Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][S:34][CH3:35])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:45]OS([O-])=O.[K+]>CN(C=O)C.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][S:34]([CH3:35])=[O:45])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CSCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CS(C)=O)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.7 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylthio)acetamide (Example 19) (20 mg, 0.03 mmol) in a mixture of DMF/H2O (1:1 v/v, 1.0 mL) was added Oxone (10 mg, 0.03 mmol) and the reaction was stirred at RT for 3 days. A second portion of Oxone® (10 mg, 0.03 mmol) was added, the mixture was stirred for a further 24 hr and was then partitioned between brine (20 mL) and DCM (20 mL). The organic extract was washed with brine (20 mL), dried (MgSO4) and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 4 g, 30-100% EtOAc in isohexane, gradient elution) and subjected to SCX capture and release to afford the title compound (Example 20) as a tan coloured solid (11 mg, 52%): m/z 625 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.69 (3H, s), 3.88 (2H, d), 4.04 (2H, d) 5.39 (2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.31 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.64 (3H, overlapping m), 7.93 (1H, m), 8.30-8.33 (2H, overlapping m), 8.37 (1H, d), 8.59 (1H, br s), 8.79 (1H, br s), 10.85 (1H, br s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH:21]C(=O)C4C=CC=CC=4)=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][CH:38]=1.N>C1COCC1.CO>[NH2:21][C:17]1[O:18][CH2:19][CH2:20][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([NH:41][C:39]([C:36]2[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][N:37]=2)=[O:40])=[CH:11][CH:10]=3)[N:16]=1
Reactant: COc1cnc(C(N)=O)cn1
Reactant: O=C(NC1=N[C@@]2(CCO1)c1cc(I)ccc1Oc1ncc(Br)cc12)c1ccccc1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(CCOC(N)=N2)c2cc(Br)cnc2O3)cn1
Reaction time: 5 h

Procedure:
The title compound was synthesized analogous to step 1 (Method D) described in example 34, but using (S)—N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-yl)benzamide (88 mg, 0.153 mmol, Intermediate 24B) and 5-methoxypyrazine-2-carboxamide (28.1 mg, 0.183 mmol). The residue from step 1 was dissolved in THF (1 mL) and treated with ammonia (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) at 50° C. After 12 hours another portion of ammonia, (2.0 M solution in methanol; 1.145 mL, 2.291 mmol) was added and the reaction mixture was allowed to stir for additional 5 hours The solvent was removed under reduced pressure and the residue was purified by preparative reversed-phase HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CNH2O, gradient 10% to 100% over 20 min. The combined fractions were concentrated. The residue was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column. The product was eluted with a 2M solution of NH3 in MeOH. 10 mg of (S)—N-(2′-amino-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-methoxypyrazine-2-10 carboxamide were obtained as an off-white solid. MS m/z=497.1 [M]+. Calculated for C21H17BrN6O4: 497.30. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82-1.92 (m, 1H) 1.94-2.04 (m, 1H) 4.08 (s, 3H) 4.11-4.18 (m, 1H) 4.20-4.30 (m, 1H) 7.31 (d, J=9.21 Hz, 1H) 7.69-7.77 (m, 2H) 7.94 (d, J=2.34 Hz, 1H) 8.18 (d, J=1.32 Hz, 1H) 8.32 (d, J=2.48 Hz, 1H) 9.04 (d, J=1.32 Hz, 1H) 9.55 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][N:5]([CH:7]([F:9])[F:8])[CH:6]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH:7]([F:9])[F:8])[N:4]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1nn(C(F)F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1nn(C(F)F)cc1Cl
Reaction time: 16 h
Yield: 90.1 %

Procedure:
A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid (150 mg, 0.76 mmole) in dichloromethane (5 ml) was subsequently treated at 22° C. with N,O-dimethylhydroxylamine hydrochloride (78 mg, 0.80 mmole), N-methylmorpholine (0.09 ml, 0.8 mmole) and EDCI.HCl (154 mg, 0.8 mmole) and stirring was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/AcOEt (2:1) to give the title compound (164 mg) as a colorless oil. MS: m/z=240.1 [M]+.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:56]1[C:60]2=[C:61]([C:65](O)=[O:66])[N:62]=[CH:63][CH:64]=[C:59]2[CH:58]=[CH:57]1>CN(C=O)C>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[CH:14]=2)[C:65]([C:61]2[N:62]=[CH:63][CH:64]=[C:59]3[CH:58]=[CH:57][NH:56][C:60]=23)=[O:66])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1nccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)F)c2)C(=O)c2nccc3cc[nH]c23)cc1
Yield: 83.8 %

Procedure:
(4-tert-Butyl-benzyl)-[2-(3-difluoromethoxy-phenyl)-ethyl]-amine (90 mg, 0.27 mmol), N-methylmorpholine (74 mg, 0.73 mmol), and HBTU (139 mg, 0.37 mmol) were added at RT to a solution of 1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid (66 mg) in DMF (3 mL), then after 64 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane-dichloromethane gradient) afforded the title compound (108 mg, 86% over 2 steps). Light yellow oil, MS (ISP) 478.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1.N1CCCCC1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1
Reactant: O=C1C=C(c2ccccc2O)CC1
Reactant: BrCC1CO1
Solvent: C1CCNCC1
Product: O=C1C=C(c2ccccc2OCC2CO2)CC1

Procedure:
2.0 g 3-(2-hydroxyphenyl)-2-cyclopenten-1-one are stirred with 30 ml epibromohydrin and catalytic amounts of piperidine for 1 hour at 100° C. After concentration, the mixture of epoxy- and bromohydrin is separated by high-pressure liquid chromatography. In this manner, 2 g 3-[2-(2,3-epoxypropoxy)phenyl]-2-cyclopenten-1-one are obtained as an oil which is then dissolved in 20 ml t-butanol. 2 ml of t-butylamine were added and the mixture is stirred at room temperature for 48 hours.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][CH3:36])[CH3:26]>>[CH2:35]([O:34][C:33]1[CH:32]=[C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:30]=[CH:29][C:28]=1[O:27][CH2:25][CH3:26])[CH3:36]
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OCC
Product: CCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC)nc2C)c(=O)n4C)cc1OCC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 49 mg, 0.126 mmol) and 2-(3,4-diethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (stage 27.1.1, 47 mg, 0.161 mmol) to give the title compound as an off-white solid. (HPLC: tR 3.02 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.18 (s, 1H), 8.08-8.02 (m, 1H), 7.95-7.84 (m, 1H), 7.52-7.48 (m, 1H), 7.06-6.97 (m, 3H), 4.22-3.98 (m, 6H), 3.58 (s, 3H), 1.97 (s, 3H) 1.45-1.25 (m, 9H))
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][S:8]2(=[O:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>O1CCCC1>[O:17]=[S:8]1(=[O:16])[N:9]([CH2:19][CH:20]2[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:21]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CN2c3ccccc3N(c3ccccc3)S2(=O)=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared analogously as in general procedure I, 246 mg, 1.00 mmol), tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (228 mg, 1.05 mmol, 1.05 equiv.) and triphenylphosphine (289 mg, 1.10 mmol, 1.1 equiv.) in tetrahydrofuran (5 mL) was cooled to 0° C. in an ice bath. Diispropyl azodicarboxylate (0.22 mL, 1.1 mmol, 1.1 equiv.) was added dropwise via a syringe. The reaction mixture was stirred overnight while warming to room temperature. Solvent was removed under reduced pressure and the residue was purified by Isco flash column chromatography (silica gel, 3-30% ethyl acetate/hexane) to give 398 mg (89%) of tert-butyl 2-[(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)methyl]morpholine-4-carboxylate as a white foam. MS (ESI) m/z 445.9 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([O:13][CH3:14])[C:6]=1[F:15])[CH3:2].[C:17]([O:21][C:22](=[O:29])[NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:26]2[CH2:27][CH2:28][CH:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:29])[CH2:25]2)=[C:7]([O:13][CH3:14])[C:6]=1[F:15])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cc(F)c(F)c(OC)c1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(OC)c1F
Yield: 77.6 %

Procedure:
A solution of 2,4,5-trifluoro-3-methoxybenzoic acid ethyl ester (Example 1f, 2.821 g, 12.05 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (3.310 g, 17.77 mmol), and triethylamine (9.13 g, 12.6 mL, 90.23 mmol) in acetonitrile (50 mL) is heated at 40° C. under nitrogen for 2 days. The yellow solution is concentrated to near dryness and poured into saturated NaHCO3 solution and extracted with dichloromethane. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue is purified by flash column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound as a yellow solid (3.743 g). MS EI: m/z 401 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[O:14][CH3:15].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>S(Cl)(Cl)=O.C(OCC)(=O)C>[CH2:16]([N:18]([CH2:19][CH3:20])[C:9](=[O:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([O:14][CH3:15])[CH:4]=1)([CH3:13])[CH3:12])[CH3:17]
Reactant: COc1cc(C(C)(C)C(=O)O)ccc1I
Reactant: CCNCC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C(C)(C)c1ccc(I)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of 2-(4-iodo-3-methoxy-phenyl)-2-methyl-propionic acid (326 mg, 0.976 mmol, prepared by saponification of ethyl dimethyl-(3-ethoxy-4-iodophenyl)acetate, example 4) in thionyl chloride (5 mL) was heated at reflux for 1 h. It was concentrated to dryness then taken in 5 mL of tetrahydrofuran. Diethylamine (1 mL, 2 mmol, 2M solution in tetrahydrofuran) was added. The reaction mixture was stirred at room temperature overnight. It was diluted with ethyl acetate, washed with brine (1×), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, IntelliFlash 280, eluting with a gradient of 5-95% ethyl acetate in hexanes) gave N,N-diethyl-2-(4-iodo-3-methoxy-phenyl)-isobutyramide (361.4 mg, 95%) as clear oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@:10]([CH3:17])([CH:12]([O:15][CH3:16])[O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH2:19])[C:7]=2[CH:20]=1)#[N:2].[Na].[C:22]([NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=S)#[N:23].Cl.CN(C)CCCCCN=C=N.C(OCC)(=O)C>CN(C=O)C>[C:22]([N:24]=[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[NH:19][C@@H:8]1[C:7]2[CH:20]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C@:10]([CH3:17])([CH:12]([O:15][CH3:16])[O:13][CH3:14])[C@H:9]1[OH:18])#[N:23]
Reactant: N#CNC(=S)Nc1ccc(Cl)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Agent: CN(C)CCCCCN=C=N
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(OC)[C@@]1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Nc2ccc(Cl)cc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.7 %

Procedure:
To a solution of 100 mg of (2S,3S,4R)-6-cyano-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-benzopyran prepared in the preparation example 6 is dissolved in 3 ml of DMF, were added 92 mg of N-cyano-N′-(4-chlorophenyl)thiourea sodium salt and 89 mg of 1-[3-(dimethylamino)propyl]-2-ethylcarbodiimide hydrochloride. The reaction mixture was stirred for 6 hours at room temperature, and extracted with 30 ml of ethyl acetate after acidifying the mixture by adding 5 ml of 1N HCl. The organic Layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by siLica gel chromatography (n-hexane:ethyl acetate=1:1 to afford 70 mg (yield: 43%) of the desired compound Of (2S,3R,4S) stereochemistry.
Reaction SMILES: [NH:1]1C=CN=C1.[C:6]1([CH2:12][C:13](O)=[S:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[C:6]1([CH2:12][C:13]([NH2:1])=[S:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: OC(=S)Cc1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: NC(=S)Cc1ccccc1
Reaction time: 12 h

Procedure:
To a solution of amino acid methyl ester VI and imidazole in DMF, is added phenylthioacetic acid followed by diisopropylcarbodiimide at room temperature. The reaction mixture is stirred for 12 hours. After filtration on silica gel pad, the filtrate is poured into water and EtOAc. The organic layer is washed twice with water, dried over Na2SO4, and concentrated to afford α-phenylthioacetamide VII.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH3:10].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([OH:9])[C:3]=1[CH3:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(O)cc(O)nc1Cl
Solvent: CC(=O)O
Product: Cc1c(Cl)nc(O)c([N+](=O)[O-])c1O
Temperature: 0 °C
Yield: 28 %

Procedure:
6-Chloro-2,4-dihydroxy-5-methyl-pyridine (500 mg, 3.1 mmol) was taken up in acetic acid (1 mL), cooled to 0° C. and nitric acid added (4 mL) dropwise with stirring. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to warm to room temperature over 16 h. Ice was added to the mixture to provide a precipitate, which was collected by filtration and dried in vacuo to give the title compound as a yellow solid (180 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1.ClCC(Cl)=O>[O:19]=[C:13]1[CH:12]([N:5]2[CH2:4][C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:23])[CH2:21][Cl:20])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(NC(=O)CCl)cccc3C2=O)C(=O)N1
Yield: 92.1 %

Procedure:
To a stirred suspension of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.89 g, 15.0 mmol) in THF (50 ml) was added chloroacetyl chloride (1.86 g, 16.5 mmol). The mixture was heated to reflux for 45 minutes. To the reaction mixture was added additional chloroacetyl chloride (0.15 g, 0.13 mmol). The reaction mixture was heated at reflux for an additional 30 minutes. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 4.64 g (92%) of product as an off-white solid: 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.22 (s, 1H), 7.82 (dd, J=1.6 and 7.2 Hz, 1H), 7.59-7.50 (m, 2H), 5.16 (dd, J=5.1 and 13.2 Hz, 1H), 4.46-4.30 (m, 4H), 3.00-2.85 (m, 1H), 2.65-2.58 (m, 1H), 2.44-2.28 (m, 1H), 2.06-2.01 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[O:30]1[C:34]2([CH2:38][CH2:37][CH:36]([CH2:39][CH:40]=[O:41])[CH2:35]2)[O:33][CH2:32][CH2:31]1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:40]([OH:41])[CH2:39][CH:36]2[CH2:37][CH2:38][C:34]3([O:30][CH2:31][CH2:32][O:33]3)[CH2:35]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCC1CCC2(C1)OCCO2
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCC3(C2)OCCO3)cc2cccnc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (4.2 g, 16 mmol) in dry tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (1.6 M, 15 mL, 24 mmol) dropwise. The mixture was stirred at −78° C. for 15 min and then treated with (1,4-dioxa-spiro[4.4]non-7-yl)-acetaldehyde (5 g, 29 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 30% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(1,4-dioxa-spiro[4.4]non-7-yl)-ethanol as a colorless oil (5.5 g, 74%): LC/MS m/e calcd for C22H24N2O5S [M+H]+ 429.51, observed 429.3.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[CH2:13]([N:20]1[C:28]2[C:27](Cl)=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1.O>[CH2:13]([N:20]1[C:28]2[C:27]([O:12][C:5]3[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=3[CH3:3])=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(Oc2nc(N)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a stirred suspension of NaH (56 mg, 2.33 mmol) in dry NMP (2 mL) was added 2,4,6-trimethyl phenol (317 mg, 2.33 mmol). The mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (200 mg, 0.78 mmol) in dry NMP (1.5 mL) and the resulting solution was heated at 90° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, and brine and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (3:1) to give the product as a white solid (140 mg, 50%).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[N:18]([CH:19]=2)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)=[CH:8][CH:7]=1.[N:24]([O-])=[O:25].[Na+]>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[N:24]=[O:25])[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: Clc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To 700 ml of acetic acid was added 14 g of 2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole and after adding thereto 5 g of sodium nitrite with stirring at room temperature, the mixture was stirred for 3 hours. Thereafter, 500 ml of water was added to the mixture and the crystals thus formed were recovered by filtration and washed with water, then n-hexane, and further with 400 ml of chloroform to provide 10 g of 2-(p-chlorophenyl)-3-nitrosoimidazo[2,1-b]benzothiazole. The product was recrystallized from chloroform to provide crystals having a melting point of 203°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: Nc1ccc(Cl)cc1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-chloro-N2-phenylbenzene-1,2-diamine (975 mg, 4.46 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (928 mg, 4.90 mmol), HOAt (668 mg, 4.90 mmol), 4-methylmorpholine (1.08 mL, 9.81 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (940 mg, 4.90 mmol) in DCM (30 mL) was stirred at RT for 19 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried and concentrated in vacuo to afford [(S)-1-(4-chloro-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tert-butyl ester as a purple solid (quantitative). A solution of the compound thus obtained (4.46 mmol) in AcOH (30 mL) was heated at 70° C. for 22 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic layer was washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) to afford the title compound as a yellow solid (1.20 g, 72% over two steps). LCMS (Method C): RT 3.82 min [M+H]+ 372.3