Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:15])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)C(C)C)c(Cl)c1Cl
Temperature: 5 °C

Procedure:
A stirred mixture of 2,3-dichloroanisole (I) (100 g., 0.565 mole) and isobutyryl chloride (II) (66 g., 0.62 mole) in methylene chloride (400 ml.) is cooled to 5°C. and treated with aluminum chloride (83 g., 0.62 mole) during a 1 hour period. The reaction mixture is allowed to warm to 25°C. and after 24 hours is poured into ice water (400 ml.) and hydrochloric acid (30 ml.). The organic phase is washed with 5% sodium hydroxide, water, dried over magnesium sulfate and distilled at reduced pressure affording 68 g. of 2',3'-dichloro-4'-methoxyisobutyrophenone (III) which distills at 120°-130°C./0.5 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: O=C(Cl)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 99.9 %

Procedure:
To a 250 ml round bottom flask fitted with a magnetic stirrer was added 4-bromophenylacetic acid (100.0 g; 0.465 mol) and 100 ml of thionyl chloride (163.1 g; 1.37 mol). The resulting slurry was stirred at room temperature for 22.5 hrs. The excess thionyl chloride was evaporated under vacuum to afford 108.5 g of the subtitle compound as a brown liquid.
Reaction SMILES: O[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:5]1(=[O:6])[C:4]2[C:3](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:2][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: O=C(NCCCCSc1ccncc1)c1ccccc1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CCCCSc1ccncc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 1.58 g (5.0 mmol) of 4-[4-(2-hydroxymethylbenzoyl)aminobutylthio]pyridine and 2.09 ml (15.0 mmol) of triethylamine in 50 ml of methylene chloride, 0.77 ml (10.0 mmol) of methanesulfonyl chloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethyl acetate) to give 1.075 g of the desired compound (72.1% yield, pale brown crystals), top. 57°-58° C.
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[CH3:7][C@@H:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[CH3:7][C@@H:8]([N:15]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C1CCCO1
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1CCCC1=O
Temperature: 180 °C
Reaction time: 48 h

Procedure:
According the the procedure of J. Am. Chem. Soc., 74, 1952 (1959), combine butyrolactone (8.6 g, 100 mmol) and (R)-α-methylbenzylamine (15.0 g, 123 mmol) and heat to 180° C. After 48 hours, heat to 210° C. After 6 hours, cool the reaction mixture and evaporate in vacuo using a short path distillation apparatus to obtain a residue: bp 110° C. at 0.5 mm Hg. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.45 (silica gel, ethyl acetate).
Reaction SMILES: Cl[S:2]([CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10])(=[O:4])=[O:3].C(N(CC)CC)C.[OH:19][CH2:20][C:21]([CH3:38])([CH3:37])[C@@H:22]([O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26]>ClCCl.CN(C1C=CN=CC=1)C>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][S:2]([O:19][CH2:20][C:21]([CH3:38])([CH3:37])[C@@H:22]([O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:32])([CH3:34])[CH3:33])/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])(=[O:4])=[O:3])(=[O:11])[CH3:10]
Reactant: CC(=O)NCCCS(=O)(=O)Cl
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Yield: 54.2 %

Procedure:
Following the general procedure for the preparation of neopentyl sulfonylester intermediates of Description 10, N-[3-(chlorosulfonyl)propyl]acetamide (9) (4.0 g, 19.8 mmol) in 40 mL of dichloromethane (DCM) in the presence of 1.2 g (9.8 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP) and 2.8 mL (2.0 g, 19.8 mmol) of triethylamine (Et3N, TEA) was reacted at ca. 0° C. with 3.0 g (9.9 mmol) of methyl (2E)(4S)-6-hydroxy-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (4). After work-up and isolation, the crude material was purified by silica gel column chromatography using ethyl acetate (EtOAc) and methanol (MeOH) mixtures (EtOAc/MeOH=9:1) as eluent to provide 2.5 g (55% yield) the title compound (19a) as a colorless oil. Rf=0.46 (EtOAc). 1H NMR (400 MHz, CDCl3): δ=0.01 (s, 3H), 0.08 (s, 3H), 0.93 (s, 9H), 0.97 (s, 6H), 2.06 (s, 3H) 2.07-2.11 (m, 2H), 3.14-3.18 (m, 2H), 3.40-3.45 (m, 2H), 3.77 (s, 3H), 3.98 (d, J=9.6 Hz, 1H), 4.06 (d, J=9.2 Hz, 1H), 4.09 (dd, superimposed, J=6.4, 1.6 Hz, 1H), 5.93 (br., 1H), 5.96 (dd, J=15.6, 1H), 6.90 (dd, J=15.6, 6.4 Hz, 1H) ppm. MS (ESI) m/z 466.10 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: CO
Reactant: NC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-3-(3-nitrophenyl)propanoic acid (20.00 g; 95.15 mmol; 1.00 eq.) in MeOH (300 mL) was added thionyl chloride (50.00 ml; 761.22 mmol; 8.00 eq.) at 0° C. slowly. Then the mixture was warmed to room temperature and stirred overnight. The reaction mixture was evaporated and the crude product was purified by flash chromatography on silica gel (MeOH: DCM=15:85) to obtain 20 g of the title compound. LCMS [225 (M+1)].
Reaction SMILES: CO[CH2:3][CH2:4][C:5]([NH2:7])=[O:6].[CH2:8](N)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N.[OH-].[Na+]>>[CH2:19]([NH:7][C:5](=[O:6])[CH:4]=[CH2:3])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: COCCC(N)=O
Reactant: CCCCCCCCCCCCN
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCCCCCCCCCCCC

Procedure:
103.1 g (1.0 mole) of 3-methoxypropionamide are heated with 194.6 g (1.05 mole) of dodecylamine in a temperature range of 130°-170° C. until the evolution of ammonia is complete. The mixture is allowed to cool, 1.5 g of sodium hydroxide is added and the mixture is heated in a high vacuum at 90° to 110° C. The methanol is split off within about 30 minutes, vigorous foaming occurring. The temperature is increased and 172.4 g (0.72 mole=72% of the theoretical yield) of N-dodecylacrylamide having a Bp0.1 of 165°-170° C., which solidifies into crystalline form in the receiver, are distilled off.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:31]2[CH:32]=[CH:33][S:34][C:30]=2[CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:31]5[CH:32]=[CH:33][S:34][C:30]=5[CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nccc2sccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nccc5sccc45)cc3CC[C@@H]12
Yield: 24.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 4-chlorothieno[3,2-c]pyridine (78 mg, 0.46 mmol) and 1 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 37 mg (25%) of the title compound as a white solid. mp 196°-197°. FDMS: m/e=394. α[D]589 =+75.17 (c=0.57, chloroform).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[OH:16]O.[OH-].[NH4+]>C(O)(=O)C>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-:16])=[CH:9][CH:8]=[CH:7]2
Reactant: OO
Reactant: FC(F)(F)Oc1ccc2ncccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: [O-][n+]1cccc2cc(OC(F)(F)F)ccc21
Temperature: 82 °C

Procedure:
To a solution of the crude 6-trifluoromethoxy-quinoline of Step A (obtained from 50 mmol of 4-trifluoromethoxy aniline) in glacial acetic acid (54 mL) is added dropwise 30% hydrogen peroxide (8 mL). The mixture is heated at 82° C. under nitrogen for 16 hours, cooled, carefully basified with concentrated ammonium hydroxide and extracted with ethyl acetate. The extracts are washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is twice azeotroped with benzene, and then flash chromatographed on silica gel Merck-60 using dichloromethane followed by a gradient of methanol (0.5–2%) in dichloromethane to provide the title compound as a pale brown oil that solidifies upon standing. The pale brown crystals (4.8 g) melt at 68–70° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29]CC)=O)=[N:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[NH3:32].CO>>[NH2:24][C:21]1[CH:22]=[CH:23][C:17]2=[CH:16][CH:15]=[C:14]3[C:19]([N:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([NH2:1])(=[O:3])=[O:4])[CH:6]=4)[N:12]=[C:13]3[C:27]([NH2:32])=[O:29])=[C:18]2[CH:20]=1
Reactant: CCOC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Reactant: N
Solvent: CO
Product: NC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1ccc1ccc(N)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sealed solution of ethyl 1-[3-(aminosulfonyl)phenyl]-8-nitro-4,5-dihydro-1H-benzo[g]indazole-3-carboxylat from step 1 (2.20 g, 4.98 mmol) in excess NH3/MeOH was heated at 110° C. for 10 h. The mixture was then concentrated to 10 mL, cooled to RT and the solid product collected by filtration. The solid was dissolved in HOAc, exposed to H2 (5 psi) at RT in the presence of Pd—C (5%) for 2 h. The mixture was filtered through celite pad, concentrated, taken into MeOH, filtered again through celite. The clear solution was concentrated, recrystallized in EtOH to give a grey solid (450 mg). Its structure was confirmed by 1H NMR and MS (382, M+1). C18H15N5O3S.H2O.(Et2O)0.2, Calc.: C: 54.51, H: 4.62, N: 16.91; Found, C: 54.79, H: 4.06, N: 16.72.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([NH2:39])=[N:31][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:39][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]([C:2]2[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]3[S:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=3[N:7]=2)=[CH:30][N:31]=1
Reactant: CC(C)(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cnc(N)c3ccccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1cc2nc(-c3cnc(N)c4ccccc34)nc(N3CCOCC3)c2s1
Temperature: 140 °C
Yield: 5.6 %

Procedure:
To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol (63 mg, 0.20 mmol) in acetonitrile (3.6 ml) in a microwave reaction vessel was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine (110 mg, 0.40 mmol), Bis(triphenylphosphine)palladium(II) chloride (7.02 mg, 0.010 mmol) and 1M sodium carbonate in water (0.60 ml). The reaction vessel was sealed and heated in the microwave at 140° C. for 20 minutes. LC-MS of the reaction mixture showed no more starting material. The solvent was evaporated and the resulting oil was purified on silica gel (0 to 20% of 2N NH3 in MeOH/DCM). The resulting oil was further purified by reversed phase HPLC to give 141 as an off-white solid (4.7 mg, 6%) 1H NMR (DMSO d6, 400 MHz) 9.02 (d, 1H, J=8.4 Hz), 8.26 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 7.67 (t, 1H, J=7.6 Hz), 7.50 (t, 1H, J=7.6)m 7.33 (s, 1H), 7.11 (s, 2H), 5.84 (s, 1H), 3.98-3.94 (m, 4H), 3.81-3.78 (m, 4H), 1.61 (m, 6H). LCMS m/z: 422 (MH+)
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.Cl[CH:19]([CH3:34])[C:20]([O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:21].CN(C)C=O>O>[Cl:2][C:3]1[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:19]([CH3:34])[C:20]([O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[O:21])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CC(Cl)C(=O)OCCOCc1ccc(F)cc1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)OCCOCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
30.6 g of 4-(3,5-dichloro-2-pyridyloxy)phenol sodium salt and 30.5 g of 2-(4-fluorobenzyloxy)ethyl 2-chloropropionate were added to 100 ml of dimethylformamide, and the mixture was heated to 70° to 80° C. for 3 hours with stirring. After cooling to room temperature, the reaction solution was poured into 300 ml of water, then extracted with ether. The ether layer was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, followed by dehydration. Upon distilling off the ether, there were obtained 38 g of a pale yellow, viscous, oily end product, 2-(4-fluorobenzyloxy)ethyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate. nD20 1.5643
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][CH:5]([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]3=[C:9]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[N:24]4)=[CH:19][CH:18]=3)[N:8]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[CH3:42][C:43](OC(C)=O)=[O:44]>C(Cl)Cl>[NH2:16][C:15]1[C:10]2[N:11]([C:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:43](=[O:44])[CH3:42])[CH2:6]3)=[N:8][C:9]=2[C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:24]3)=[CH:19][CH:18]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 3-[3-(aminomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine (0.237 mmol, 100 mg) in DCM (6 mL) was charged with DIEA (0.475 mmol, 83 μL) and Ac2O (0.237 mmol, 22.43 μL) at −40° C. The reaction solution was warmed to rt slowly and stirred under N2 for 1.5 h. The reaction was quenched with water (3 mL), diluted with methylene chloride (20 mL), washed with water (30 mL) and brine (30 mL), and dried (Na2SO4). The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel flush column chromatography (Jones Flashmaster, 10 g/70 mL cartridge), eluting with 3% MeOH (7 N NH3) in DCM, yielding the title compound as a light yellow solid. The sample was recrystallized from DCM (minimal amount) and EtOAc. The final product was obtained as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 8.43-8.42 (m, 1H), 8.28 (dd, J=8.0 Hz, 0.4 Hz, 1H), 8.20-8.18 (m, 2H), 7.97-7.92 (m, 3H), 7.57-7.48 (m, 3H), 7.15 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 5.19 (b, 2H), 3.78-3.70 (m, 1H), 3.38 (t, J=5.6 Hz, 2H), 2.77-2.66 (m, 3H), 2.42-2.34 (m, 2H), 1.87 (s, 3H); MS (ES+): m/z 463 (100) [MH+]; HPLC: tR=2.06 min (OpenLynx, polar—5 min).
Reaction SMILES: [OH-].[K+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:47]([O:49]C)=[O:48])=[CH:14][C:15]=3[N:16]3[C:22]=2[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH:18]([CH2:27][N:28]([CH3:46])[CH2:29][CH2:30][N:31]([CH3:45])[CH2:32][CH2:33][S:34](=[O:44])(=[O:43])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:17]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>C1COCC1.CCOCC>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:47]([OH:49])=[O:48])=[CH:14][C:15]=3[N:16]3[C:22]=2[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH:18]([CH2:27][N:28]([CH3:46])[CH2:29][CH2:30][N:31]([CH3:45])[CH2:32][CH2:33][S:34](=[O:44])(=[O:43])[NH:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:17]3)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCS(=O)(=O)NCc1ccccc1)Oc1ccccc1-3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(CCN(C)CC1Cn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2O1)CCS(=O)(=O)NCc1ccccc1
Temperature: 60 °C

Procedure:
KOH (5.0 eq.) was added to a solution of methyl 13-cyclohexyl-6-(2,5-dimethyl-8,8-dioxido-10-phenyl-8-thia-2,5,9-triazadec-1-yl)-6,7-dihydroindolo[1,2-d][1,4]benzoxazepine-10-carboxylate (0.02 M) in dioxane/H2O (1/1). The reaction was heated at 60° C. for 4.5 h. The reaction was allowed to cool to RT and acidified with 1N HCl (aq), the mixture was extracted two times with DCM. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product (quant.). (ES+) m/z 659 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1[NH2:15])([O-:3])=[O:2].[I:16][C:17]1[CH:18]=[C:19]([C:23]2[O:28]C(C)(C)[O:26][C:25](=O)[CH:24]=2)[CH:20]=[CH:21][CH:22]=1>>[I:16][C:17]1[CH:18]=[C:19]([C:23](=[O:28])[CH2:24][C:25]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[O:26])[CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(I)c2)O1
Reactant: Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]
Product: O=C(CC(=O)c1cccc(I)c1)Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 2-nitro-4-pyrrol-1-yl-phenylamine (Example E1) (610 mg, 3 mmol) and 6-(3-iodo-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example L4) (1.49 g, 4.5 mmol) according to the general procedure M. Obtained as a brown solid (876 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([N:17]=[C:18]=[O:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)=[O:19])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: Nc1nc(=O)n(C(=O)Nc2cccc(Cl)c2)cc1F
Yield: 82.1 %

Procedure:
Using the procedure of Example 5 but using tetrahydrofuran (THF) instead of DMF as solvent, 4-amino-5-fluoro-pyrimidin-2-ol (0.25 g, 1.94 mmol) and 3-chlorophenyl isocyanate (0.260 mL, 2.13 mmol) were reacted to yield 4-amino-N-(3-chlorophenyl)-5-fluoro-2-oxopyrimidine-1(2H)-carboxamide (0.45 g, 82%) as a white solid: mp 250-252° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.65 (s, 1H), 8.43 (d, J=7.3 Hz, 1H), 8.35 (s, 1H), 7.29-7.20 (m, 2H), 7.06 (d, J=7.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H); ESIMS m/z 280.9 ([M−H]−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]Cl)=[CH:3][CH:2]=1.[SH:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][S:10][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCS
Reactant: ClCCc1ccncc1
Product: OCCSCCc1ccncc1

Procedure:
Using the procedures of Examples 1 to 4, 2-(4-pyridyl)ethyl chloride is reacted with 2-mercaptoethanol to yield 4-[2-(2-hydroxyethylthio)ethyl]pyridine, with 3-mercapto-2-butanol to yield 4-[2-(3-hydroxy-2-butylthio)ethyl]pyridine, with 3-mercapto-1,2-propanediol to yield 4-[2-(2,3-dihydroxy-1-propylthio)ethyl]pyridine, with 2-mercaptophenol to yield 4-[2-(2-hydroxyphenylthio)ethyl]pyridine, with methyl mercaptoacetate (preferably in methanol rather than ethanol solution) to yield methyl 2-[2-(4-pyridyl)ethylthio]acetate and with mercaptoacetone to yield 2-(4-pyridyl)ethylthioacetone.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](OCC)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc2nc(Br)sc2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a solution of ethyl 2-bromobenzo[d]thiazole-6-carboxylate (5.0 g, 17.5 mmol) from Step 1 of this Example in anhydrous CH2Cl2 was added DIBAL-H (1.0 M in CH2Cl2, 36.7 mL, 36.7 mmol) slowly at −78° C. The solution was stirred at −78° C. for 2 h. The resulting mixture was quenched with 10 mL of saturated aq sodium potassium tartrate at −78° C. After slowly warming to 0° C., the mixture was further treated with 50 mL of saturated aq sodium potassium tartrate and stirred at rt for 2 h. The aqueous layer was separated and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of EtOAc-hexanes (2:3, v/v) as eluent to give (2-bromobenzo[d]thiazol-6-yl)methanol as a white solid (3.4 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J=8.3 Hz, 1H), 7.85 (s, 1H), 7.45 (dd, J=1.4, 8.4 Hz, 1H), 4.83 (s, 2H), 1.86 (br s, 1H). LCMS (ESI) m/z 244, 246 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH2:5][C:6]1[CH:11]=[C:10]([C:12]2([CH3:17])OCCO2)[CH:9]=[CH:8][C:7]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][N:4]=[C:12]([C:10]1[CH:9]=[CH:8][C:7]([OH:18])=[C:6]([NH2:5])[CH:11]=1)[CH3:17]
Reactant: CON
Reactant: CC1(c2ccc(O)c(N)c2)OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=C(C)c1ccc(O)c(N)c1
Temperature: 25 °C

Procedure:
A mixture of O-methylhydroxylamine hydrochloride (535 mg, 6.40 mmol), 2-amino-4-(2-methyl-1,3-dioxolan-2-yl)phenol D130 (250 mg, 1.28 mmol) and potassium carbonate (442 mg, 3.20 mmol) in ethanol (10 mL) was heated to reflux for 2 hr. The mixture was cooled to rt and concentrated to dryness under vacuum and the residue partitioned between DCM and water. The organic phase was separated washed with brine, dried (MgSO4) and concentrated to dryness in vacuo. The residue was purified using silica gel chromatography eluting with 0 to 10% MeOH in DCM. The title product was isolated as a pale brown solid, 224 mg, 97%.