Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.[Cl-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:6][CH2:7]1)(=[O:4])=[O:3]
Reactant: c1ccc2c(c1)CNCN2
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CNc2ccccc2C1
Reaction time: 0.08 h

Procedure:
0.17 ml of methanesulfonyl chloride is added to a mixture of 300 mg of 1,2,3,4-tetrahydroquinazoline (prepared by the method described by R. F. Smith et al. in J.Heterocycl. Chem.2 (1965)) and 0.47 ml of triethylamine in 14 ml of methylene chloride at 0° C., while stirring. After 5 min, saturated sodium chloride solution is added, the mixture is subsequently stirred briefly and, after drying over sodium sulfate, the organic phase is concentrated. Purification of the crude product by means of FC over 30 g of silica gel (mobile phase P) gives 3-methylsulfonyl-1,2,3,4-tetrahydroquinazoline: Rf (K)=0.65; IR(KBr): 3360(m), 1600(m), 1500(m), 1320(s), 1145(s), 770(s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([I:31])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.CO[C:34](OC)([N:36]([CH3:38])C)[CH3:35].CO[C:43]1[CH:50]=[CH:49][C:46](CN)=[CH:45][CH:44]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO.CC(O)=O.ClCCCl>[CH2:38]([NH:36][CH:34]([CH3:35])[CH2:8][C:6]1[C:5]2[C:9]([I:31])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1)[C:43]1[CH:50]=[CH:49][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(C)(OC)N(C)C
Reactant: Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
6-chloro-3-iodo-trityl-1H-pyrazolo[4.3-c]pyridine (Intermediate 1C, 2 g, 3.73 mmol), N, N dimethylacetamide-dimethyl acetal (DMA-DMA) (4.97 g, 37.3 mmol) were stirred at 125° C. for 12 hrs. Reaction was concentrated and excess DMF-DMA azeotroped with Toluene. The resulting intermediate and p-methoxybenzylamine (2.05 g, 14.9 mmol) were stirred in a 3:1:1 solution of DCE:AcOH:EtOH (20 ml) at 85° C. for 3 hrs. Solvent was removed by vacuum and the residue was taken in DCE (15 ml) followed with addition of sodium triacetoxyborohydride (3.16 g, 14.9 mmol) and acetic acid (0.9 g, 14.9 mmol) before the mixture was stirred at room temperature for 6 hours. The reaction mixture was partitioned between DCM and aqueous sodium bicarbonate and the organics was separated, washed with brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-90% -EtOAc-hexanes) gave N-benzyl-1-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-amine MS ESI calc'd. for C35H30ClIN4 [M+H]+ 700. found 700.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:17][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]([OH:16])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(O)c(C(C)C)ccc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(O)c(C(C)C)cc(Br)c2c1
Yield: 91.3 %

Procedure:
In 100 ml of DMF was dissolved 5 g of 2-isopropyl-6-methoxy-1-naphthol, and a solution of 4.03 g of N-bromosuccinimide in DMF (50 ml) was added under ice-cooling. The mixture was stirred under ice-cooling for 3 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent:diethyl ether:n-hexane:chloroform=10:50:1) to provide 6.1 g of 4-bromo-2-isopropyl-6-methoxy-1-naphthol. m.p. 81.5°-83.5° C.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[Cl:12][C:13]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:14]=1N.NC1C=CC=CC=1>CC#N>[CH2:3]([C:14]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=1[Cl:12])[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: Nc1ccccc1
Solvent: C=CCBr
Solvent: CC#N
Product: C=CCc1ccc([N+](=O)[O-])cc1Cl
Temperature: 12 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 2-chloro-4-nitroaniline (518 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 11-13° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 23° C. for one hour. The volatile material in the reaction mixture was then removed at reduced pressure. Column chromatography (heptane-ethyl acetate 97:3) gave 497 mg (84%) allyl-2-chloro-4-nitrobenzene as a light yellow oil containing 5% of 2-chloro-4-nitrobromobenzene. This corresponds to 79% yield of allyl-2-chloro-4-nitrobenzene. 1H NMR (CDCl3, 400 MHz) δ 8.25, (d, 1H, J=2.4 Hz), 8.08, (dd, 1H, J=8.5, 2.3 Hz), 7.42, (d, 1H, J=8.5 Hz), 6.01-5.89, (m, 1H), 5.23-5.10, (m, 2H), 3.59, (d, 2H, J=6.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 147.3, 145.9, 135.3, 134.0, 131.2, 125.0, 122.2, 118.5, 38.0; Anal HRMS Calcd. for C9H8ClNO2 (M): 197.0244. Found: 197.0247.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>CO.O>[OH:28][CH2:27][C:26]([NH:25][C:21]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])([CH3:30])[CH3:29]
Reactant: CC(C)(N)CO
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Solvent: CO
Solvent: O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC(C)(C)CO
Yield: 30 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (25 mg, 30%) which was obtained as a white solid after trituration from methanol/water. MS: m/e=417.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:6][N:5]=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(S)CC>>[CH2:26]([C:16]1[N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:18]=[C:13]2[C:12](=[O:28])[NH:11][C:10]([C:9]3[C:4]([O:3][CH3:1])=[N:5][CH:6]=[C:7]([S:29]([N:32]4[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH:8]=3)=[N:15][C:14]=12)[CH3:27]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Agent: CCCS
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OC)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 110 °C
Yield: 50.1 %

Procedure:
A stirred mixture of the title compound of Example 1 (350 mg, 0.63 mmol), potassium bis(trimethylsilyl)amide (630 mg, 3.15 mmol) and n-propanethiol (5 ml) was heated in a sealed vessel at 110° C. for 48 hours, then allowed to cool and evaporated under reduced pressure, The residue was azeotroped with dichloromethane:methanol (95:5), then partitioned between water (10 ml) and dichloromethane (15 ml). The phases were separated, the aqueous phase extracted with dichloromethane (2×15 ml) and the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. This residue was purified by column chromatography on silica gel, using dichloromethane:methanol (97:3) as eluant, to yield the title compound (170 mg, 50%) as a yellow is solid. Found: C, 54.50; H, 5.64; N, 19.93. C25H30N8O4S; 0.75H2O requires C, 54.38; H, 5.75; N, 20.29%. δ (CDCl3): 1.02 (3H, t), 1.32 (3H, t,) 2.40 (2H, q), 2.55 (4H, m), 3.06 (2H, q), 3.14 (4H, m), 4.26 (3H, s), 5.68 (2H, s), 7.14 (1H, d), 7.22 (1H, m), 7.64 (1H, m), 8.58 (1H, d), 8.66 (1H, s), 9.05 (1H, s), 10.59 (1H, s). LRMS: m/z 540 (M+2)+.
Reaction SMILES: [C:1]([C:6]([O-:8])=[O:7])#[C:2][C:3]([O-:5])=O.[CH:9]1([C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH2:14])[CH2:11][CH2:10]1.[CH3:19]O>>[OH:5][C:3]1[C:15]2[C:13](=[C:12]([CH:9]3[CH2:11][CH2:10]3)[CH:18]=[CH:17][CH:16]=2)[N:14]=[C:1]([C:6]([O:8][CH3:19])=[O:7])[CH:2]=1
Reactant: CO
Reactant: Nc1ccccc1C1CC1
Reactant: O=C([O-])C#CC(=O)[O-]
Product: COC(=O)c1cc(O)c2cccc(C3CC3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 21.8 mL of acetylenedicarboxylate (0.18 mol) in 50 mL of MeOH was added dropwise to a solution of 22.5 g of 2-cyclopropylaniline (0.17 mol) in 150 mL of MeOH over 1 hr and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated and the residue was taken up into 30 mL of diphenyl ether. The solution was added dropwise to 200 mL of diphenyl ether heated at 250 C and the mixture was stirred at the temperature for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified on a SiO2 column chromatography (eluted with n-Hex/AcOEt=1/1) to give methyl 4-hydroxy-8-cyclopropylquinoline-2-carboxylate as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1cc2c(cc1OC)CN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH3:11])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.[H][H]>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH3:11])=[CH:6][C:5]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:4]([F:15])[CH:3]=1
Reactant: CCCOc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CCCOc1cc(Nc2ccccc2)c(F)cc1Cl
Yield: 69.3 %

Procedure:
A suspension of 4-chloro-2-fluoro-5-n-propoxy-nitrobenzene (13.5 g) and platinum dioxide (0.4 g) in ethanol (300 ml) was subjected to catalytic reduction with hydrogen under room temperature and atmospheric pressure, whereby a designed amount of hydrogen was absorbed. The resultant mixture was filtered to remove insoluble materials, and the filtrate was concentrated. The residue was subjected to purification by silica gel chromatography to obtain 5.6 g of 4-chloro-2-fluoro-5-n-propoxyphenylaniline. nD24.5 1.5386.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[C:29](O)=[O:30])[N:14]=2)=[CH:4][CH:3]=1.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.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>C1COCC1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[C:29]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[O:30])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccnc(Nc3ccc4[nH]nc(C(=O)O)c4c3)n2)c2ccccc12
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(Nc3ccc4[nH]nc(C(=O)N5CCOCC5)c4c3)n2)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of the carboxylic acid described above (460 mg, 80% pure, 0.90 mmol) in THF (6.0 mL) at RT was added HATU (613 mg, 1.61 mmol) and DIPEA (0.340 μL, 1.97 mmol). After 10 min the resulting mixture was treated with morpholine (0.141 mL, 1.61 mmol) and after a further 16 hr at RT additional portions of HATU (170 mg, 0.45 mmol), DIPEA (80 μL, 0.45 mmol) and morpholine (39 μL, 0.45 mmol) were added. The resulting mixture was maintained at RT for a further 24 hr and was then partitioned between saturated aq. NaHCO3 (20 mL) and EtOAc (20 mL). The organic phase was separated and was washed sequentially with 1M hydrochloric acid (20 mL), water (2×30 mL) and brine (2×30 mL) and was then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 0-100% [10% MeOH in EtOAc] in isohexane, gradient elution) to afford the title compound, Intermediate B18, as a dark purple solid (165 mg, 82% pure, 24%); Rt 1.55 min (Method 2, acidic); m/z 482 (M+H)+ (ES+). The material was used in subsequent reactions without additional purification.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][CH3:29])[CH3:27])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:16]=1[CH3:37])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][CH3:29])[CH3:27])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:16]=1[CH3:37])#[N:14]
Reactant: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 2.75 h
Yield: 52.2 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (80 μl, 633 μmol) was added at 140 to 150° C. to a dimethyl sulfoxide (10 ml) solution of 4-cyano-N-ethyl-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-285) (178 mg, 528 μmol) and triethylamine (96 μl, 686 μmol), followed by stirring at the same temperature for 165 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under the reduced pressure. The resulting residue was purified by preparative TLC (eluent, dichloromethane:methanol=10:1, v/v) to obtain the entitled compound (119 mg, 52%) as an amorphous substance.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH:13]=O)([CH3:3])[CH3:2].[CH3:15][NH2:16].C(O)C.[BH4-].[Na+]>CO>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:13][NH:16][CH3:15])([CH3:3])[CH3:2]
Reactant: CC(C)c1c(C=O)oc2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CNCc1oc2ccccc2c1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 3-isopropylbenzofuran-2-carbaldehyde (250 mg, 1.33 mmol) in anhydrous methanol (8 mL) is added a solution of n-methylamine in ethanol (0.281 mL, 5.32 mmol) and the reaction is stirred at room temperature overnight under an atmosphere of argon. The solution is then concentrated, and re-solvated in methanol (8 mL) and cooled in an ice bath. Sodium borohydride (0.152 g, 4 mmol) was added portion wise and the reaction was stirred at room temperature under argon for 6 h. The solution is concentrated, and re-solvated in 1.3N NaOH (5 mL) and ether (5 mL) and stirred for 1 h. The ether layer was collected. The aqueous layer was washed with ether (2×10 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica gel, 9:1 DCM:MeOH) yielded the title compound as a yellow oil (228 mg, 85%): 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J=4.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.25-7.16 (m, 2H), 3.75 (s, 2H), 3.15-3.22 (m, 1H), 2.25 (s, 3H), 1.36-1.34 (2s, 6H).
Reaction SMILES: C(N(C[N:7]1[CH2:12][CH2:11][CH2:10][C:9](=[C:13](O)[C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)C1=O)CC)C.[ClH:23]>CC(C)=O.C(O)(C)C>[ClH:23].[ClH:23].[CH3:20][C:18]1[CH:19]=[C:14]([C:13]2[CH2:9][CH2:10][CH2:11][CH2:12][N:7]=2)[CH:15]=[N:16][CH:17]=1
Reactant: CCN(CC)CN1CCCC(=C(O)c2cncc(C)c2)C1=O
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)=O
Product: Cc1cncc(C2=NCCCC2)c1
Temperature: 100 °C
Yield: 85 %

Procedure:
To a solution of diisopropylamine (4.4 mL, 31.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (12 mL, 30 mmol). The solution was allowed to warm to rt over 30 min and was re-cooled to −78° C. A solution of 1-diethylaminomethyl-piperidin-2-one (3.87 g, 21.0 mmol) in tetrahydrofuran (10 mL) was added to the lithium diisopropylamide via syringe. The reaction mixture was maintained at −78° C. for 1 h and was treated with a solution of 5-methylnicotinic acid methyl ester (2.12 g, 14.0 mmol) in tetrahydrofuran (20 mL) via syringe. The reaction mixture was allowed to warm to rt and was maintained overnight. The reaction mixture was quenched with water (30 mL) and was extracted with ether (2 x). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography [1/0 to 1/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] to provide 560 mg (13%) of 1-diethylaminomethyl-3-[hydroxy-(5-methylpyridin-3-yl)methylene]piperidin-2-one. To a solution of the piperidin-2-one (550 mg, 1.8 mmol) in acetone (101 mL) was added conc. hydrochloric acid (2 L) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was allowed to cool to rt, diluted with isopropyl alcohol, and allowed to stand at 0° C. The product was isolated by filtration, thus providing 400 mg (85%) of 5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl dihydrochloride.
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.C1(C)C=CC=CC=1.[CH2:12]([O:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:28]=2)[NH:23]C(=O)[C:21]1=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([O:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:28]=2)[N:23]=[C:1]([Cl:4])[C:21]1=[O:36])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1[nH]c2ccc(-n3ccnc3)cc2n(OCc2ccccc2)c1=O
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1c(Cl)nc2ccc(-n3ccnc3)cc2n1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 20% phosgene in toluene (57 ml; 118 mmol) was added to a stirred solution of 4-benzyloxy-6-(1H-imidazol-1-yl)-quinoxaline-2,3(1H,4H)-dione (9.2 g; 27.5 mmol) in 200 ml dry N,N-dimethylformamide at 0° C. The mixture was stirred at 25° C. overnight and then evaporated in vacuo. The residue was stirred with ice-cooled water and 4N sodium hydroxide was added until pH was about 6 which resulted in the title compound (9.5 g; 98%) as a precipitate. M.p. 140° C. (decomp.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=O.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C.[F:33][C:34]([F:46])([F:45])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=O)=[CH:37][CH:36]=1>C(OCC)(=O)C.O>[C:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:3]3[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=3)[O:1][C:42](=[O:44])[C:41]=2[C:38]2[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:46])[F:45])=[CH:40][CH:39]=2)=[CH:13][CH:14]=1)(=[O:21])[CH3:20]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)c2ccc(O)cc2)c(O)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(-c3ccc(OC(C)=O)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Temperature: 135 °C
Reaction time: 18 h

Procedure:
A mixture of (2-hydroxy-4-methoxyphenyl)-(4-hydroxyphenyl)-methanone (7.33 g, 30.0 mmol), acetic anhydride (15 ml), triethylamine (5.5 ml, 39.5 mmol), and 4-(trifluoromethyl)phenyl acetic acid (4.63 g, 30.0 mmol) was stirred at 135° C. for 18 h, and the resulting orange coloured solution poured into water (120 ml) and stirred for 3 h. The resulting mixture of aqueous solution plus sticky solid was diluted with ethyl acetate (300 ml) to dissolve the solid, and the organic layer separated. The aqueous phase was further extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water, saturated sodium chloride solution, dried over sodium sulfate and evaporated to give a yellow/orange solid, which was recrystallised from 6:1 ethanol/water (350 ml) to give the product as a colourless solid, which was vacuum dried.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: COC(=O)c1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-aminobenzoate (10 g, 66.2 mmol) was dissolved in DCM (100 ml), and pyridine (8.1 ml, 99.2 mmol, 1.5 eq.) was added thereto. A solution of 3,4-dichlorobenzenesulfonyl chloride (24.4 g, 99.2 mmol, 1.5 eq.) in DCM (150 ml) was then added dropwise at 0° C., and the reaction mixture was stirred overnight at room temperature. TLC monitoring (silica gel, DCM) showed complete conversion. When the reaction was complete, the reaction solution was diluted with DCM (250 ml) and washed with 0.5 M KHSO4 (500 ml), saturated NaHCO3 (500 ml) and saturated NaCl solution (500 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. For purification, filtration over a thin layer of silica gel was carried out (gradient: heptane/DCM (3:1) to DCM).