Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1)#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[CH:21][C:22]([CH:25]=[O:26])=[CH:23][CH:24]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccccc1-c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of 53 ml of oxalyl chloride in 2 l of dichloromethane is cooled to -60°. A solution of 88 ml of dimethyl sulfoxide in 150 ml of dichloromethane is added dropwise at this temperature and the mixture is then stirred for 2 minutes. After this, a solution of 117 g of 2'-cyano-4-hydroxymethyl-biphenyl in 1 l of dichloromethane is added dropwise at -60°. After the addition has ended (after about 5 minutes), the mixture is stirred for 15 minutes. After this, 390 ml of triethylamine are added dropwise. The mixture is stirred at -60° for 2 minutes, then allowed to warm to room temperature and poured onto water. The mixture is extracted with dichloromethane, and the organic phase is washed in succession with dilute hydrochloric acid and brine, dried and concentrated. The residue is suspended in hexane, the suspension is filtered with suction, the filter cake is washed, and the product thus obtained is dried at 60° in a high vacuum (elemental analysis: 80.7% C; 4.5% H; 6.7% N; 7.7% O).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:15]=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:25][CH2:26][C@@:27]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(#N)C>[CH3:37][C@@:27]([S:33]([CH3:36])(=[O:34])=[O:35])([CH2:26][CH2:25][N:1]1[CH:5]=[C:4]([C:6]2[CH:15]=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH:3]=[N:2]1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: c1ccc2nc(-c3cn[nH]c3)cnc2c1
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)[C@@](C)(CCn1cc(-c2cnc3ccccc3n2)cn1)S(C)(=O)=O
Temperature: 50 °C
Yield: 13.9 %

Procedure:
To a solution of 2-(1H-pyrazol-4-yl)quinoxaline (0.400 g, 1.39 mmol) in acetonitrile (10 mL) was added cesium carbonate (8.73 g, 2.68 mmol, 2.5 eq), sodium iodide (0.032 g, 0.214 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.400 g 1.39 mmol, 1.3 eq). The reaction mixture was heated at 50° C. overnight. The reaction was filtered over a pad of diatomateous earth. The filtrate was evaporated and the crude was purified by flash chromatography on silica gel eluting with 40-100% ethyl acetate/heptane to give ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(quinoxalin-2-yl)-1H-pyrazol-1-yl]butanoate (0.078 g, 14% yield) as a colorless oil. LC-MS M+H+403.1.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][C@H:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:6]([C:16]([O:18]CC3C=CC=CC=3)=[O:17])[N:5](C(OCC3C=CC=CC=3)=O)[CH2:4]2)[CH2:2]1.[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:12]([O:11][C:9]([C@H:7]1[CH2:8][C:3]2([CH2:1][CH2:2]2)[CH2:4][NH:5][C@@H:6]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)O
Yield: 99.6 %

Procedure:
5,6-dibenzyl 7-tert-butyl (6S,7S)-5-azaspiro[2.5]octane-5,6,7-tricarboxylate (2.0 g) was hydrogenated in methanol (100 mL) with 5% Pd—BaSO4 (750 mg) under a hydrogen atmosphere (hydrogen-balloon) at RT. The catalyst was removed by filtration. The filtrate was concentrated. The residue was dried under reduced pressure to produce (6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid (1.06 g). MS (ESI): 256.1 (M+H+); 200.1 (M+H+-t-Bu).
Reaction SMILES: [OH:1][C:2]1[C:3]([F:16])=[C:4]([C:13]([OH:15])=[O:14])[C:5](=[C:9]([F:12])[C:10]=1[F:11])C(O)=O.Cl>>[OH:1][C:2]1[C:3]([F:16])=[C:4]([CH:5]=[C:9]([F:12])[C:10]=1[F:11])[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1c(F)c(O)c(F)c(F)c1C(=O)O
Agent: Cl
Product: O=C(O)c1cc(F)c(F)c(O)c1F
Yield: 96.1 %

Procedure:
The procedure as described in Example 1 is followed, but only 9 g of a mixture of various aliphatic trialkylamines each having 6 to 14 carbon atoms in the alkyl radical (Hostarex A 327; a commercial product of Hoechst AG) and 518 g of an aqueous solution which contains 29.8 g (0.126 mol) of 4-hydroxy-3,5,6-trifluorophthalic acid in the form of corresponding alkali metal salts are used and, with addition of in total 158.3 g of 30% strength aqueous hydrochloric acid, likewise in 6 hours, 23.25 g (95.9% of theory) of 3-hydroxy-2,4,5-trifluorobenzoic acid are obtained.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=S)[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:23][CH3:24])/[N:7]([CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:39]#[C:40][NH2:41]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:23][CH3:24])=[N:41][C:40]#[N:39])/[N:7]([CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CN
Reactant: CCOc1ccc(C(F)(F)F)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(F)(F)F)cc1C(=NC#N)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Yield: 309.1 %

Procedure:
The product of Example 36C (0.26 g, 0.55 mmol), triethylamine (0.21 mL, 1.5 mmol), cyanamide (50 mg, 1.1 mmol) and Hg(OAc)2 (0.23 g, 0.71 mmol) in acetonitrile (10 mL) were processed as described in Example 16E to provide the title compound (0.84 g, 1.7 mmol, 85% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (s, 9H), 1.49 (t, J=6.8 Hz, 3H), 1.56-1.66 (m, 1H), 1.77-1.95 (m, 2H), 1.98-2.12 (m, 1H), 3.73-3.89 (m, 2H), 4.13-4.28 (m, 4H), 4.40-4.52 (m, 1H), 7.01 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 7.58-7.66 (m, 2H); MS (DCI/NH3) m/z 481 (M+H)+. Anal. calculated for C23H27F3N4O2S: C, 57.49; H, 5.66; N, 11.66. Found: C, 57.38; H, 5.59; N, 11.60.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[N:4]=[C:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][CH:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=Nc1ccccc1Cl)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(Nc1ccccc1Cl)c1ccccc1

Procedure:
o-Chloro-N-(α-methyl benzylidene) aniline (XXI) (15 g) prepared by the procedure described in example XXVIIIA was hydrogenated using 5% Pd/C as the catalyst and 95% ethanol as the solvent. o-Chloro-N-(α-methyl benzyl) aniline (XXII) was obtained by fractional distillation. XXII had a boiling point of 134° C. at 1.2 millimeter.
Reaction SMILES: [CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:17])([CH3:16])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[Cl:27][C:28](OC(Cl)(Cl)Cl)=[O:29]>ClCCl>[CH2:1]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([CH3:16])([CH3:17])[N:7]([C:28]([Cl:27])=[O:29])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC1=NNC(C)(C)C1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC1=NN(C(=O)Cl)C(C)(C)C1c1ccccc1
Yield: 43 %

Procedure:
To a magnetically stirred solution of 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate (IV-1) (0.47 gram, 1.43 mmol) in dichloromethane (10 ml) was successively added DIPEA (0.35 ml, 2.07 mmol) and trichloromethyl chloroformate (0.25 ml, 2.07 mmol, dissolved in 10 ml dichloromethane) at 0° C. and the resulting solution was allowed to attain room temperature and subsequently reacted at room temperature for 1 hour in a nitrogen atmosphere. Subsequent Sepacore column chromatographic purification (eluant: petroleum ether/diethyl ether=93/7 (v/v)) gave pure 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-(1H)-pyrazole-1-carbonyl chloride (Intermediate VIII-1) (0.20 g, 43% yield). (Intermediate VIII-1). 1H-NMR (400 MHz, CDCl3) δ 0.87 (t, J=7, 3H), 1.11 (s, 3H), 1.27-1.39 (m, 2H), 1.45-1.59 (m, 5H), 2.10-2.20 (m, 1H), 2.36-2.46 (m, 1H), 3.91 (s, 1H), 7.01 (br d, J˜8 Hz, 2H), 7.30-7.40 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[C:6](=[O:13])[CH:5]=[C:4]([Cl:14])[N:3]=1.[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CN(C=O)C>[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[C:6](=[O:13])[CH:5]=[C:4]([Cl:14])[N:3]=2)[CH2:24][CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COCCCn1c(Cl)nc(Cl)cc1=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)cc1=O
Yield: 74.2 %

Procedure:
A solution of 2,6-dichloro-3-(3-methoxy-propyl)-3H-pyrimidin-4-one (400 mg, 1.68 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (405 mg, 2 mmol) and DIEA (260 mg, 2.0 mmol) in DMF (20 mL) was stirred at 85° C. for 2 h. The solvent was concentrated, and the residue was purified by silica chromatography to give 500 mg of the title compound (75%). [M+H] Calc'd for C18H29ClN4O4, 400. Found, 400.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (450 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (136 mg).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5](=[CH2:19])[CH2:6][NH:7][C:8]1[NH:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH:24]=O.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH:3][CH2:4][C:5](=[CH2:19])[CH2:6][NH:7][C:8]1[NH:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: C=C(CN)CNc1cc(=O)c2ccccc2[nH]1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Product: C=C(CNCc1ccc(Cl)c(Cl)c1)CNc1cc(=O)c2ccccc2[nH]1

Procedure:
The title compound was prepared according to the method described in Example 23(b) from 2-(2-aminomethylallylamino)-1H-quinolin-4-one dihydrochloride (85 mg, 0.28 mmol), 3,4-dichlorobenzaldehyde (50 mg, 0.29 mmol), sodium acetate (47 mg, 0.58 mmol) and sodium cyanoborohydride (18 mg, 0.29 mmol). The crude product was purified by silica gel chromatography eluting with dichloromethane and increasing concentrations of methanol containing 10% concentrated aqueous ammonia to yield a white solid. δH (CD3OD) 3.21(2H, s), 3.66(2H, s), 3.89(2H, s), 5.07(2H, d, J=8.41 Hz), 5.55(1H, s), 7.1-7.2(3H, m), 7.33(1H, d, J=8.2 Hz), 7.4-7.5(2H, m), 7.97(1H, d, J=8.75); MS (ES+) 388 (100%) MH+.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([OH:11])=O>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:4][CH2:2][CH3:3])=[O:11]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc(F)c(Cl)c1
Yield: 77 %

Procedure:
Using ethanamine hydrochloride and 3-chloro-4-fluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (77% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 3.28 (qd, J=7.16, 5.56 Hz, 2 H) 7.53 (t, J=8.84 Hz, 1 H) 7.87 (ddd, J=8.72, 4.80, 2.15 Hz, 1 H) 8.06 (dd, J=7.33, 2.27 Hz, 1 H) 8.61 (t, J=4.67 Hz, 1 H). ESI-MS: m/z 202.0 (M+H)+. mp=101.7-101.8° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([F:20])=[CH:18][C:17]([Br:21])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([F:20])=[CH:18][C:17]([Br:21])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:25][CH2:22][CH2:23][CH3:24])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Br)cc(F)c3o2)c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)cc(F)c2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-bromo-7-fluorobenzoxazole (284 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH:38]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]3)[CH:37]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].O1CCOCC1.O>[C:45]([O:44][C:42]([N:40]1[CH2:41][CH:38]([N:36]2[CH:37]=[C:33]([C:2]3[C:3]([O:17][C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]4)[CH:34]=[N:35]2)[CH2:39]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: COC(=O)N1c2ccc(Br)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 71.9 %

Procedure:
A mixture of methyl (S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.100 g, 0.254 mmol), tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.106 g, 0.304 mmol), XPhos Precatalyst 2nd Generation (0.004 g, 0.005 mmol), and cesium carbonate (0.246 g, 0.761 mmol) in 1,4-dioxane (2.0 mL) and water (0.40 mL) was heated at 100° C. for 16 h. The reaction mixture was filtered through Celite and concentrated to afford a green oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 25-50% ethyl acetate-hexane) to afford methyl (S)-6-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.098 g, 72%) as a colorless oil. MS (ESI, pos. ion) m/z 537 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([O:11][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Cc2ccc(Cl)cc2Cl)nn1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(Cc2ccc(Cl)cc2Cl)nn1)c1ccccc1
Yield: 80.7 %

Procedure:
A solution of 6-(2,4-dichlorobenzyl)-3-pyridazinol (98 mg, 0.38 mmol), N-methyl-N-phenylcarbamoyl chloride (65 mg, 0.38 mmol) and 1,4-diazabicyclo[2.2.2]octane (43 mg, 0.38 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (119 mg, 80% yield) as a yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH:10]([O:12][Si](C(C)(C)C)(C)C)[CH3:11])(=[O:3])[CH3:2]>C(O)(=O)C.O>[C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH:10]([OH:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1C(C)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1C(C)O
Reaction time: 2.5 h
Yield: 24.9 %

Procedure:
Trans-4-acetoxy-3-[1-(tert-butyldimethylsilyloxy)-ethyl]-2-azetidinone (0.20 g) is dissolved in a mixture of acetic acid (5 ml) and water (2 ml), and the solution is stirred at 70°-80° C. for 2.5 hours and then concentrated under reduced pressure. The residue is subjected to silica gel column chromatography to give 0.03 g of trans-4-acetoxy-3-(1-hydroxyethyl)-2-azetidinone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:30]>CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:30])=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C=O)cc2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)O)cc2)c1

Procedure:
To a stirring solution of Methyl 3-(benzyloxy)-5-(4-formylphenoxy)benzoate (30 g) (Intermediate 11) in acetone, Jones reagent was added drop wise at 0° C. until the brown color persists in the reaction mixture. After completion of the reaction mixture was diluted with water and extracted with DCM. All organic layers were combined and washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to get pure white solid (30 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])C)(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:13][NH:14][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: CN(CCc1ccccc1NS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCc1ccccc1NS(C)(=O)=O
Reaction time: 0.83 h
Yield: 51.9 %

Procedure:
At 0° C., trifluoroacetic acid (6 ml) was added to a solution of N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (870 mg, 2.6 mmol) in dichloromethane (6 ml). The reaction mixture was stirred for 50 min. Dichloromethane (24 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (34 ml) was added. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash crhomatography on silica (60 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent to give 308 mg of N-(2-(2-(methylamino)ethyl)phenyl)methanesulfonamide.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2=[C:9](C(O)=O)[S:10][C:11](C(O)=O)=[C:6]2[O:5][CH2:4]1.C(OCC)(=O)C>CN(C)C(=O)C.N1C2C(=CC=CC=2)C=CC=1>[O:8]1[CH:3]([CH2:2][OH:1])[CH2:4][O:5][C:6]2=[CH:11][S:10][CH:9]=[C:7]12
Reactant: O=C(O)c1sc(C(=O)O)c2c1OCC(CO)O2
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: OCC1COc2cscc2O1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
2-Hydroxymethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid (48 g, 0.184 mol) was dissolved in N,N-dimethylacetamide (500 mL), and Cu2Cr2O7 (8.6 g) and quinoline (15 drops) were added. This mixture was subsequently stirred for 2 hours at 150° C., after which it was cooled to 25° C. It was then poured into ethyl acetate, the catalyst was removed by filtration and the filtrate was washed with acidic water and an aqueous saturated sodium chloride solution. Subsequently, the solvent was removed after which pure (2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol was isolated by vacuum distillation (115–120° C.; 0.05 mm Hg).
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]1[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][N:13]=1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:14]1[CH:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[N:13]=1
Reactant: COc1nccnc1OC
Reactant: NC(=O)CCC(=O)NBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Br)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
A solution of 14.6 gm of N-bromosuccinamide, 32 ml of dry DMF was added to a stirred solution of 11 gm (0.078 mol) of 2,3-dimethoxypyrazine in 14 ml of DMF at 0° C. whereupon the reaction was warmed to 25° C. and stirred for 16 hours. The reaction mixture was then cooled in an ice bath and to it was added aqueous Na2SO3 to remove the bromine and this was poured into ice water. The resulting crystalline solid was filtered, triturated with water and dried to give 10.48 gm of the title compound. NMR (CDCl3)δ4.0, 4.02(2s, 6H, OCH3), 7.70(s,1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:6]1=2)=[O:4].Cl.[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:20]=1)=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[C:6]2[C:7](=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:9][N:10]1[CH2:17][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:23][CH:24]=1)=[O:4]
Reactant: COC(=O)C1NCCc2cc(O)ccc21
Reactant: CC(=O)N[C@@H](C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1c2ccc(O)cc2CCN1Cc1ccc([C@H](C)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 200 mg (0.821 mmol) 7-hydroxy-1,2,3,4-tetrahydro-3-isoquinoline-4-carboxylic acid methyl ester hydrochloride and 157 mg (0.821 mmol) (S)—N-(1-(4-formylphenyl) ethyl) acetamide (example III) in 5 mL THF are added 141 μL (2.46 mmol) AcOH and the mixture is stirred at r.t. for 10 min. After that time, the resulting mixture is cooled to 0° C., 261 mg (1.23 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by addition of 500 μL water and purified by HPLC (ACN/H2O/NH3).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:11]1[C:2]([F:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1F
Yield: 41.4 %

Procedure:
To a mixture of methyl 2-fluoro-3-methylbenzoate (1.5 g, 8.9 mmol) and N-bromosuccinimide (1.67 g, 9.4 mmol) was added carbon tetrachloride (24 mL) and benzoyl peroxide (5 mg), and the mixture was heated at reflux for 16 h. The reaction mixture was cooled, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 5:95 to 60:40 EtOAc/hexanes) afforded methyl 3-bromomethyl-2-fluorobenzoate as a light yellow solid (0.91 g, 41%): 1H NMR (300 MHz, CDCl3) δ 7.93-7.88 (m, 1H), 7.61-7.56 (m, 1H), 7.20 (t, J=8 Hz, 1H), 4.53 (d, J=3 Hz, 2H), 3.94 (s, 3H).