calcd. for C27H22BrClFNO3: 541, observed (M+H)+: 542.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24](O)=[O:25])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:28]([NH2:30])[CH3:29]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]([NH:30][O:28][CH3:29])=[O:25])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(C(=O)O)c3)CC2)c(Cl)c1Cl
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)ccn1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyridine-2-carboxylic acid (Example 293) and methoxylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([Cl:17])=[O:13])=[CH:5]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloroindole-2-carboxylic acid (59 mg, 0.30 mmol) was suspended in dichloromethane (10 mL). Oxalyl chloride (41 μL, 0.45 mmol) and N,N-dimethylformamide (5 μL) were added, and the reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated, and the residue was dried under high vacuum to provide the crude product which was used without additional purification.