Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]1[C:11]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:12]2)[CH2:10]1.CI>C1COCC1>[CH3:2][C:13]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12][C:11]2([CH2:10][CH2:9]2)[CH2:14]1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(OCc1ccccc1)C1CC2(CC2)C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)OCc2ccccc2)CC2(CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of LDA (3.47 mL, 6.94 mmol 2M in THF) in THF (5 mL) cooled to −78° C., was added dropwise a solution of benzyl spiro[2.3]hexane-5-carboxylate (0.5 g, 2.312 mmol) in THF (2 mL). The resulting solution was stirred for 30 min. prior to the dropwise addition of MeI (0.723 mL, 11.56 mmol) at −78° C. The resulting reaction mixture was allowed to warm to RT and stir for 12 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (20 mL) and extracted with EtOAc (3×10 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 5% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford the Intermediate 317A as a colorless liquid (200 mg, 38% yield). MS(ES): m/z=231.2 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.50-7.28 (m, 5H), 5.36-4.94 (s, 2H), 2.87-2.47 (m, 2H), 2.01-1.77 (m, 2H), 1.62-1.39 (s, 3H), 0.60-0.22 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:9]=2)[C:5]([CH3:15])([CH3:14])[CH2:6]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CC(C)(C)c2cc(Br)ccc21
Reactant: O=S(=O)(O)Cl
Product: CC(=O)N1CC(C)(C)c2cc(Br)c(S(=O)(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(5-Bromo-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (2.0 g, 7.5 mmol) was slowly added to chlorosulfonic acid (20 mL) and the resulting solution was stirred at room temperature for 3 days. The mixture was then carefully poured over ice and the resulting solid filtered, washed with water and dried in vacuo to give the title compound (2.7 g) as a pale brown solid. 1H NMR (Acetone-d6): 9.02 (1H, s), 7.89 (1H, s), 4.11 (2H, s), 2.26 (3H, s), 1.49 (6H, s).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1/[CH:11]=[CH:12]/[NH:13][CH:14]=[O:15].B(Br)(Br)Br>ClCCl>[CH:7]1[C:6]([OH:9])=[CH:5][C:4](/[CH:11]=[CH:12]/[NH:13][CH:14]=[O:15])=[C:3]([OH:2])[CH:8]=1
Reactant: COc1ccc(OC)c(/C=C/NC=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=CN/C=C/c1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 800.3 %

Procedure:
To a stirred solution of (E)-N-[2-(2,5-dimethoxyphenyl) ethenyl] formamide (2.071 g, 10 mmol) in anhydrous dichloromethane (100 ml) is added, at -78° C. under nitrogen over a period of 10 min, a 1.0M solution of boron tribromide in dichloromethane (30 ml, 30 mmol). The resulting mixture is stirred for another 1 h at -78° and then allowed to warm to room temperature. After stirring for 1.5 h at 20°-25° C. the mixture is cooled to -10° C. and then quenched by the dropwise addition of water (100 ml) over a 10 min period. After addition of ethyl acetate (100 ml) the organic layer is separated, washed with water, dried with Na2SO4 and evaporated under vacuum to dryness. After venting with nitrogen the residue is dissolved in 80 ml of CHCl3 /MeOH 10% and the solution diluted with CHCl3 (60 ml) to faint turbidity. The mixture is kept for 5 h at 0°-5° C., the precipitate filtered and dried at 20°-25° C. under vacuum. Thus 14.34 g (80% yield) of pure title compound is obtained with m.p. 149°-153° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23]C)=[O:22])[N:17]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:13]3[N:30]=[CH:29][S:28][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([OH:23])=[O:22])[N:17]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1cccc(-c2nc(Nc3cccc(S(C)(=O)=O)c3)c3ncsc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1cccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)c1
Reaction time: 0.15 h
Yield: 40.4 %

Procedure:
Methyl 3-(7-(3-(methylsulfonyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (130 mg, 0.29 mmol) and NaOH (130 mg, 3.25 mmol) in 3 mL of 1,4-dioxane and 3 mL of H2O were stirred at room temperature for 3 hours and then treated by conc. HCl until pH=3-4. The solvent was removed under reduce pressure the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3-(methylsulfonyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (50 mg, 40%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 13.18 (brs, 1H), 10.76 (s, 1H), 9.45 (s, 1H), 8.99-8.95 (m, 2H), 8.72 (dt, 1H, J1=7.8 Hz, J2=1.5 Hz), 8.22-8.18 (m, 1H), 8.08 (dt, 1H, J2=8.1 Hz, J2=1.4 Hz), 7.69-7.61 (m, 3H), 3.24 (s, 3H). LC-MS: 427 [M+H]+, tR=1.48 min. HPLC: 98.42% at 214 nm, 99.23% at 254 nm, tR=5.75 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[NH:9]2)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=[C:20]=[O:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[N:9]2[C:20]([NH:19][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Cl)cc2)N1
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Cl)cc2)N1C(=O)Nc1ccc(C#N)cc1
Reaction time: 5 h

Procedure:
To a solution of (1R,3S)-1-(4-chlorophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline (50 mg, 194 μmol, example 80, step 2) in CH2Cl2 (1.0 mL) at RT was added 4-isocyanatobenzonitrile (42 mg, 291 μmol). The reaction was stirred 5 h and directly purified by reverse phase HPLC to give (1R,3S)-1-(4-chlorophenyl)-N-(4-cyanophenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 402 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[BH3-]C#[N:14].[Na+]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:14]
Reactant: [BH3-]C#N
Reactant: O=C1CCc2c(Br)cccc21
Agent: [Na+]
Product: NC1CCc2c(Br)cccc21

Procedure:
The title amine was generated from 4-bromo-indan-1-one (5.00 g, 23.70 mmol), NaBH3CN (10.40 g, 165.50 mmol) and NH4OAc (54.80 g, 710.95 mmol) according to the protocols as outlined in general procedure B described above.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:5][N:6]=1.[C:11]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([S:19](Cl)(=[O:21])=[O:20])=[CH:17][CH:16]=1)(=[O:13])[CH3:12].Cl>N1C=CC=CC=1>[C:7]([C:4]1[S:3][C:2]([NH:1][S:19]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:11](=[O:13])[CH3:12])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:6][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
2-Amino-5-tert-butyl-1,3,4-thiadiazole (1.0 g, 6.36 mmol) was suspended in pyridine (1.6 mL). N-Acetylsulfanilyl chloride (1.9 g, 5.1 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3N HCl and the mixture extracted with ethyl acetate. The organic extracts were washed with water (3×65 mL), brine (3×65 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated. The residue was crystallized from MeOH to give the product (1.59 mg, 4.3 mmol, 84%) as a solid, mp 137-138° C.; 1H NMR (500 MHz, DMSO) δ 1.28 (9, t, J=7.0 Hz), 2.08 (3, s), 7.73 (2, d, J=8.5 Hz), 7.78 (2, d, J=8.5 Hz), 10.48 (1, s), 14.00 (1, brs); 13C NMR (125 MHz, DMSO) δ 24.1, 29.3, 36.1, 118.6, 126.8, 135.6, 142.8, 166.9, 167.2, 169.0; MS (LCQ, ESI+) Calculated for C14H19N4O3S2 355.1. found 355.1 (M+H)+; HRMS (FAB+, m/z) Calculated for C14H19N4O3S2 355.0899. found 355.0900 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.Cl>N1C=CC=CC=1>[CH3:1][N:2]([C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N(C)C(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-methylaminobenzoate (1.0 g, 6.05 mmol) in anhydrous pyridine (20 mL) was added dropwise hydrocinnamoyl chloride (1080 μL) at rt. After 16 hrs water (5 mL) was added and the resulting mixture was stirred for 1 hr at rt. The resulting mixture was poured into water (300 mL) and HCl (5 N, 50 mL) was added. The compound was extracted with AcOEt (2×300 mL) and washed with a saturated aqueous solution of NaHCO3 (150 mL). The combined organic layers were dried over MgSO4 and evaporated under vacuo to give the title compound (1.80 g) was obtained as a beige solid (95%) in 95.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[CH:26]1[CH2:27][CH2:28][O:23][CH2:24][CH2:25]1)=[O:7])#[N:3]
Reactant: O=C1CCOCC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C1CCOCC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was reductively aminated with tetrahydro-4H-pyran-4-one in analogy to experiment L3 to give to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 412.1 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[BH4-].[Na+].O>C(O)(=O)C>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(SCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 1-benzylsulfanyl-4-((E)-2-nitro-vinyl)-benzene (950 mg, 3.5 mmol) described in Manufacturing Example 205-1-3 in acetic acid (0.6 mL) and dimethyl sulfoxide (10 mL) was added sodium borohydride (212 mg, 5.6 mmol) while the internal temperature was held at 30° C. or lower, which was stirred for 30 minutes at room temperature. The mixture was cooled with ice water, water was added, which was stirred for another 30 minutes. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (936 mg). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:12]=3[CH2:14]O)[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.S(Cl)([Cl:31])=O>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:12]=3[CH2:14][Cl:31])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn(C2CC2)c2c(CO)c(N3CCOCC3)c(F)cc2c1=O
Product: CCOC(=O)c1cn(C2CC2)c2c(CCl)c(N3CCOCC3)c(F)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (80 mg) is added thionyl chloride (1 ml), and the mixture is stirred at room temperature for 4 hours and further at 50° C. for one hour. The solvent is concentrated under reduced pressure to give crude ethyl 1-cyclopropyl-7-morpholino-6-fluoro-8-chloromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (84 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([F:30])[CH:29]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:26]4[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cc(F)cc(F)c1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cc(F)cc(F)c4)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3,5-difluorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2,3′,5′-trifluorobiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 3%): m/z (ES+) 401 [MH+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl>O1CCOCC1>[N:11]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3(C#N)CCOCC3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N#CC1(c2ccc(OCCCN3CCNCC3)cc2)CCOCC1
Yield: 72 %

Procedure:
4-{3-[4-(4-Cyano-tetrahydro-pyran-4-yl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.16 mmol), MeOH (5 ml), 1,4-dioxane (1 ml) and HCl in dioxane (4M, 1.8 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo at 40° C., and diluted with TBME (5 ml). Aqueous NaOH (2M solution) was added to attain a pH of 14 and the mixture separated and extracted with TBME (2×5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide title compound as a yellow oil (275 mg, 72%). 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.11-4.05 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 2.90 (t, 4H), 2.51 (t, 2H), 2.44 (br s, 4H), 2.15-2.00 (m, 4H), 1.97 (m, 2H), 1.74 (br s, 1H).
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.Cl.N([O-])=O.[Na+].[I-:21].[K+]>ClCCl.C(O)(=O)C>[I:21][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc2c(c1)CCc1ccccc1-2
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Ic1ccc2c(c1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
Under an argon atmosphere, 220 g of 2-amino-9,10-dihydrophenanthrene, 3 L of 3N HCl, and 2 L of acetic acid were added, and then the mixture was stirred for 3 hours under heat. After having been cooled to room temperature, the mixture was cooled with ice, and then an aqueous solution of 91 g of sodium nitrite was dropped to the mixture. After the resultant mixture had been stirred for 1 hour under ice cooling, an aqueous solution of 660 g of potassium iodide was added to the mixture. Subsequently, 2 L of dichloromethane were added to the mixture, and then the whole was stirred at room temperature for 3 hours. After that, the mixture was extracted with dichloromethane. The organic layer was repeatedly washed with an aqueous solution of potassium carbonate, and was then dried with magnesium sulfate. After that, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 210 g of a pale yellow solid were obtained (in 62% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35]Br)=[CH:29][CH:28]=2)=[O:26])=[C:23]([OH:39])[CH:22]=1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][O:20][C:21]2[CH:38]=[CH:37][C:24]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:1][C:2]4[CH:3]=[CH:4][C:5]([C:8]5[S:9][C:10]6[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=6[N:12]=5)=[CH:6][CH:7]=4)=[CH:29][CH:28]=3)=[O:26])=[C:23]([OH:39])[CH:22]=2)=[CH:7][CH:6]=1
Reactant: O=C(c1ccc(OCCBr)cc1)c1ccc(OCCBr)cc1O
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Product: O=C(c1ccc(OCCOc2ccc(-c3nc4ccccc4s3)cc2)cc1)c1ccc(OCCOc2ccc(-c3nc4ccccc4s3)cc2)cc1O

Procedure:
A hot solution of 16 g. of zinc o-aminophenylmercaptide and 125 g. of 4-hydroxybenzaldehyde in 1 liter of acetic acid was treated with hydrogen sulfide for two hours, filtered hot, diluted with an equal volume of water and cooled. 2-(4-Hydroxyphenyl)benzothiazole (47% yield, m.p. 227°-229°) was obtained. The 2-(4-hydroxyphenyl)benzothiazole was reacted with 4,4'-bis(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce Compound V.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:39]#[N:40])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18][CH:17]([C:25]([OH:27])=O)[CH:16]2[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH2:36][CH2:37][OH:38])=[C:11]([F:41])[CH:10]=1.CC1(C)[O:47][C@@H:46]([CH2:48][CH2:49][NH2:50])[CH2:45][O:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:47][C@H:46]([CH2:45][OH:44])[CH2:48][CH2:49][NH:50][C:25]([CH:17]1[CH:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH2:36][CH2:37][OH:38])[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[F:41])([C:39]#[N:40])[CH:19]([CH2:20][C:21]([CH3:22])([CH3:24])[CH3:23])[NH:18]1)=[O:27]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Cl)ccc2OCCO)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cc(Cl)ccc2OCCO)C1(C#N)c1ccc(Cl)cc1F
Yield: 13.1 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 84c (0.4 g, 0.64 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.28 g, 1.93 mmol), HATU (0.44 g, 1.15 mmol) and iPr2NEt (0.56 mL, 3.21 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (50 mg, 13%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:16])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28])=O>CO>[CH2:1]([N:3]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[CH:18][S:16]/[C:4]/1=[N:5]\[C:6]1[CH:7]=[CH:8][C:9]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: COc1ccccc1C(=O)CBr
Reactant: CCNC(=S)Nc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCn1c(-c2ccccc2OC)cs/c1=N\c1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(3-ethylthioureido)benzenesulfonic acid (1-4) (50 mg, 0.19 mmol) and 2-bromo-1-(2-methoxyphenyl)ethanone (30 mg, 0.13 mmol) in MeOH (1 mL) is heated to 80° C. for 1 hour and then cooled to room temperature and concentrated. The residual is purified by preparative LC/MS to provide (Z)-4-(3-ethyl-4-(2-methoxyphenyl)thiazol-2(3H)-ylideneamino)benzenesulfonic acid (1-5) as white solid. HPLC-MS calculated for C18H18N2O4S2 (M+H+) 391.1. found 391.1.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[O:53]1[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]1.C(O)(=O)C>C(#N)C.ClCCl>[F:52][C:16]([F:51])([F:15])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=1)[CH2:20][N:21]([C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([CH:56]2[CH2:57][CH2:58][O:53][CH2:54][CH2:55]2)[C:24]2[CH:29]=[C:30]([C:34]([F:35])([F:36])[F:37])[C:31]([CH3:33])=[CH:32][C:23]1=2)[C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2c(cc1C(F)(F)F)N(C1CCOCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 24 h
Yield: 60.8 %

Procedure:
Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol) portionwise to a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.100 g, 0.181 mmol), tetrahydro-4-pyranone (0.054 g, 0.543 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as an off-white solid (0.070 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 0.87-0.95 (m, 1H), 1.24-1.34 (m, 1H), 1.61-2.10 (m, 6 H), 2.30 (s, 3H), 2.75-2.90 (m, 1H), 3.15-3.22 (m, 1H), 3.41-3.62 (m, 3H), 3.96-4.10 (m, 2H), 4.14 (s, 3H), 4.75-4.95 (m, 2H), 5.37-5.50 (m, 1H), 6.96 (s, 1H), 7.20 (s, 1H), 7.30 (s, 1H), 7.65 (s, 1H), 7.72 (s, 1H); ESI MS m/z 637 [C28H29F9N6O+H]+.