Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1>C(O)CCC>[Cl:13][C:14]1[N:15]=[N:16][C:17]([NH:10][CH:5]2[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Solvent: CCCCO
Product: CN1C(C)(C)CC(Nc2ccc(Cl)nn2)CC1(C)C
Temperature: 120 °C

Procedure:
A mixture of 1,2,2,6,6-pentamethylpiperidin-4-amine (14.2 g, 83 mmol) and 3,6-dichloropyridazine (6.2 g, 41.6 mmol) in n-butanol (10 mL) was heated at 120° C. for 120 min. The crude material solidified and was re-suspended in n-butanol (15 mL) and heated at 120° C. for 1 h. This crude material was combined with batch 1 for workup and purification. Water and CH2Cl2 were added to the combined crude material and the organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated. The crude material was recyrstallized from CH3CN (400 mL) to give 6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-5 (15.5 g, first crop). Recrystallization was repeated using CH3CN to give a 2nd crop of 6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine Intermediate 1-5 (3.98 g). LCMS Rt=1.10 min (condition B); MS (M+1)=283.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.15 (d, J=9.3 Hz, 1H), 6.65 (d, J=9.3 Hz, 1H), 4.70 (d, J=7.3 Hz, 1H), 4.08-4.26 (m, 1H), 2.31 (s, 3H), 1.89-2.09 (m, 2H), 1.42 (apparent t, J=12.1 Hz, 2H), 1.21 (s, 6H), 1.15 (s, 6H).
Reaction SMILES: [OH:1][C@@H:2]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[C-:19]#[N:20].[Na+]>CS(C)=O>[OH:1][C@@H:2]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:3][C:19]#[N:20]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)C(C)(C)C)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)[C@H](O)CC#N
Temperature: 60 °C

Procedure:
To a stirred solution of 4-methyl-benzenesulfonic acid [(2S)-2-hydroxy-3,3-dimethyl-butyl]ester (4.2 g, 14.4 mmol) in dimethylsulfoxide (30 ml) is added sodium cyanide (3.6 g, 71.9 mmol) and the reaction mixture is heated at 60° C. for 16 h. The reaction mixture is poured onto water (100 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (3×50 ml), dried over sodium sulfate and evaporated to dryness affording (3R)-3-hydroxy-4,4-dimethyl-pentanenitrile, which is used in next step without further purification (1.3 g, 10.2 mmol, 71%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinoxalin-2(1H)-one (Intermediate 146, 60 mg crude, 0.20 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol), and sodium triacetoxy borohydride (130 mg, 0.60 mmol) were reacted as described for Example 69 to give the free base of the title compound as an oil. The free base was taken up in isopropanol and treated with 4.0M HCl in dioxane (3 eq). Solvent was removed under reduced pressure to give 28 mg (27% yield) of the bis-hydrochloride salt of the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH3:5].[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:39][CH2:40][CH3:41])[C:33]=1[N:34]1[CH:38]=[N:37][CH:36]=[N:35]1)[CH:29]=O)[CH3:24].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:29][C:28]3[CH:31]=[C:32]([O:39][CH2:40][CH3:41])[C:33]([N:34]4[CH:38]=[N:37][CH:36]=[N:35]4)=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=3)[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)([CH3:5])[CH3:21]
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCNCC2)cc1
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cncn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)(C)C(=O)OC)cc3)CC2)cc(OCC)c1-n1cncn1

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[4-(piperidin-4-ylcarbamoyl)-phenyl]-propionic acid methyl ester (example 60e) was reacted with 3,5-diethoxy-4-[1,2,4]triazol-1-yl-benzaldehyde, sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless oil. MS: 550.2 (MH+).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([SH:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1](=[O:12])([S:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCCCCCCCCCS
Product: CCCCCCC/C=C/C(=O)SCCCCCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-decanethiol as starting materials to give the aimed compound.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]([O:21][CH3:22])=[CH:18][CH:17]=[C:16]([C:23](OC3C=CC([N+]([O-])=O)=CC=3)=[O:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH2:43].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH:43][C:23]([C:16]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:20]=2[C:19]([O:21][CH3:22])=[CH:18][CH:17]=1)=[O:24]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3cc(Cl)ccc3n(Cc3ccccc3)c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(Cl)ccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of 4-Nitrophenyl 9-benzyl-6-chloro-1-methoxy-4-carbazole carboxylate (124 mg, 0.255 mmoles) in dry DMF (3 ml) under nitrogen atmosphere, 3,5-dichloro-4-amino pyridine (41.5 mg, 0.255 mmoles) was added followed by sodium hydride (60% suspension, 16.7 mg, 0.382 mmoles) and the reaction mixture was stirred at room temperature for one hour. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water, dried and purified by column chromatography to give 60 mg of the title compound as an off white solid, m. p: 210-213° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[S:22])[NH2:21])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20](=[S:22])[NH2:21]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=S)[C@H](N)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
((1R)-2-(2-Naphthyl)-1-thiocarbamoylethyl)carbamic acid tert-butylester (0.45 g; 1.36 mmol) was dissolved in methylene chloride (1.5 ml) and trifluoroacetic acid (1.5 ml) was added. The reaction mixture was stirred for 40 min at room temperature. The solvent was removed in vacuo and the residue was dissolved in methylene chloride. Aqueous sodium hydrogencarbonate was added until basic reaction and the aqueous phase was extracted with methylene chloride (3×15 ml). The combined organic phases were dried (MgSO4) and the solvent was removed in vacuo to afford 0.311 g of (2R)-2-amino-3-(2-naphthyl)propionthioamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][C:25]1[C:30](=[O:31])[C:29]([CH3:32])=[C:28]([CH3:33])[C:27](=[O:34])[C:26]=1[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:45]C(=O)C)=[C:40]([CH:44]=1)[C:41](O)=[O:42]>O.C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:26]3[C:27](=[O:34])[C:28]([CH3:33])=[C:29]([CH3:32])[C:30](=[O:31])[C:25]=3[CH3:24])[CH:37]=[CH:38][C:39]=2[OH:45])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccncc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.7 %

Procedure:
4-Aminopyridine (0.103 g, 1.096 mmol), triethylamine (0.111 g, 1.096 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.185 g, 1.096 mmol) were added to a methylene chloride solution (100 ml) of 5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.730 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=95:5) to obtain the titled compound (0.020 g, 0.049 mmol, 7%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccc([N+](=O)[O-])c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
3-Nitroaniline (0.222 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.149 g, 0.301 mmol, 56%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][F:21]>CN(C=O)C>[F:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCCF
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of 3-hydroxy-4-methoxy-benzaldehyde (10.0 g, 66.0 mmol, 1.0 equiv) in anhydrous DMF (40 mL) was added K2CO3 (13.6 g, 99.0 mmol, 1.5 equiv) and 1-bromo-2-fluoro-ethane (9.2 mg, 72.0 mmol, 1.1 equiv) and the mixture stirred at rt for 48 h. The K2CO3 was removed by filtration and the organic phase concentrated under reduced pressure. To the residue was added a sat. solution of NaCl (100 mL) and the solution extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and the product crystallized from a mixture of isopropanol/diethylether to yield 12.69 g (97%) of the title compound. 1H NMR (300 MHz, DMSO): δ 3.89 (s, 3H), 4.24-4.27 (m, 1H), 4.34-4.37 (m, 1H), 4.67-4.70 (m, 1H), 4.83-4.86 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.4 Hz, J=1.9 Hz, 1H), 9.84 (s, 1H). MS (ISP): 198.6 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH3:29][C:30]1([O:33][CH2:32]1)[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[OH:33][C:30]([CH3:32])([CH3:31])[CH2:29][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CC1(C)CO1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)O)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), isobutylene oxide (1.9 mL), potassium carbonate (0.6 g) and N,N-dimethylacetamide (5 mL) was stirred in a sealed tube at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 79%).
Reaction SMILES: [F:1][C:2]1([F:21])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13]/[C:12]/3=[N:17]\C(=O)C)=[CH:10][C:4]=2[O:3]1.CB(O)O.C(O)(=O)C>CCOC(C)=O>[F:21][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13][C:12]3=[NH:17])=[CH:10][C:4]=2[O:3]1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(C)=O)S1
Agent: CB(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)C(=N)S1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
The acetyl-imine (Example 5, 9.37 g, 30.0 mmol) and methylboronic acid (1.796 g, 30.0 mmol) were dissolved into acetic acid (75 mL) and treated with NaBO3 (˜2.45 g, 30.0 mmol). After 40 minutes, more NaBO3 (˜2.45 g, 30.0 mmol) was added while the reaction vessel was in a water bath. More NaBO3 (2.45+g, 30.0 mmol) was added after a total of 80 minutes and again at 120 minutes (600 mg, 7.3 mmol). The mixture was stirred at room temperature overnight, transferred to a larger flask with an EtOAc rinse, and concentrated three times from toluene. The residue was mixed with water and basified with concentrated aqueous NH4OH, and then partitioned into 2:1 EtOAc/hexanes (150 mL). The aqueous phase was separated and extracted three times with more 2:1 EtOAc/hexanes. The combined organic phases were washed with a mixture of water (30 mL), concentrated aqueous NH4OH (5 mL) and brine (5 mL), then dried (Na2SO4), concentrated, and chromatographed on silica (15 to 30 to 50% EtOAc/hexanes) to give the titled compound. 1H NMR (400 MHz, CD3OD) δ ppm 4.77 (2H), 5.16 (1H), 5.32 (1H), 7.19 (1H), 7.23 (1H), 7.46 (1H); MS (ESI) 271 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>ClCCl>[C:20]1([S:26]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.7 %

Procedure:
To a stirred suspension of tert-butyl azetidin-3-ylcarbamate (4.61 g, contaminated with diphenylmethane 1:1, ˜13.39 mmoles) in dichloromethane (150 mL), was added triethylamine (3.73 mL, 26.77 mmoles) and benzenesulfonyl chloride (2.57 mL, 20.08 mmoles). The reaction was stirred at room temperature for ˜4 hours and became a solution. Sat. ammonium chloride was added to the mixture and the aqueous phase was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous magnesium sulphate, filtered and concentrated. The residue was precipitated from dichloromethane/hexanes 1:1 to give the title material (1.073 g, ˜26%) as a solid. The mother liquor was concentrated and the residue was purified on Biotage (0 to 20% acetonitrile in dichloromethane) to afford the title material (2.46 g, ˜58%). 1H NMR 400 MHz CDCl3 δ (ppm): 1.42 (9H, s), 3.60 (2H, br s), 4.06 (2H, dd, J=8.7 and 7.7 Hz), 4.35 (1H, br s), 4.70 (1H, br s), 7.60-7.64 (2H, m), 7.68-7.72 (1H, m), 7.86-7.88 (2H, m).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[CH2:24](N(CC)CC)[CH3:25]>CN(C=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:24][CH3:25])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CC1
Yield: 72 %

Procedure:
A mixture of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.96 g) (3 millimole), iodoethyl (0.94 g) (6 millimole), triethylamine (0.6 g) (6 millimole) and 10 ml DMF was heated to 70° to 80° C. for 2.5 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous Na2SO4 and the solvent was removed. The residue was recrystallized from a mixture of CHCl3 and benzene to obtain 0.75 g (72%) of 1-ethyl-6-fluoro-7-(4-ethyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][NH2:27])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCc1ccc(F)cc1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCc3ccc(F)cc3)cc2F)cn1
Reaction time: 8 h
Yield: 65.1 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 4-fluorophenethylamine (0.234 g, 1.68 mmol) and 3 Å molecular-sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid up in dichloromethane (100 mL) and wash with 1.0 N NaOH (2× 25 mL) to give the title compound (0.383 g, 65%): TOF MS ES+ 385.1 (M+H)+, HRMS calcd for C20H19N4O2F2 385.1476 (M+H)+, found 385.1480, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=11.1 min, 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:28]=[CH:27][C:26](I)=[CH:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])=[CH:4][CH:3]=1.[S:32]1(=[O:38])(=[O:37])[CH2:36][CH2:35][CH2:34][NH:33]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.[Cu]I>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:28]=[CH:27][C:26]([N:33]4[CH2:34][CH2:35][CH2:36][S:32]4(=[O:38])=[O:37])=[CH:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: O=C(NCc1ccc(F)cc1)c1nc2ccc(I)cn2c(=O)c1OCc1ccccc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1nc2ccc(N3CCCS3(=O)=O)cn2c(=O)c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
The product from Example 26.1.2 (100 mg, 0.189 mmol), isothiazolidine 1,1-dioxide (46 mg, 0.378 mmol), copper(I) iodide (4 mg, 0.019 mmol), N,N-dimethylethyl diamine (3 mg, 0.039 mmol) and potassium carbonate (55 mg, 0.378 mmol) were mixed in DMF (4.0 mL) and heated to 80° C. After 2 h, TLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature and poured into aqueous hydrochloric acid (1.0 M, 40 mL. The resulting solid was collected by filtration and washed with water, dried and subjected to column chromatography (dichloromethane/methanol 50:1) to afford the desired product (93 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CC(C)(C)C(=O)Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C(C)(C)C)nc23)CC1
Yield: 48.4 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.067 mL (0.048 mMol) 2,2-dimethylpropanoyl chloride, 0.0067 gm (48%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[OH-].[Na+].C(OCC)(=O)C.CCCCCC.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CSc1ccc(C(=O)C(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
A solution of ethyl 2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetate (12 g, 0.49 mol) in toluene (120 mL, 10 times) was heated to 50° C. 3M NaOH solution (2.23 g, 1.2 eq) was added drop wise at 50° C. and the contents were allowed to reflux for 3 h at 60° C. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.1). On completion of the reaction, toluene was distilled off and the residue obtained was taken in ice cold water. Then the contents were acidified with diluted HCl at 0° C. and allowed to stir for 1 h at room temperature. The precipitate was filtered and dried to yield 2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetic acid as an yellow colored solid (10 g, 93%).