Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][CH:56]([S:58](Cl)(=[O:60])=[O:59])[CH3:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:58]([CH:56]([CH3:57])[CH3:55])(=[O:60])=[O:59])[CH2:49][CH2:48]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 25 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and propane-2-sulfonyl chloride as starting materials in 25% yield. LCMS for C27H33ClN7O3S (M+H)+: m/z=570.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][Br:23])[N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(Oc3ccnc(C)n3)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc2cc(Oc3ccnc(CBr)n3)ccc12

Procedure:
A solution of 8.55 g (29.05 mMol) 6-(2-methyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid methyl ester, 13.5 g N-bromo-succinimide (95%; 72.6 mMol) and 3.31 g (20 mMol) α,α-azoisobytyronitrile in 1.85 l CCl4 is heated to 80° C. and irradiated (125 W lamp) for 2 days. Then 5.44 g N-bromo-succinimide and 1.66 g α,α-azoisobytyronitrile are added and irradiation at 80° C. is continued for another day. The reaction mixture is concentrated, the residue re-dissolved in EtOAc and water, the aq. layer separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/EtOAc 1:1) gives the title compound: MS: [M+1]+=373/375; TLC(hexane/EtOAc 1:1): Rf=0.35.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][NH2:29])=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[N:7]([C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][NH:29][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A solution of {(S)-1-[(S)-1-((S)-2-aminomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (intermediate 3) (100 mg 0.23 mmol) in DCM (4 mL) was cooled to 0-5° C. and triethylamine (0.08 mL 0.57 mmol) followed by benzoyl chloride (0.027 mL, 0.23 mmol) were added. The reaction was stirred at rt for 4 h. The reaction mixture was partitioned between water and DCM and the organic layer was then washed with water (30 mL×2) and brine (30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by preparative-HPLC (acetonitrile and NH4OAc] to give ((S)-1-{(S)-1-[(S)-2-(benzoylamino-methyl)-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl]-2-methyl-propylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester as a white solid (35 mg), m/z=538 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:28]=1)[CH2:3][N:4]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])CC1C=CC=CC=1.C(O)C>CO.[H][H].[Pd]>[OH:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:28]=1)[CH2:3][NH:4][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)c1ccc(C)c(S(N)(=O)=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: COc1ccccc1OCCNCC(O)c1ccc(C)c(S(N)(=O)=O)c1
Reaction time: 8 h

Procedure:
In 200 ml of methanol was dissolved 20 g of 5-{1-hydroxy-2-[N-benzyl-2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide. After adding thereto 20 ml of ethanol containing about 10% hydrogen chloride and 1 g of 10% palladium charcoal, the mixture was shaked in hydrogen gas stream. When the absorption of hydrogen stopped, the catalyst was filtered away and the filtrate was distilled off under reduced pressure. The residue was dissolved in 100 ml of ethanol while it was hot and the solution was allowed to stand overnight in ice chamber, whereby 12.8 g of the α-type crystals of 5-{1-hydroxy-2-[2-(2-methoxyphenoxy)ethylamino]-ethyl}-2-methylbenzenesulfonamide were obtained as the colorless crystals. The physical and chemical properties of the product were as follows:
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:22])[CH2:17][CH2:18][C@H:19]([OH:21])[CH2:20][C@@H:15]4[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1.C(OCC)C>[C:24]([O:21][C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C@@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:11]2[CH2:10][CH2:9][C@@:8]2([CH3:23])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:2](=[O:3])[CH3:1])[CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a stirred suspension of 5α-pregnan-3β-ol-20-one (110) (200 g; 0.628 mol) in pyridine (1750 mL) was added acetic anhydride (593 mL; 6.28 mol). Solid was dissolved after 2 hours and the reaction was left for overnight at room temperature. The reaction mixture was diluted with diethyl ether (5 L) and transferred into a 12 L separatory funnel. The mixture was stirred, while 10% HCl (150 mL) was added by careful monitoring of temperature (maximum temp 35° C.) by an ice bath. The organic layer was washed with ice cold 10% HCl (8×500 mL), with saturated NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The pale yellow solid was dried at 40° C. overnight to give the 3-acetylated compound 111 (223 g; 99%). 1H NMR (300 MHz, CDCl3) δ: 0.58(s, 3H), 0.81(s, 3H), 2.01(s, 3H), 2.10(s, 3H), 2.51(t, 1H, J=9 Hz), 4.67(sept, 1H, J=5 Hz).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(=O)([O-])[O-:11].[K+].[K+].OO.O>CS(C)=O.CC(C)=O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:9])=[O:11])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cnc(Br)cn1
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cnc(Br)cn1
Temperature: 65 °C
Yield: 27.5 %

Procedure:
A suspension of 5-bromo-pyrazine-2-carbonitrile (1.84 g, 10.0 mmol) and potassium carbonate (1.38 g, 10.0 mmol) in DMSO/acetone (16 mL, 1:3) was treated with H2O2 (2.42 mL, 25.0 mmol) at 65° C. over 15 min. The reaction was kept stirring at 65° C. 1 h. Water (2 mL) was added at 40° C. and the suspension was cooled to 0° C. The precipitate was filtered to give the title compound as a yellow solid (556 mg). 1H NMR (300 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.94 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N+:14]([O-])=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc2ccccc2cc1CCCCOCc1ccccc1
Product: Clc1nc(CCCCOCc2ccccc2)cc2ccccc12

Procedure:
3-(4-Benzyloxybutyl)isoquinoline-2-oxide (2.0 g) and phosphorous oxychloride (5 ml) were reacted at 110° C. for 2 hr. The reaction solution was evaporated, to the resulting residue were added ethyl acetate and aqueous solution of saturated sodium bicarbonate, and the resulting organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate followed by evaporating the solvent. The resulting 1-chloro-3-(4-benzyloxybutyl)isoquinoline obtained as a yellow oil was reacted with N-ethylpiperazine (5 ml) and potassium carbonate (0.5 g) at 120° C. for 5 hr. The reaction solution was then cooled and then partitioned by adding ethyl acetate and water thereto. The resulting organic layer was washe with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system) to give 1.32 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2.[OH-].[Na+]>CO.O>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3CO)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3CO)nc2c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of (R)-methyl 3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (120 mg, 0.33 mmol, 1.00 equiv) and sodium hydroxide (66 mg, 1.65 mmol, 4.99 equiv) in methanol/H2O (20/5 mL). The reaction was stirred for 5 h at 70° C. and concentrated to dryness. The residue was dissolved in 20 mL H2O and washed with 10 mL EtOAc. The pH of the aqueous layer was adjusted to 7 with 1N HCl and extracted with DCM/MeOH (10/1, 20 mL×5). The organic layers were combined and dried over Na2SO4 and concentrated to dryness. This resulted in 80 mg (66%) of (R)-3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: COCC[O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[C:34](=[O:35])[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26]5)[C:20]=4[CH3:36])=[CH:17][N:16]=[C:15]([C:37]([NH2:39])=[O:38])[C:11]=3[NH:12]2)=[CH:8][CH:7]=1.[I-].[I-].[I-].[Al+3]>C(#N)C>[OH:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[C:34](=[O:35])[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26]5)[C:20]=4[CH3:36])=[CH:17][N:16]=[C:15]([C:37]([NH2:39])=[O:38])[C:11]=3[NH:12]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Agent: [Al+3]
Agent: [I-]
Solvent: CC#N
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Yield: 19.3 %

Procedure:
A mixture of 7-(2-methoxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (70 mg, 0.135 mmol) and aluminum triiodide (137 mg, 0.337 mmol) in acetonitrile (6 mL) was heated at reflux for 4 hr. Upon cooling to room temperature, the reaction was quenched with ice water (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined extract was with brine (25 mL) and dried over anhydrous MgSO4. After the solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (12.9 mg, 0.026 mmol, 19.54% yield) as a yellow solid. LCMS (M+H)+=462.23. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.56 (s, 1H), 9.84 (s, 1H), 8.16 (s, 1H), 7.19 (s, 1H), 7.16 (d, J=8.6 Hz, 1H), 1.81 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([CH:10]=[CH:11][C:12]([CH3:16])([OH:15])[CH:13]=[CH2:14])=[C:3]1[CH3:17].C(N(CC)CC)C.[CH3:25][Si:26]([CH3:29])([CH3:28])Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.CCCCCC>[CH3:25][Si:26]([CH3:29])([CH3:28])[O:15][C:12]([CH3:16])([CH:13]=[CH2:14])[CH:11]=[CH:10][C:4]1[C:5]([CH3:8])([CH3:9])[CH2:6][CH:7]=[C:2]([O:1][Si:26]([CH3:29])([CH3:28])[CH3:25])[C:3]=1[CH3:17]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(C)(O)C=CC1=C(C)C(=O)CCC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(C)(C=CC1=C(C)C(O[Si](C)(C)C)=CCC1(C)C)O[Si](C)(C)C
Temperature: 120 °C

Procedure:
A solution of 23.1 g of 96.5% 1-(3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-1,4-pentadien-3-ol in 85 ml of dimethylformamide in a four-necked flask equipped with a stirrer and reflux condenser was treated with 80 ml of triethylamine and 73 ml of trimethylchlorosilane. The mixture was heated to reflux (heating bath temperature 120° C.) for 2 hours while stirring and under a light argon stream. The mixture was subsequently cooled to about 0° C. with an ice-bath and treated while stirring with 400 ml of hexane and 200 ml of semi-saturated sodium hydrogen carbonate solution. The phases were separated and the aqueous phase was extracted with 200 ml of hexane. The combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over sodium sulphate and concentrated at 40° C. in a rotary evaporator. Distillation of the resulting brown oil (39.5 g) at 102°-107° C./0.1 Torr gave 35.0 g of trimethyl[[1-methyl-3-[2,6,6-trimethyl-3-(trimethylsiloxy)-1,3-cyclohexadien-1-yl]-1-vinylallyl]oxy]silane as a pale yellowish oil; purity about 77%.
Reaction SMILES: C([O:4][C@@H:5]([CH3:51])[C:6]([N:8]([CH2:34][C@H:35]1[C@@H:39]([F:40])[CH2:38][N:37](C(OCC2C=CC=CC=2)=O)[CH2:36]1)[C@@H:9]([C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[C:16]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[N:15]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CO.[Pd]>[CH2:19]([N:18]1[C:14]([C@H:9]([N:8]([CH2:34][C@H:35]2[C@@H:39]([F:40])[CH2:38][NH:37][CH2:36]2)[C:6](=[O:7])[C@@H:5]([OH:4])[CH3:51])[C:10]([CH3:13])([CH3:11])[CH3:12])=[N:15][C:16]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])=[N:17]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](O)C(=O)N(C[C@@H]1CNC[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((S)-2-acetoxy-N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)propanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (1.78 g, 2.53 mmol) in degassed EtOAc (25 mL, 0.1 M solution) was added Pd/C (178 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for overnight. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude amine (LC/MS (uplc): MH+ 572.4, 1.11 min). Then, the crude product was dissolved in MeOH (168 mL, 0.015 M solution) followed by addition of anhydrous potassium carbonate (3.5 g, 25 mmol). The reaction was then stirred for 15 min at room temperature. After white precipitate was removed by filtration, the organic filtrate was concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (S)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide was obtained in 65.5% yield (876 mg, over 3 steps) as a free amine 1H NMR (CD3Cl, 400 MHz): 7.82 (1H, m), 7.52 (2H, m), 7.34-7.25 (3H, m), 7.16 (1H, m), 7.07 (1H, m), 6.09 (1H, s), 5.44 (2H, s), 4.61 (2H, m), 4.39 (1H, m), 3.78 (1H, m), 3.60 (1H, m), 2.92 (1H, m), 2.56 (1H, m), 2.16 (2H, m), 1.44 (3H, m), 1.22 (1H, m), 0.99 (9H, s), 0.42 (1H, m). LC/MS (uplc): MH+ 530.3, 1.05 min.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2nc(NCC3CCCCC3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2nc(NCC3CCCCC3)sc2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
To the solution of N-(cyclohexylmethyl)-6-methoxybenzo[d]thiazol-2-amine (1.40 g, 5.05 mmol) in 12 ml of DCM was added 1 M boron tribromide in DCM (10.6 ml, 10.6 mmol) slowly over about 3 minutes at 0° C. The reaction solution was stirred at 0° C. for 20 min and then at RT. for 2 hr. The reaction mixture was concentrated to a solid. To the residual solids add 200 ml of ethyl acetate and 50 ml of water and stir at RT. for 10 minutes. With stirring, carefully add excess solid NaHCO3 until basic. Stir at RT. about 1 hour to dissolve the solids. Remove the aqueous layer and extract with 100 ml of ethyl acetate. Combine organic layers and wash with 1×30 ml water, 1×25 ml saturated NaCl solution and dry with sodium sulfate. This mixture was filter through a silica gel plug (1.25 in.×3 in.) and flushed with ethyl acetate. The filtrate was concentrated under reduced pressure to give 2-(cyclohexylmethylamino)benzo[d]thiazol-6-ol as solid (1.32 grams). ES/MS m/z 263.1 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[OH:18][C@:19]1([C:47]([F:50])([F:49])[F:48])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=O)=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1.[CH3:51][C:52]1[C:57]([NH2:58])=[CH:56][CH:55]=[CH:54][N:53]=1>C1COCC1>[OH:18][C@:19]1([C:47]([F:49])([F:48])[F:50])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([NH:58][C:57]3[C:52]([CH3:51])=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:42])=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1
Reactant: Cc1ncccc1N
Reactant: COC(=O)c1ccc([C@H]2CC[C@@](O)(C(F)(F)F)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)Nc2cccnc2C)ccc1[C@H]1CC[C@@](O)(C(F)(F)F)Cc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
1 M lithium bis(trimethylsilyl)amide in toluene (0.13 mL, 0.13 mmol) was added dropwise to a solution of rac-methyl 4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.018 g, 0.04 mmol) and 2-methylpyridin-3-amine (6.4 mg, 0.06 mmol, Appollo) in THF (1 mL) at 0° C. The mixture was allowed to warm to rt. After about 2 h, the mixture was cooled to about 0° C. 2-Methylpyridin-3-amine (4.2 mg, 0.04 mmol) and 1 M lithium bis(trimethylsilyl)amide in toluene (0.04 mL, 0.04 mmol) were added then the mixture was allowed to warm to rt. After about 5 h a saturated aqueous NH4 Cl solution (20 mL) was added and then mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 2-6% MeOH/DCM) to give rac-4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.001 g, 5%): LC-MS (Table 1, Method g) Rt=1.94 min, m/z 536 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 9.81 (s, 1H), 8.37-8.34 (m, 1H), 8.31-8.27 (m, 1H), 7.79-7.75 (m, 1H), 7.71-7.62 (m, 3H), 7.56-7.51 (m, 1H), 7.26-7.22 (m, 1H), 7.13-7.08 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.32 (s, 1H), 5.28-5.21 (m, 1H), 3.86 (s, 3H), 3.36-3.32 (m, 2H), 2.65 (s, 3H), 2.39 (s, 3H), 2.22-2.12 (m, 1H), 2.00-1.90 (m, 1H), 1.88-1.76 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H](NC(=O)C(C)(C)C)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, trimethylacetylchloride and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white foam after removal of the solvent: m.p. 85°-94° C.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([NH:2][OH:1])=[O:5])=[N:21][CH:22]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccc(F)cc2)cn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1ccc(-c2ccc(F)cc2)cn1)NO
Reaction time: 72 h
Yield: 70 %

Procedure:
HONH2 (50% aqueous, 0.5 mL) was added to II (2.5 mg, 0.006 mmol) in DMF (0.2 mL) and MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:6) to furnish III as a colourless oil (1.63 mg, 70%).