Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2=O.C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:5]1[C:4]2[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1C=Nc2cc(F)c(F)cc2C1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl
Temperature: 95 °C
Yield: 84.7 %

Procedure:
A suspension of 58.3 g of ethyl 6,7-difluoro-4-oxoquinoline-3-carboxylate in 490 g of phosphorus oxychloride was heated at 95° C. for 5 hours with stirring. After evaporation to dryness under reduced pressure (5.2 kPa), the viscous residue obtained was supplemented with 500 cm3 of ice-cold water and decomposed by slow addition of a saturated aqueous potassium carbonate solution up to pH 8. The insoluble material formed was extracted twice with 400 cm3 of dichloromethane. The organic extracts obtained were dried over sodium sulphate in the presence of animal charcoal, filtered, and concentrated under reduced pressure (5.2 kPa). The residue obtained was recrystallized from 800 cm3 of hexane. 53 g of ethyl 4-chloro-6,7-difluoroquinoline-3-carboxylate was obtained in the form of white crystals, which melted at 111° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8](S(C)(=O)=O)[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([I:17])=[CH:4][N:3]=1.C1COCC1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([I:17])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)N(c1cc(Br)ncc1I)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cc(Br)ncc1I
Yield: 84.4 %

Procedure:
N-(2-Bromo-5-iodopyridin-4-yl)-N-(methylsulfonyl)methanesulfonamide (7) (228 mg, 0.50 mmol) was stirred with THF (1.3 ml) and 10% sodium hydroxide in water (1.3 mL) at r.t. for 3 hours. The THF was evaporated and the aqueous was neutralised using 10% citric acid solution. The deposited white solid was filtered off and washed with water, then dried in a vacuum desiccator over sodium hydroxide to give the title compound (159 mg 84%). 1H-NMR (d6-DMSO, 500 MHz): δ 3.29 (s, 3H), 7.54 (s, 1H), 8.64 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:47][NH:48][C:49](=[NH:55])[C:50]([O:52][CH2:53][CH3:54])=[O:51]>C(#N)C>[OH:47][N:48]=[C:49]([NH:55][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[C:50]([O:52][CH2:53][CH3:54])=[O:51]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: CCOC(=O)C(=N)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=NO)NC(=O)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 92.4 %

Procedure:
To a solution of 5-methyl-2-nitro-benzoic acid (100 mg, 0.55 mmol) and HATU (210 mg, 0.55 mmol) in acetonitrile (4 mL) and DIEA (96 μL, 0.55 mmol) was added ethyl 2-(hydroxyamino)-2-imino-acetate (73 mg, 0.55 mmol). The reaction was stirred at room temperature for 25 min resulting in a thick white precipitate. The solid was filtered, washed with water and dried to yield ethyl 2-(hydroxyimino)-2-(5-methyl-2-nitrobenzamido)acetate as a white solid (150 mg, 92% yield). LC/MS m/z 296.1 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 8.05 (d, J=8.3 Hz, 1H), 7.74 (d, J=0.9 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.16 (br s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]([CH2:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])[CH:2]=C.O=O.[O:28]=[O+][O-].CSC>C(Cl)Cl.O>[CH3:8][O:7][C:5](=[O:6])[C:4]([CH2:1][CH:2]=[O:28])([CH2:13][C:14](=[O:25])[C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: C=CCC(CC(=O)c1ccc(C(F)(F)F)cc1)(C(=O)OC)C(=O)OC
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: COC(=O)C(CC=O)(CC(=O)c1ccc(C(F)(F)F)cc1)C(=O)OC
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Dimethyl allyl{2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}malonate (20 g, 0.055 mol) was dissolved in DCM (180 ml) and the solution was cooled to −78° C. Oxygen, containing ozone, was bubbled through the solution until a blue coloration persisted. The mixture was then purged with nitrogen for 10 min in then dimethyl sulfide (20 ml, 0.275 mol) was added and the mixture was stirred overnight at room temperature. Water (500 ml) was added and the mixture was extracted with DCM. The organic layer was separated and was washed with brine, then dried (MgSO4) and concentrated in vacuo to give the product as an oil. This was purified by chromatography on silica using hexane/EtOAc (9:1 to 1:1) as eluant to afford the product (4 g). 1H NMR (500 MHz, CDCl3): δ 3.46 (2H, s), 3.77 (7H, s), 3.93 (2H, s), 7.74 (2H, d, J 8.2), 8.06 (2H, d, J 8.1), 9.73 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:32][C:33]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH3:46])=[C:39]2[C:34]=1[C:35](=[O:58])[C:36]([C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)=[CH:37][N:38]2[CH2:47][C:48](O)=[O:49]>C(N(CC)CC)C.O.CN(C=O)C>[F:32][C:33]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH3:46])=[C:39]2[C:34]=1[C:35](=[O:58])[C:36]([C:51]1[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=1)=[CH:37][N:38]2[CH2:47][C:48]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[O:49]
Reactant: NCCN1CCOCC1
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3)cn(CC(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Temperature: 25 °C
Reaction time: 23 h
Yield: 24.2 %

Procedure:
4-(2-Aminoethyl)morpholine (184 mg, 1.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC, 295 mg, 1.54 mmol) and 1-hydroxybenzotriazole (HOBT, 215 mg, 1.41 mmol) were added to a DMF solution (7 ml) of [5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetic acid (500 mg, 1.34 mmol) and then the mixture was stirred at room temperature for 23 hours. Water and triethylamine were added to the reaction mixture to make the reaction mixture basic, followed by extraction using ethyl acetate. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=30:1→10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, giving a white powder of 2-[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]-N-(2-morpholin-4-ylethyl)acetamide (157 mg, yield: 24%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>C(O)(C)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:32][C@H:33]4[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1

Procedure:
1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (50.0 g, 148 mmol) was suspended in isopropanol (400 mL) and DIPEA (35.0 mL, 207 mmol) was added, followed by trans-4-aminocyclohexanol (18.7 g, 163 mmol). The mixture was heated at reflux for 2 hours, then cooled and concentrated under vacuum. The residue was dissolved in dichloromethane and washed with water (added 1 N HCl to bring pH to 6-7). The organic layer was dried (Na2SO4) and concentrated under vacuum. The residual foam was taken up in ethanol and the resulting precipitate collected to give 65.0 g (quant) of crude trans 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol. NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H), 9.03 (d, 1H), 8.19 (dd, 2H), 7.62 (m, 2H), 7.52 (m, 2H), 6.71 (d, 1H), 3.95 (m, 1H), 3.79 (m, 1H), 3.78-3.67 (m, 2H), 2.22 (m, 2H), 2.08 (m, 2H), 1.59 (m, 1H), 1.54 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:16][CH:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:16][CH:15]3[CH2:17][CH2:18][NH:19][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: NCCC1CC1C1CCN(c2ncc(Cl)cn2)CC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(NCCC2CC2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine from step 3 of this example (50 mg, 0.178 mmol) was in 0.594 mL NMP. 1-fluoro-4-(methylsulfonyl)benzene (37.2 mg, 0.2141 mol) and DBU (0.040 mL, 0.267 mmol) were sequentially added. The reaction mixture was stirred at 110° C. overnight before cooled back to room temperature. The reaction mixture was diluted with water and aqueous phase was further extracted with ethyl acetate for 3 times. The combined organic layers were washed with water and brine, then dried over Na2SO4 and concentrated. The residue was purified by column chromatography using gradient elution (0 to 65% ethyl acetate in hexane) to give the titled compound. LRMS calc: 434.9; obs: 435 (M+1).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[NH3:13]>>[C:2]([NH2:13])(=[O:3])[C:1]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:6].[NH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([OH:4])=[O:3])[C:5]([NH2:13])=[O:12]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: N
Product: NC(=O)Nc1ccccc1C(=O)O
Product: NC(=O)c1ccccc1N

Procedure:
It is reported in J. prakt. Chem., 30 (1884), [2], 467 et seq. and in J. org. Chem. 13 (1948), 347 et seq. and 24 (1959), 1214 et seq. that isatoic anhydride reacts with aqueous ammonia to give anthranilic acid amide and o-ureidobenzoic acid. The reaction of 5,7-dichloroisatoic anhydride with ammonia leads to 6,8-dichlorobenzoylurea (J. org. Chem . 3 (1938), 414 et seq. and 12 (1947), 743), whilst other chlorine-substituted isatoic anhydrides give only moderate yields of chlorinated anthranilic acid amides (J. org. Chem. 26 (1961) 613 et seq.). A corresponding reaction of 6-nitroisatoic anhydride, as described in J. prakt. Chem., 30 (1884), [2], 467 et seq., gives 5-nitroanthranilic acid amide in poor yield and purity. It was only possible to establish a decomposition point for the resulting end product, and this lay about 30° C. below the melting point of the pure end product. The product is apparently contaminated by nitroureidobenzoic acid and can be separated off and purified only by a complicated procedure, for example by salt formation with hydrochloric acid or sulfuric acid and subsequent precipitation with alkali metal hydroxide solution; this process is therefore unsuitable, particularly for a large-scale industrial preparation.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:13]1([NH:1][C:2]2[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cccc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cccc(NC2CCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a stirred solution of methyl 3-amino-2-methylbenzoate (2 g, 12.1 mmol) and cyclopentanone (5 g, 60.6 mmol) in methanol (20 mL) was added acetic acid (0.72 g, 12.12 mmol) and the reaction stirred at room temperature for 3 h. Sodium cyanoborohydride (1.13 g, 18.2 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the product was purified by column chromatography to afford methyl 3-(cyclopentylamino)-2-methylbenzoate (2.2 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31].[OH-].[Na+].Cl.[CH2:36](Cl)Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:36])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:30]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[O:31])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(N)n3)cc2C1=O
Reactant: ClCCl
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(-c2ccnc(NC(=O)c3ccco3)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 2-(2-amino-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester (prepared as described in Example 9) (0.255 mmol, 1 eq) in 2.5 mL of dry DCM and TEA (1.617 mmol, 6.3 eq) under argon atmosphere, 2-furane-carbonylchloride (0.803 mmol, 3.15 eq) was added at room temperature within 10 minutes. After stirring for 3 h at room temperature, the solvent was evaporated, the crude dissolved in 2 ml of MeOH and treated with 2.1 equivalents of NaOH 1N. The mixture was stirred for 2 h at room temperature until HPLC revealed conversion of starting diacylated product into the monoacylated; finally stoichiometric amount of HCl 2N was added. The methanol was evaporated under vacuum and the crude was washed with water and extracted twice with CH2Cl2, dried over Na2SO4 and evaporated to dryness. The residue was then purified by flash column chromatography (98:2 CH2Cl2:MeOH) affording 2-{2-[(furan-2-carbonyl)-amino]-pyrimidin-4-yl}-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester as a white solid in 24% yield.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:15]1[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH:18]=[N:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:15]2[CH:16]=[C:17]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH3:28])[CH:18]=[N:19][CH:20]=2)[CH:2]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cnc3ccccc3c2)c1

Procedure:
To a solution of the compound from step 35a and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (271 mg, 1.0 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2M solution), and the mixture was heated at reflux for 4 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with 2 to 5% methanol in methylene chloride in a first column, followed by rechromatography, eluting with 0.1 to 1% ether in hexane, to afford 120 mg of the title compound. MS (CI/NH3) m/z 320 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.82, (m, 3H), 2.06 (m, 1H), 2.34 (m, 1H), 2.52 (s, 3H), 2.73 (m, 1H), 3.13 (m, 1H), 4.09 (m, 2H), 7.52 (m, 1H), 7.62, (m, 1H), 7.76 (m, 1H), 7.90 (m, 1H), 8.16 (m, 1H), 8.32 (m, 1H), 8.40 (m, 1H), 8.58 (m, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10]Br)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-:12].[Na+]>CC(C)=O.CN(C)C=O>[Si:1]([O:8][CH2:9][CH2:10][I:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCI
Reaction time: 4 h

Procedure:
Combine 2-(t-butyldimethylsilyloxy)ethyl bromide (116.2 g, 486 mmol), and sodium iodide (100 g, 663 mol) in acetone (350 mL) and dimethylformamide (25 mL). Heat to reflux. After 4 hours, cool, filter and evaporate in vacuo to give a residue. Distill the residue to give 2-(t-butyldimethylsilyloxy)ethyl iodide: bp; 60° C. at 0.5 mm Hg.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(O)C.[H][H]>[Pd].C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CSc1nccc(Oc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1nccc(Oc2ccc(N)cc2)n1
Yield: 96.4 %

Procedure:
A mixture of 120.0 g (456 mmol) 2-methylsulfanyl-4-(4-nitrophenoxy)-pyrimidine, 1200 ml ethanol, 1200 ml THF, and 24.0 g 10% palladium/C is hydrogenated at 46 mbar hydrogen pressure at r.t. for 8 h. The catalyst was removed by filtration, washed with 600 ml ethanol, then 300 ml THF and the combined filtrates evaporated. The residue was dissolved in a mixture of 700 ml ethyl acetate and 300 ml THF. The solution was dried over sodium sulphate and evaporated. The residue was stirred with 250 ml isohexane, the precipitate isolated and washed with 400 ml isohexane. Drying in vacuum at r.t. gave 102.5 g (96%) 4-(2-Methylsulfanyl-pyrimidin-4-yloxy)-phenylamine.
Reaction SMILES: [Br:1]C1C(C(OC)=O)=NC(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=CN=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[C:32]([C:48]([O:50][CH3:51])=[O:49])=[N:33][C:34]([NH:37][C@@H:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][C@@H:39]2[OH:47])=[CH:35][N:36]=1>>[Br:1][C:35]1[N:36]=[C:31]([C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[Cl:23])[C:32]([C:48]([O:50][CH3:51])=[O:49])=[N:33][C:34]=1[NH:37][C@@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][C@@H:39]1[OH:47]
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1-c1ccc(Cl)cc1Cl
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(Br)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate but substituting methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 2.99-3.04, 3.20-3.25, 3.70, 3.99-4.08, 4.77, 5.59-5.62, 6.11, 7.24-7.38; MS (ESI+) for C21H16BrCl2N3O3 m/z 509 (M+H)+.
Reaction SMILES: [C:1](=[O:16])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:15])([F:14])[F:13])[O:2][CH3:3].[N+:17]([O-:20])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[C:1](=[O:16])([O:4][C:5]1[CH:10]=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:15])([F:13])[F:14])[O:2][CH3:3].[C:1](=[O:16])([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:17]([O-:20])=[O:18])=[CH:7][C:6]=1[O:11][C:12]([F:15])([F:13])[F:14])[O:2][CH3:3]
Reactant: COC(=O)Oc1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])ccc1OC(F)(F)F
Product: COC(=O)Oc1ccc([N+](=O)[O-])cc1OC(F)(F)F
Reaction time: 2 h

Procedure:
Methyl 2-(trifluoromethoxy)phenyl carbonate (200 mg, 0.85 mmol) was added portion-wise to H2SO4 (600 μL) at 0° C. to generate a colorless homogeneous solution. KNO3 (103 mg, 1.02 mmol) was added portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-10% ethyl acetate/hexanes) provided the two regioisomers methyl 5-nitro-2-(trifluoromethoxy)phenyl carbonate (Isomer A, 120 mg) and methyl 4-nitro-2-(trifluoromethoxy)phenyl carbonate (Isomer B, 75 mg).
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Li]CCCC.CCCCCC.[Al](Cl)(CC)CC.[N:26]1[C:35]2[C:30](=[CH:31][C:32]([C:36](Cl)=[O:37])=[CH:33][CH:34]=2)[N:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:7][C:6]1[N:1]=[C:2]([CH2:8][C:36]([C:32]2[CH:31]=[C:30]3[C:35](=[CH:34][CH:33]=2)[N:26]=[CH:27][CH:28]=[N:29]3)=[O:37])[CH:3]=[CH:4][CH:5]=1
Reactant: Cc1cccc(C)n1
Reactant: O=C(Cl)c1ccc2nccnc2c1
Agent: CC[Al](Cl)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccc3nccnc3c2)n1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
A stirred solution of 2,6-lutidine (1.4 g, 13 mmole) in dry THF (100 ml) at −60° C. under Ar was treated dropwise with a solution of BuLi in hexane (2.5 M, 5.2 ml, 13 mmole). After 30 mins a solution of Et2AlCl in hexane (14 ml, 14 mmole) was added dropwise and the solution warmed to 20° C. After a further 30 mins the solution was cooled to −50° C. and transferred via canula to a stirred solution of quinoxaline-6-carbonyl chloride (2.0 g, 10.3 mmole) in THF (100 ml) at −60° C. Stirring was continued for 20 min and the solution quenched with sat. aq. NH4Cl solution and warmed to 20° C. The mixture was filtered through Kieselguhr and the filtrate worked up as normal (EtOAc, water, Na2SO4). Filtration through silica eluting with EtOAc gave the product as a yellow solid (1.65 g, 51%). m/z [ESMS]: 264 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][C:4]=2[C:3]=1[C:18]([O:20]CC)=O.C(O)(=O)C.[CH:27](N)=[NH:28]>CN(C=O)C>[O:20]=[C:18]1[NH:28][CH:27]=[N:1][C:2]2[S:10][C:9]3[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:5][C:4]=3[C:3]1=2
Reactant: CCOC(=O)c1c(N)sc2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: N=CN
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2sc3nc[nH]c(=O)c3c2C1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
5-tert-Butyl 3-ethyl 2-amino-6,7-dihydrothieno[3,2-c]pyridine-3,5(4H)-dicarboxylate from Example 73A (780 mg, 2.39 mmol) was dissolved in DMF (8 mL), and formamidine acetate (373 mg, 3.58 mmol) was added. The reaction mixture was heated to 100° C. overnight. The solvent was then removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether, and the precipitate was collected by suction filtration to yield 414 mg (56%) of the title compound as a tan solid. The mother liquor was concentrated and purified by preparative HPLC to yield a second batch of 36 mg (5%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1(=O)[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>C(O)(=O)C>[O:12]=[C:11]1[CH:10]=[CH:9][C:8](=[O:13])[N:1]1[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: NCCCC(=O)O
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C(O)CCCN1C(=O)C=CC1=O
Temperature: 130 °C
Yield: 48.2 %

Procedure:
20.0 g (193.9 mmol) of 4-aminobutyric acid is mixed with 19 g of maleic acid anhydride, 290 ml of acetic acid, and it is heated for 4 hours in an oil bath at 130° C. It is azeotropically concentrated by evaporation with repeated addition of toluene, the residue is dissolved in dichloromethane and purified by chromatography on fine silica gel. 17.1 g (93.4 mmol, 48%) of the title compound is isolated as a crystalline solid.