Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:16][CH2:15][N:14]([C:17]([C:19]4[S:27][C:26]5[CH2:25][CH2:24][NH:23][CH2:22][C:21]=5[CH:20]=4)=[O:18])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42]([S:46](Cl)(=[O:48])=[O:47])=[C:41]([CH3:50])[CH:40]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH3:50])[C:42]([S:46]([N:23]2[CH2:24][CH2:25][C:26]3[S:27][C:19]([C:17]([N:14]4[CH2:15][CH2:16][C:11]5([CH2:28][CH2:29][N:8]([C:5]6[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=6)[CH2:9][CH2:10]5)[CH2:12][CH2:13]4)=[O:18])=[CH:20][C:21]=3[CH2:22]2)(=[O:47])=[O:48])=[C:43]([CH3:45])[CH:44]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: O=C(c1cc2c(s1)CCNC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCc3sc(C(=O)N4CCC5(CC4)CCN(c4ccncc4)CC5)cc3C2)c(C)c1
Reaction time: 15 h

Procedure:
(9-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)(4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-2-yl)methanone hydrochloride (89 mg, 0.208 mmol) was dissolved in dichloromethane (5 ml) and cooled, and triethylamine (0.07 ml, 0.52 mmol) was added thereto. At 0° C., a solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (50 mg, 0.208 mmol) in dichloromethane (5 ml) was added dropwise, and then stirring was carried out for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (10 ml) was added, the mixture was stirred for 15 min. and the phases were separated. The aqueous phase was extracted with dichloromethane (30 ml), and then the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol/-ammonia (25% aq.), 400:20:1). Yield: 70 mg (56%). MS, R=3.4 min; m/z=595.3 [MH]+
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].Br[CH2:31][C:32]([C:34]1[CH:38]=[CH:37][S:36][CH:35]=1)=[O:33]>O1CCCC1>[S:36]1[CH:37]=[CH:38][C:34]([C:32]([CH2:31][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:4][CH:3]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]2=[O:1])=[O:33])=[CH:35]1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Reactant: O=C(CBr)c1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccsc1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.0 g) obtained from Step 1 of Example 89 was dissolved in tetrahydrofuran (10 ml), 60% sodium hydride (0.16 g) was added under argon atmosphere, the mixture was stirred for 30 minutes at room temperature. A solution of 3-bromoacetylthiophene (0.90 g) in tetrahydrofuran (5 ml) was added,stirred for one hour. The reaction mixture was poured into ice-water, extracted with ethyl acetate, the organic layer was successively washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 0.94 g of the titled compound (Yield: 71%).
Reaction SMILES: O.[OH:2][CH2:3][C:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12]O)[OH:11])O)O)=O.[ClH:14]>C1(C)C=CC=CC=1>[Cl:14][CH2:12][C:10]1[O:11][C:4]([CH:3]=[O:2])=[CH:6][CH:8]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)o1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
150 Ml of toluene was introduced to the same flask as used in Example 1, and while introducing a nitrogen gas with slow stirring of toluene, the temperature of the water bath was set at 75° C. Thereafter, a paste-like liquid prepared by well-mixing 18.0 g of crystalline fructose with 2.2 g of water, and then 20.4 g (one equivalent based on the fed fructose) of MgCl2.6H2O were successively added to the stirred toluene layer. After completion of the addition, stirring was carried out at 400 r.p.m. for about 30 minutes. Thereafter, 31.4 g of 35% hydrochloric acid was added dropwise in 5 minutes from the dropping funnel to the stirred solution. After completion of the dropwise addition, stirring was continued at 400 r.p.m. at 75° C. for 1 hour, at which point heating was stopped and the reaction system was immediately lowered to room temperature (about 25° C.). During that period, stirring was still continued. After standing at room temperature, the post treatment of the solution was carried out in the same manner as in Example 1 and was obtained 12.5 g (yield 86.6%) of 5-chloromethylfurfural as product.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:26][CH:25]([CH2:27][OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:26][CH:25]([CH2:27][OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OCC1CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 128.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and azetidin-3-yl-methanol. HPLC (Condition 4) tR=5.33 min, UPLC-MS (Condition 3) tR=1.06 min, m/z=446.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[C:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)(=[O:11])[CH3:10].C([Li])CCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)([OH:11])[CH3:10])=[N:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Reactant: Clc1cnc(I)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(Cl)cn2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-2-iodopyrimidine (0.2 g, 0.83 mmol) and methyl trans-4-acetylcyclohexanecarboxylate (0.15 g, 0.83 mmol) in THF (4 mL) was added n-butyllithium (2.5 M in hexanes, 0.33 mL, 0.83 mmol) dropwise under a nitrogen atmosphere at −78° C. The mixture was stirred at −78° C. for 2 hours, and then quenched with saturate aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to afford methyl trans-4-[1-(5-chloropyrimidin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate. MS ESI calc'd for C14H20ClN2O3 [M+H]+ 299. found 299. 1H NMR: (400 MHz, CDCl3) δ 8.67 (s, 2H), 3.63 (s, 3H), 2.22-2.16 (m, 1H), 2.07-1.97 (m, 2H), 1.86-1.83 (m, 2H), 1.52 (s, 3H), 1.46-1.19 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH:3]([NH:6][C:7]1[C:12]([C:13](=O)[CH3:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1)([CH3:5])[CH3:4].[Cl-].[Na+].[O:20]1[CH2:25][CH2:24]OCC1>>[CH:3]([N:6]1[C:7]2[N:8]=[C:9]([S:16][CH3:17])[N:10]=[CH:11][C:12]=2[C:13]([CH3:14])=[CH:24][C:25]1=[O:20])([CH3:4])[CH3:5]
Reactant: CSc1ncc(C(C)=O)c(NC(C)C)n1
Reactant: C1COCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: CSc1ncc2c(C)cc(=O)n(C(C)C)c2n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Sodium hydride (16.75 g, 0.042 mol) is placed in 200 mL dioxane and combined with triethylphosphonoacetate (83.8 mL, 0.419 mmol), so that the temperature does not exceed 5° C. After the addition is complete, the mixture is heated to 20° C. and 1-(4-isopropylamino-2-methylsulphanyl-pyrimidin-5-yl)-ethanone (11.1 g, 0.049 mol) dissolved in 100 mL dioxane is added thereto. The mixture is stirred for 16 h at 90° C., then combined with 10% sodium chloride solution and extracted with ethyl acetate. The organic phase is dried, the solvent is eliminated in vacuo and the crude product is purified by normal phase chromatography (cyclohexane/ethyl acetate 90:10→50:50 in 45 min; flow 200 mL/min) and 8-isopropyl-5-methyl-2-methylsulphanyl-8H-pyrido[2,3-d]pyrimidin-7-one (HPLC-MS: tRet.=1.74 min; MS(M+H)+=250; method FECS1) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[C:20](=O)[CH2:19]1)=[O:17].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.[BH3-]C#N.[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:19]1)=[O:17]
Reactant: C1CCNC1
Reactant: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1N1CCCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-chloro-thiophene-2-carboxylic acid {(1S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentyl}-amide (75 mg) in THF (3 ml) were added pyrrolidine (0.03 ml) and acetic acid (0.02 ml). After stirring for 1 hr at r.t., NaBH3CN (11 mg) was added and stirring of the yellow reaction mixture was continued over night, then concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2MeOH 85:15) to give 5-chloro-thiophene-2-carboxylic acid {(1S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-pyrrolidin-1-yl-cyclopentyl}-amide (40 mg) as crystalline solid. MS 529.3 ([M+H]+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[F:11])=[O:5])C.[OH-].[Na+]>CO>[C:12]([C:9]1[C:10]([F:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:16])[N:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1c(F)c(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(C)(C)C)c(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-tert-Butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (61.4 mg, 0.269 mmol, prepared as described in the previous step) was dissolved in MeOH (1 mL) then 2 M NaOH (175 μL, 0.350 mmol) was added. The resulting mixture was stirred at room temperature for 18 h and the solvent was removed under reduced pressure. The resulting residue was dissolved in H2O (10 mL) and acidified to pH ˜2 using 3 M HCl. The aqueous layer was extracted with DCM (3×5 mL), the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 5-tert-Butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid. 1H-NMRH-NMR (400 MHz, CDCl3) δ: 9.89 (br. s., 1H), 4.06 (d, J=1.0 Hz, 3H), 1.36 (s, 9H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Cl[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[CH:29][CH:28]=2)[CH2:24][NH:25][CH3:26])=[CH:19][CH:18]=1>>[CH3:26][NH:25][CH2:24][CH:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)=[CH:29][CH:28]=1)[C:20]1[CH:19]=[CH:18][C:17]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: CNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Product: CNCC(c1ccc(-c2cccnc2)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 1 but substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and coupling to {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine*, the title compound was obtained. LC/MS: (PS-B3) Rt 2.42 [M+H]+ 355. 1H NMR (Me-d3-OD) δ 1.94 (AcOH, s), 2.72 (3H, s), 3.73 (2H, d), 4.46 (1H, t), 7.41 (2H, d), 7.51-7.56 (3H, m), 7.63 (2H, d), 7.70 (2H, d), 7.96 (2H, s), 8.10 (1H, dt), 8.53 (1H, dd), 8.80 (1H, d). *This starting material can be made by the method described in Example 21.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[N:17]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:27]([O:26][C:24]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=2)[CH2:19][CH2:18]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
N-(5-Fluoro-2-nitrophenyl)-N-methyhnethanesulfonamide (3.1 g, 12.5 mmol), tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) were heated together in DMSO (50 mL) at 80° C. overnight. The solution was allowed to cool and poured into 500 mL of water. The solid product was collected by filtration, washed with water and dried. Yield 4.6 g (86%); 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9 H), 2.0 (br s, 2 H), 3.01 (s, 3 H), 3.28 (s, 3 H), 3.3-3.8 (br, 8 H), 6.64 (d, J=8.1 Hz, 1 H), 6.74 (d, J=4.8 Hz, 1 H), 8.09 (d, J=8.1 Hz, 1 H); MS (ESI+) for C18H28N4O6S m/z 428.1709 (M+) (calc. 428.1730).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N:10]([O-])=O.[Na+]>O.CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[N:10][NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2nn[nH]c2c1
Yield: 137.7 %

Procedure:
The mixture of 4-bromobenzene-1,2-diamine (200 mg, 1.1 mmol) and NaNO2 (569 mg, 5.3 mmol) in H2O/AcOH (5 mL/50 mL) was reacted at 80° C. for 6 hours. The mixture was concentrated, the residue was dissolved in DCM and extracted with water, and the organic phase dried by Na2SO4 and concentrated to give 300 mg of crude product which was used without further purification. LCMS (m/z): 198.1/199.1 [M+H]+/[M+2H]+
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:8]2[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][N:29]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:17][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([C@@H:4]([NH:3][C:25]3[N:33]=[CH:32][N:31]=[C:30]4[C:26]=3[N:27]=[CH:28][NH:29]4)[CH3:5])[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:8]=2[C:14]=1[C:15]#[N:16]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C#N)c2n1-c1ccccn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 2-((S)-1-aminoethyl)-5-fluoro-3-pyridin-2-yl-3H-benzoimidazole-4-carbonitrile dihydrochloride (250 mg, 0.71 mmol) in IPA (7 mL) was added 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (220 mg, 0.92 mmol) and DIPEA (361 μL, 2.1 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc). LCMS (Method C): RT=2.86 min, [M+H]+=484. The product was dissolved HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue loaded onto an SCX 2 cartridge, washed with methanol then eluted with ammonia in methanol (2M). The eluent was concentrated in vacuo and the residue triturated with diethyl ether to give 290 as a white solid (174 mg, 51%) 1H NMR 400 MHz (DMSO-d6): δ 12.57 (1H, br s), 8.53-8.50 (1H, m), 8.04 (1H, dd, J=9.0, 4.72 Hz), 8.00 (1H, s), 7.96-7.88 (1H, m), 7.74 (1H, d, J=8.0 Hz), 7.47 (1H, dd, J=7.2, 4.9 Hz), 7.43-7.34 (1H, m), 7.30 (1H, dd, J=10.3, 9.2 Hz), 5.71 (1H, br s), 1.62 (3H, d, J=7.0 Hz). LCMS (Method K): RT=2.88 min, [M+H]+=400
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH2:27])[C:5]2=3)[CH:14]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[C:5]2=3)[CH:14]=1
Reactant: Cc1cc2c3c(c1)c1c(OCCN)cccc1n3C(c1ccccc1)CO2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NCCOc1cccc2c1c1cc(C)cc3c1n2C(c1ccccc1)CO3
Temperature: 95 °C
Yield: 99.5 %

Procedure:
To a mixture of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine (0.0.442 g, 1.23 mmol) in DMF (10 mL) is added acetic anhydride (0.126 g, 1.23 mmol) and DMAP (0.08 g, 0.66 mmol). The mixture is heated at 95° C. for 1 h and then partitioned between water and ether after cooling. The organic layer is washed three times with water (60 mL), dried over magnesium sulfate and concentrated to give 0.49 g (99%) of N-{2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}acetamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11]
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 12.7 g of N-t-butoxycarbonyl-4-hydroxyproline methyl ester and 44.7 g of pyridinium chlorochromate in 150 ml of methylene chloride is stirred at room temperature for 30 hours, diluted with 200 ml of ether and filtered through Florisil washing with ether (500 ml). The solution is evaporated to dryness, the residue is purified by flash chromatography on silica gel using ethyl acetate/hexane (40:60) as eluent to give N-t-butoxycarbonyl-4-oxoproline methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=2)[N:9]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:8]1=[O:26].Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[NH2:19][CH2:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:8](=[O:26])[N:7]([CH2:6][C:5]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]2=[O:17]
Reactant: COc1ccc(Cn2c(=O)c3cc(C#N)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(CN)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
A mixture of 0.55 g of the compound obtained in Step 12.1, and 2.94 ml of a 2M borane/dimethyl sulfide complex in THF, in 15 ml of THF is irradiated in a microwave field for 1 minute at 100° C. The reaction medium is taken up in DCM. 50 ml of 1N HCl are added and the mixture is stirred for 2 hours at room temperature. The resulting mixture is neutralized with 2N sodium hydroxide solution. This resulting mixture is extracted with DCM, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on an RP18 column, eluting with a water/ACN mixture from (90/10, v/v) to (50/50, v/v) to give 0.23 g of the expected product.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[CH2:36]>C(O)(=O)C>[O:11]([C:10]1[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[S:1][CH2:36][CH2:35][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=Cc1ccncc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Oc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCCc2ccncc2)c1Oc1ccccc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 3-mercapto-4-phenoxy-5-sulfamylbenzoic acid (1.7 g), sodium hydrogen carbonate (1 g), sodium dithionite (1 g), 4-vinylpyridine (0.8 ml) and saturated aqueous sodium hydrogen carbonate (17 ml) is stirred at 70°C. for 4 hours. After cooling, pH of the mixture is adjusted to 4.5 by addition of acetic acid. The precipitated material is collected by filtration, washed with water, and recrystallized from aqueous ethanol to yield 4-phenoxy-3-(4-pyridylethylthio)-5-sulfamylbenzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:14]2([CH2:17][C:16](=[O:18])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]2([CH2:17][C:16]([OH:18])([CH3:21])[CH2:15]2)[CH2:19][CH2:20]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Yield: 55 %

Procedure:
To a stirred solution of 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (164 mg, 0.60 mmol) in dry THF (2 mL) was added dropwise a 1.4 M solution of methylmagnesium bromide in toluene/THF (0.56 mL, 0.78 mmol) under an atmosphere of nitrogen, at −78° C. After 1 h the solution was quenched with saturated NH4Cl(aq) and the resulting mixture partitioned between EtOAc and water. The organic layer was dried (Na2SO4) and evaporated to give a residue, which was purified by column chromatography (Si—PCC, 0-70% EtOAc in cyclohexane) to give 2-Hydroxy-2-methyl-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (96 mg, 55%) as a colourless oil. LCMS (Method H): RT 4.13 min, [M+H]+ 290.4
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][NH2:14]>>[NH:13]([C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: NN
Reactant: Cc1cc(Cl)nc2ccccc12
Product: Cc1cc(NN)nc2ccccc12

Procedure:
A solution of 2-chloro-4-methylquinoline (1.00 g, 5.63 mmol) in NH2NH2 was reacted as outlined in Scheme 1 above to give the title compound which was used in the next step without further purification.