Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([O:19][C:18]2[C:13]3[C:12]4[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]=4[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])[C:14]=3[CH:15]=[N:16][C:17]=2[C:20]#[N:21])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Yield: 78.1 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (15.8 g, 36.8 mmol), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (18.5 g, 92.0 mmol) and triphenylphosphine (24.1 g, 92.0 mmol) in anhydrous THF (100 mL) was treated dropwise with diethyl azodicarboxylate (18.1 mL, 92.0 mmol) and the mixture heated to 50° C. for 40 minutes. After this time, the reaction mixture was concentrated in-vacuo and the resultant residue purified by flash chromatography (silica, 2×330 g column, ISCO, 0-10% ethyl acetate in dichloromethane). The resultant product was further purified by trituration with diethyl ether to afford the title compound as an off-white solid (17.6 g, 78%). 1H NMR (300 MHz, CDCl3): 9.57 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.57 (d, J=2.3 Hz, 1H), 8.23-8.22 (m, 2H), 7.64-7.63 (m, 1H), 7.53-7.51 (m, 2H), 5.20-5.20 (m, 1H), 4.07 (d, J=13.6 Hz, 2H), 3.06 (t, J=12.1 Hz, 2H), 2.20-2.19 (m, 2H), 1.85-1.85 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[Cl:1][C:2]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:15])[C:9](=[O:11])[CH:10]=1
Reactant: COc1ccc(Oc2cnn(C(CC3CCCCC3)C(=O)O)c(=O)c2)c(Cl)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: COc1ccc(Oc2cnn(C(CC3CCCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)c(=O)c2)c(Cl)c1
Yield: 63 %

Procedure:
Using the method described in Example 49, 2-[4-(2-chloro-4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-propionic acid (Intermediate 90) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-chloro-4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as an off-white solid (190 mg, 63%); ES+-HRMS m/e calcd for C27H34N5O5Cl [M+H+] 544.2321 found 544.2324. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88-1.22 (m, 6H), 1.05 (s, 3H), 1.06 (s, 3H), 1.62 (br. s., 5H), 1.74-1.88 (m, 1H), 2.06-2.24 (m, 1H), 3.81 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.53 (dd, J=11.2, 3.9 Hz, 1H), 5.65 (d, J=2.7 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H), 7.04 (dd, J=9.0, 3.0 Hz, 1H), 7.27 (d, J=3.0 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 8.18 (d, J=2.7 Hz, 1H), 10.83 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:30][NH:31][O:32][CH3:33]>C(Cl)Cl>[CH3:33][O:32][N:31]([CH3:30])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (11 g, 48 mmol) in DCM (120 mL) was added CDI (11 g). After stirring at rt for 2 h, N,O-dimethylhydroxylamine hydrochloride was added in portions. The mixture was stirred for 3 h at rt and was then left to stand overnight. The solvent was removed under vacuum, the residue was extracted with DCM, washed with brine and water, dried over anhydrous sodium sulfate and concentrated to give crude tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (8 g, 61% yield) as a white solid which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26](O)=[O:27])=[CH:9]2.[CH2:29]([S:36][CH:37]([CH:40]([O:43][CH3:44])[O:41][CH3:42])[CH2:38][NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CCCCCC.C(OCC)(=O)C.CN(C)C=O>[CH2:29]([S:36][CH:37]([CH:40]([O:41][CH3:42])[O:43][CH3:44])[CH2:38][NH:39][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=1)(=[O:17])=[O:18])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C(=O)O)cc2c1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.9 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxylic acid (2.3 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (1.7 g), 1H-1,2,3-benzotriazol-1-ol (1.2 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.6 g) and N,N-dimethylformamide (70 mL) was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80-80:20) to give the title compound (3.2 g, yield 89%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)CCc1ccccc1Br
Reactant: C#CCCCCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1CCC(=O)OC

Procedure:
Palladium acetate (60 mg) was added to a deaerated solution of methyl 3-(2-bromophenyl)propanoate (11.10 g, 25 mmole), 1-tridecyne (6.75 g) and triphenylphosphine (200 mg) in anhydrous triethylamine (100 ml) and the mixture was stirred at reflux under nitrogen for 24 hrs. After cooling, the precipitated triethylamine hydrobromide was filtered off and the filtrate was evaporated to a red oil. Chromatography on silica eluting with 1:1 dichloromethane-petrol (bp 60°-80° C.) gave the title product, 1.91 g (22%) as an oil, νmax (film) 2920, 2850, 1745 cm-1, δ(CDCl3) 0.84 (3H, distorted t, terminal CH3), 1.28 (18H, m, alkylene chain), 2.39 (2H, t, J 7 Hz; C=C--CH2), 2.62 (2H, m, ArCH2), 3.04 (2H, m, CH2CO2), 3.62 (3H, s, ester CH3), 7.12 (3H, m, arom), 7.31 (1H, m, arom).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[CH:11]([F:13])[F:12].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:1][C:2]2[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)[CH:11]([F:12])[F:13]
Reactant: Nc1cccc(S)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: FC(F)C(F)(F)Oc1cccc(CNc2cccc(S)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
3-Aminobenzenethiol (2.4 mL, 22.5 mmol) and 3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (5 g, 22.5 mmol) were dissolved in 40 mL of dichloroethane and acetic acid (1.35 mL, 23.7 mmol), then solid NaBH(OAc)3 (6.2 g, 29.3 mmol) was added. The mixture was stirred at room temperature for 18 hours, then quenched with water and diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give 5.36 g (72%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzenethiol product as a brown oil. 1H NMR (CDCl3) δ3.4 (s, 1H), 4.4 (s, 2H), 5.9 (tt, 1H), 6.4 (dd, 1H), 6.55 (m, 1H), 6.65 (d, 1H), 7.05 (t, 1H), 7.2-7.4 (m, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([OH:26])[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:27](Cl)Cl>O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][CH3:27])[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCCCOC(=O)c1nc(O)c2ccccc2c1OCc1ccccc1
Solvent: O
Product: CCCCOC(=O)c1nc(OC)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
A mixture of 4-benzyloxy-1-hydroxy-isoquinoline-3-carboxylic acid butyl ester (1 eq.), Me3OBF4 (6 eq), KHCO3 (14 eq) and CH2Cl2 (10 ml/mmol 4-benzyloxy-1-hydroxy-isoquinoline-3-carboxylic acid butyl ester) was stirred at ambient temperature for 24 h. Then water (10 ml/mmol) was added and the mixture was extracted with CH2Cl2 (40 ml/mmol). The organic phase was separated, dried over MgSO4 and evaporated in vacuo to give a yellowish solid. The crude product was purified by flash column chromatography on silica gel using hexanes:EtOAc=85:15 as the eluent. Evaporation of the first fraction gave the title compound as a colorless oil in 20% yield; 1H NMR (CDCl3): δ=8.21 to 8.25 (m, 1H), 8.05 to 8.09 (m, 1H), 7.33 to 7.73 (m, 7H), 5.13 (s, 2H), 4.38 (t, 2H), 4.16 (s, 3H), 1.69 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>ClCCl>[CH3:22][CH:21]([CH3:23])[C:20]([N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1)=[O:24]
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 124d (160 mg, 0.952 mmol) in dichloromethane (10 mL) was added triethylamine (197 mg, 1.90 mmol). After stirring at room temperature for 5 minutes, a solution of isobutyryl chloride (111.0 mg, 1.047 mmol) in dichloromethane (2 mL) was added and the mixture was stirred for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was then concentrated under reduced pressure to afford 148a as a white solid (220 mg, 97%), which was used in the next step without further purification. MS-ESI: [M+H]+ 239.0
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10](S(C)=O)SC)[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:18].O>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:18])[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5]
Reactant: CSC(c1cc(F)c(C#N)c(F)c1)S(C)=O
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(C=O)cc1F
Reaction time: 72 h

Procedure:
2,6-Difluoro-4[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.17 g, 8.32 mmol; see step (ix) above) was dissolved in 90 mL of THF and 3.5 mL of concentrated sulfuric acid was added. The mixture was left at room temperature for 3 days and subsequently poured into 450 mL of water. Extraction three times with EtOAc followed and the combined ethereal phase was washed twice with aqueous sodium bicarbonate and with brine, dried (Na2SO4) and evaporated. Yield: 1.36 g (98%). The position of the formyl group was established by 13C NMR. The signal from the fluorinated carbons at 162.7 ppm exhibited the expected coupling pattern with two coupling constants in the order of 260 Hz and 6.3 Hz respectively corresponding to an ipso and a meta coupling from the fluorine atoms.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:28])[C:18]=1[CH3:29])(=O)C.Cl.C(=O)(O)[O-].[Na+]>CO>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[C:22](=[O:23])[C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19](=[O:28])[C:18]=1[CH3:29]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCCCOC(C)=O)=C(C)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCO)=C(C)C1=O
Reaction time: 12 h
Yield: 96.3 %

Procedure:
To a solution (200 ml) of 6-(12-acetoxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (4.4 g) in methanol is added concentrated hydrochloric acid (0.1 ml) and the mixture is allowed to stand at room temperature for 12 hours. To this reaction mixture is added sodium bicarbonate (0.2 g), and the solvent is distilled off. The product is dissolved in dichloromethane, the insoluble matter is filtered off and the dichloromethane is distilled off to give crude crystals. Recrystallization from hexane-ether (3:1) gives orange-yellow needles of 6-(12-hydroxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (3.8 g). m.p. 63° C.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH3:14].[C:15](#[N:17])[CH3:16]>>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]1[NH:17][C:15]([CH3:16])=[N:14][C:11]1=[N:10]2
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: CC#N
Reactant: N
Product: Cc1nc2nc3cc(Cl)ccc3nc2[nH]1
Yield: 46 %

Procedure:
23.4 G (0.1 mole) of 2,3,6-trichloroquinoxaline and 1 g of copper-I chloride (approximately 0.1 mole) were dissolved in 250 ml of anhydrous acetonitrile and 45 ml (approximately 2 moles) of liquid ammonia were added thereto. The reaction mixture was heated for 12 hours to 150°C in a steel autoclave of 0.7 liter capacity. In the course thereof, a pressure of 10 to 15 atmospheres gauge was set up. The crystalline precipitate produced after cooling was filtered off and dissolved in dilute sodium hydroxide solution. The solution was filtered, the filtrate was acidified with hydrochloric acid and the precipitate was filtered off, well rinsed with water and recrystallized from 30% strength acetic acid. 10 g (representing 46% of theory) of 6-chloro-2-methyl-1H-imidazo[4,5-b]quinoxaline of melting point >300°C were obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[OH:9][C@H:10]1[CH2:14][N:13]([CH3:15])[C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1.[S:20](Cl)([CH3:23])(=[O:22])=[O:21].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:23][S:20]([O:9][C@H:10]1[CH2:14][N:13]([CH3:15])[C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C
Temperature: 40 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Triethylamine (1.53 mL) was added to a suspension of methyl (2S, 4R)-4-hydroxy-1-methyl-2-pyrrolidinecarboxylate hydrochloride (1 g) obtained from Reference example 1 or 3 in tetrahydrofuran (10 mL) and the mixture was stirred at 40° C. for 3 hours. Mesyl chloride was added to the mixture under ice cooling and the mixture was stirred for 2 hours. Ethyl acetate (20 mL) and 5% aqueous sodium hydrogencarbonate solution (10 mL) were added to the reaction mixture, which was then extracted. The organic layer was separated from the aqueous layer and the solvent of the organic layer was removed by distillation under reduced pressure to give the title compound (1.0 g, yield 83%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:17]4[N:18](C(OC(C)(C)C)=O)[CH:19]=[CH:20][CH:21]=4)[CH2:15][O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:16][CH2:15][C:14]([C:17]4[NH:18][CH:19]=[CH:20][CH:21]=4)=[CH:13]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cccc1C1=C/C(=C2\C(=O)Nc3cc(F)ccc32)OC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2cc(F)ccc2/C1=C1/C=C(c2ccc[nH]2)CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 2-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,5-dihydrofuran-3-yl]-1H-pyrrole-1-carboxylate (Example 37; 30 mg) in a mixture of trifluoroacetic acid (2 mL) and CH2Cl2 (10 mL) was stirred at room temperature for 16 hours. The mixture was evaporated to dryness, and re-dissolved in 1:1 THF/MeOH (4 mL). The solution was slowly added into diluted NaHCO3 solution (100 mL) with stirring. The precipitates were filtered, washed with water, and dried in vacuum to give (3E)-6-fluoro-3-[4-(1H-pyrrol-2-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as brown solid. Yield: 15 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[S:9])[S:5][C:6]=1[CH3:7].[CH2:11]([Li])CCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>C1COCC1>[CH3:16][Sn:17]([C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7])([CH3:19])[CH3:18]
Reactant: Cc1sc(C(O)=S)cc1Br
Reactant: C[Sn](C)(C)Cl
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=S)c1cc([Sn](C)(C)C)c(C)s1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 32.4 %

Procedure:
4-Bromo-5-methylthiothiophene-2-carboxylic acid (EP 0676395 A2) (4.67 g, 18.4 mmol) was dissolved in anhydrous THF (30 mL), taken in a round bottomed flask and cooled to −78° C. under a N2 atmosphere. To this solution n-butyllithium (20.3 mL, 40.6 mmol, 2M in cyclohexane) was introduced in a dropwise manner. The resulting solution was stirred at −78° C. for 45 min and then allowed to warm up to −60° C. To this solution trimethyltin chloride (40.6 mL, 40.6 mmol, 1M in THF) was added dropwise. This solution was stirred at −60° C. for 30 min and then allowed to warm up to room temperature. The THF was removed under vacuum and the residue was treated with H2O and extracted with hexane. The hexane layer was evaporated and the residue was dissolved in Et2O. The Et2O solution was washed with 10% HCl, saturated NaCl and dried over anhydrous MgSO4. Et2O was removed under vacuum and the residue was taken in MeOH. The MeOH solution was treated with trimethylsilyldiazomethane (18.5 mL, 2M in hexane) and stirred at room temperature for 1 h. The solvents were removed under vacuum to give 2 g (31%) of methyl 4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-carboxylate as an oil. 1H-NMR (CDCl3; 300 MHz) δ0.31 (S, 9H), 2.57 (s, 3H), 3.86 (S, 3H), 6.98 (S, 1H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][OH:15].O1CCCC1>CN(C)C=O>[CH2:18]([O:17][C:13]([CH2:14][O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16])[CH3:19]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
11 g of sodium hydride was added to a mixture of 39.63 g of 2-chloro-3-nitropyridine, 31.23 g of ethyl glycolate, 250 ml of tetrahydrofuran and 20 ml of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 5 hours, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 48.3 g of 2-(ethoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Cl:9][CH2:10][C:11](O)=[O:12].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:9][CH2:10][C:11]1[O:12][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1.[Cl:9][CH2:10][C:11]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCc1nc2ccccc2o1
Product: ClCc1nc2ccccc2s1
Temperature: 120 °C

Procedure:
Using literature procedures (Addison, A. W.; Nageswara Rao, T.; Wahlgren, C. G. J. Heterocyclic Chem. 1983, 20, 1481-1484) a substituted 2-aminophenol (or a 2-aminothiophenol (5 mmol)) was mixed with chloroacetic acid (940 mg, 10 mmol) in polyphosphoric acid (5 mL), and the viscous mixture was then heated to 120° C. for 3 hours. The reaction was then cooled, and diluted with water (˜20 mL) and then neutralized with potassium carbonate to pH˜7. The mixture was then extracted with ethyl acetate, and the combined organic fractions were then dried over MgSO4 and concentrated. The residue was then purified by column chromatography on silica gel (50% ethyl acetate in hexanes) to afford the desired 2-chloromethylbenzoxazole (or 2-chloromethylbenzothiazole).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.CCN(CC)CC>O1CCOCC1.[Cu]I.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>[Cl:13][C:14]1[N:19]=[C:18]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([NH2:12])=[O:11])[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: C#Cc1ccccc1CC(N)=O
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1C#Cc1ccccc1CC(N)=O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-(2-ethynylphenyl)acetamide (I8) (5.40 g, 33.9 mmol), 2,4-dichloro-5-methylpyrimidine (6.63 g, 40.7 mmol) and CuI (0.129 g, 0.678 mmol) in 1,4-dioxane (180 mL) and Et3N (14.2 mL, 101 mmol) was placed under nitrogen. PdCl2(PPh3)2 (0.238 g, 0.339 mmol) was added and the resulting mixture was stirred at 70° C. for 20 minutes, then adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 120 g SiO2 Cartridge, 0-5% MeOH in DCM) to give the title compound I9 as a yellow solid (5.01 g, 51%); 1H NMR (300 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.35-7.52 (m, 4H), 6.97 (brs, 1H), 3.71 (s, 2H), 2.42 (s, 3H). LCMS-B: rt 5.689 min; m/z 286 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[O:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17]>>[Br:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:17][CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][O:11]2)[N:4]=1
Reactant: BrCc1cccc(CBr)n1
Reactant: OCC1CCCO1
Product: BrCc1cccc(COCC2CCCO2)n1
Yield: 19 %

Procedure:
Prepared from 2,6-bis(bromomethyl)pyridine and (RS)-tetrahydrofuran-2-methanol by the alkylation method described for the final step of Example 32 to give the title compound (19%); NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 7.5 Hz), 7.42 (1H, d, J 7.5 Hz), 7.33 (1H, d, J 7.5 Hz), 4.73-4.65 (2H, m), 4.52 (2H, s), 4.17-4.10 (1H, m), 3.93-3.87 (1H, m), 3.82-3.77 (1H, m), 3.62-3.55 (2H, m), 2.03-1.85 (3H, m), 1.71-1.62 (1H, m); (M+H)+ 286, 288.