Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][C:24]1([CH3:38])[C:28]([CH3:30])([CH3:29])[O:27][B:26]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[O:25]1.[CH2:39]([N:46]1[CH:51]=[C:50]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[C:49](=[O:59])[C:48]([C:60](O)=[O:61])=[CH:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.O>[CH2:39]([N:46]1[CH:51]=[C:50]([C:52]2[CH:53]=[CH:54][C:55]([F:58])=[CH:56][CH:57]=2)[C:49](=[O:59])[C:48]([C:60]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([B:26]3[O:25][C:24]([CH3:38])([CH3:23])[C:28]([CH3:29])([CH3:30])[O:27]3)=[CH:32][CH:33]=2)=[O:61])=[CH:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)cc(-c2ccc(F)cc2)c1=O
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(NC(=O)c3cn(Cc4ccccc4)cc(-c4ccc(F)cc4)c3=O)cc2)OC1(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
EDC.HCl (152 mg), HOBt (73 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (128 mg) were added to a solution of 1-benzyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (171 mg) in DMF (3 ml) at room temperature. The reaction mixture was stirred at 50° C. overnight. EDC.HCl (76 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (64 mg) were added to the reaction mixture at 50° C. The reaction mixture was stirred at 50° C. overnight. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was returned to room temperature and diluted by adding water. The precipitated solid was collected by filtration. The resulting solid was purified by silica gel column chromatography [hexane:ethyl acetate=5:1->4:1->3:1->1:1 (v/v)] to give 112 mg of the title compound as a solid.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH2:23][CH2:24]Br)=[C:18]3[N:26](C(OC(C)(C)C)=O)[C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:41])[CH:13]=2)(OC(C)(C)C)=O.[OH:42][C:43]1[CH2:47][CH2:46][NH:45][CH:44]=1>>[F:41][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:20]1[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:45]3[CH2:46][CH2:47][CH:43]([OH:42])[CH2:44]3)=[C:18]3[NH:26][C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]2=1
Reactant: OC1=CNCC1
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCBr)c21
Product: OC1CCN(CCCOc2c3[nH]c4ccc(F)cc4c3cc3c2[nH]c2ccc(F)cc23)C1
Reaction time: 8 h
Yield: 90 %

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the staring material is 5,7-diBOC-2,10-difluoro-6-(3-bromopropoxy)indolo[2,3-b]carbazole and the reagent is 3-hydroxypyrroline. The reaction can be completed at room temperature overnight. 1H-NMR (400 MHz, CDCl3) δ ppm 9.57 (br s, 2 H), 8.27 (s, 1 H), 7.71 (dd, J=9.2, 2.4 Hz, 2 H), 7.33 (dd, J=8.8, 4.0 Hz, 2H), 7.03 (td, J=8.8, 2.4 Hz, 2 H), 4.67-4.59 (m, 1 H), 4.40-4.26 (m, 2 H), 3.80 (t, J=5.6 Hz, 1 H), 3.15-3.00 (m, 2 H), 2.96-2.80 (m, 3 H), 2.73-2.61 (m, 1 H), 2.38-2.26 (m, 1 H), 2.12-1.93 (m, 2 H), 1.79-1.70 (m, 1 H); MS (ESI) m/z 434.2 (M−H)−; MS (ESI) m/z 436.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:21](=[O:23])[NH2:22])([CH2:15][C:16](OCC)=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][C:16](=[O:17])[NH:22][C:21]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C[C@@](NC(=O)OC(C)(C)C)(C(N)=O)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)CC(=O)NC1=O
Reaction time: 6 h
Yield: 88.5 %

Procedure:
(R)-diethyl 2-t-butyloxycarbonylamino-2-carbamoylsuccinate (590 mg) obtained in Example 15 was dissolved in acetone (6 mL) and water (6 mL), the solution was added with potassium carbonate (295 mg), the mixture was stirred for 6 hours, 1 mol/L hydrochloric acid was poured to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then recrystallized from ethyl acetate/n-hexane to obtain the title compound (450 mg, yield: 88%) as colorless crystals. Optical rotation [α]D25 was −39.1° (c 0.50, ethanol).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[C:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])=[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]2=[O:1])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2C)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 14.4 %

Procedure:
To a solution of ethyl 4-oxo-2-(o-tolylamino)-4,5-dihydrofuran-3-carboxylate (0.098 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.050 g, 0.34 mmol) in ethanol (2.0 mL), piperidine (0.0034 mL, 0.034 mmol) was added at ambient temperature. The mixture was refluxed for 32 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.019 g, y. 27%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:5][C:6]=1[CH2:7]O.C(N(CC)CC)C.CS([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:7][C:6]1[O:5][C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:3][C:2]=1[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1CCl
Temperature: 25 °C

Procedure:
4.20 g {4-Methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-yl}-methanol were dissolved in 20 ml dichloromethane and cooled in an ice bath. 3.10 ml triethylamine were added, followed by the addition of 1.37 ml methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 4.0 g 5-chloromethyl-4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole as an oil which was used without further purification.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>C1(C)C=CC=C(C)C=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>[C:1]([O:18][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1cccc(C)c1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC
Yield: 129.3 %

Procedure:
128 grams (0.5 mole) of purified palmitic acid (melting point 63° C.) and 203 grams (0.75 mole) of 1-octadecanol were added to 11 grams of toluenesulfonic acid in 130 ml of m-xylene and charged into a Dean-Stark equipped 1-liter round bottom flask. After 6 hours of reflux under nitrogen at a pot temperature of 190° C., 13 ml of water was collected. The solvent and any excess alcohol were stripped under 29 inches of mercury vacuum at 130° C. to give 329 grams of a solid having a melting point of 55° C. The acid number of the product was 0. Infrared spectroscopic analysis showed formation of the ester function.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: Brc1ncccn1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=Cc1ccc(-c2ncccn2)cc1
Yield: 73.3 %

Procedure:
To a degassed suspension of 4-formylphenylboronic acid (100 mg), 2-bromopyrimidine (107 mg) and sodium carbonate (212 mg) in acetonitrile (2 ml)/water (2 ml) was added freshly prepared tetrakis(triphenylphosphine)palladium(0), (40 mg) and the mixture was refluxed under nitrogen, for 20 hrs. The cooled reaction mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with iso-hexane/ethyl acetate (75:25) to afford the sub-title compound as a solid (90 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[N:35][CH:36]=1.O>CN(C=O)C>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:34]1[N:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[CH:32][CH:33]=1
Reactant: COCCOc1ccc(Br)cn1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of N-(4-(4-Hydroxy-2,6-dimethylphenyl)-thiazol-2-yl)isonicotinamide (5-3, 0.98 g, 3.0 mmol) in DMF (10 mL) were added cesium carbonate (1.95 g, 6.0 mmol, 2.0 equiv) and Cu (58.5 mg, 0.90 mmol, 0.3 equiv). The mixture was stirred at 100-110° C. for 1.0 h and added with 5-bromo-2-(2-methoxyethoxy)pyridine (17-2, 1.04 g, 4.5 mmol). The solution heated at 130° C. for 24 h. The reaction mixture was added with water (40 mL) and extracted with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 17 (0.94 g) in 66% yield: 1H NMR (500 MHz, CDCl3) δ 8.81 (d, 2 H), 7.93 (d, 1 H), 7.88 (d, 2 H), 7.32 (m, 1 H), 6.82 (d, 2 H), 6.57 (s, 2 H), 4.45 (t, 2 H), 3.75 (t, 2 H), 3.44 (s, 3 H), 1.99 (s, 6 H), ESI-MS=m/z 477.2 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].Cl>C1COCC1.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][CH:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=1)[C:8]([OH:10])=[O:9]
Reactant: ClCCCBr
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(CCCCl)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of p-tolylacetic acid (1 g) in THF (30 mL) was stirred at −78° C. for 30 minutes. n-Butyl lithium (2.66 M solution in hexane, 5.01 mL) was added to the solution, and the reaction solution was stirred at −78° C. for three hours. Thereafter, the reaction solution was stirred at 0° C. for 30 minutes, 1-bromo-3-chloropropane (0.725 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 24 hours. Thereafter, ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.53 g of the title compound. The property values corresponded to the reported values (CAS #2856-76-0).
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(C(C)C)CC)(C)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[C:38]1([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:47](=[O:48])[CH2:46][CH2:45][CH2:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 132.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.33 g) and diisopropylethylamine (3.2 mL) were added to a solution of N-tert-butoxycarbonylpiperazine (1.13g) and 4-phenylbutyric acid (1.0 g) in dichloromethane (50 mL) at 0° C. After stirring at room temperature for 20 hr, the solvent was evaporated in vacuo. Ethyl acetate and 10% citric acid aqueous solution were added to the residue. The separated organic layer was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate, and evaporated in vacuo to afford the titled compound (2.68 g) as a colorless solid: 1H NMR(400 MHz, CDCl3) δ 1.47(s, 9H), 1.98(t, 2H), 2.32 (t, 2H), 2.68 (t, 2H)3.34-3.59 (m, 8H), and 7.17-7.30 (m, 5H).
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].C(N(C(C)C)CC)(C)C.Br[CH2:50][CH2:51][CH2:52][C:53]#[N:54]>C(#N)C>[C:53]([CH2:52][CH2:51][CH2:50][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])#[N:54]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Reactant: N#CCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NCCCC#N)c3ccccc3)c2=O)c1F
Yield: 93.9 %

Procedure:
Compound 1f (110 mg, 0.2 mmol) was dissolved in acetonitrile (5 mL) and diisopropylethyl amine (52 mg, 0.4 mmol) was added, followed by the addition of 4-bromobutyronitrile (90 mg, 0.6 mmol). The reaction mixture was refluxed for 16 hours. Volatiles were evaporated and the residue was purified by flash chromatography (silica, 5% MeOH/CH2Cl2) to give compound 3a (115 mg, 94% ). MS (CI) m/z 613.3 (MH+).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1CCCCC1.[S:14]1[CH:18]=[CH:17][C:16](C=O)=[CH:15]1.Cl>N1C=CC=CC=1>[S:14]1[CH:18]=[CH:17][C:16](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:15]1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccsc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccsc1
Temperature: 100 °C

Procedure:
46 g of malonic acid and 2 ml of piperidine are added to 25 g of 3-thienaldehyde in solution in 100 ml of pyridine, and the mixture is heated at 100° C. for 4 hours. The reaction medium is cooled to 30° C. and it is poured over an aqueous hydrochloric acid solution (2N). The precipitate formed is filtered and it is rinsed with isopropyl ether to give, after drying, 30 g of a white solid.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:20]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([F:26])=[C:9]([N:7]3[CH2:6][CH2:5][O:4][CH:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:8]3)[C:18]=2[F:19])[C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15]1)[CH3:21]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21
Reactant: C1CCNCC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CN4CCCCC4)C3)c(F)c21

Procedure:
By the use of 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and piperidine, the reaction is similarly carried out as Example 34 to give 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(piperidinomethyl)morpholino]quinoline-3-carboxylic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.Cl[C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24]([OH:26])=[O:25]>CN(C)C=O>[CH2:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1c(F)cccc1NC1CCN(Cc2ccccc2)CC1
Temperature: 140 °C
Yield: 35.8 %

Procedure:
Potassium carbonate (8.9 g), 4-amino-1-benzyl-piperidine (18.5 g), cupric oxide (0.6 g) and dimethylformamide (25 ml) are added to 2-chloro-6-fluorobenzoic acid (11.3 g) and the mixture is reacted with heating at 140° C. for 6 hours. After the reaction, the solvent is concentrated and to the resulting residue are added water (200 ml) and active carbon (1 g). The mixture is refluxed for 30 minutes. After filtration, the filtrate is cooled and then adjusted to pH 8.0 with diluted hydrochloric acid. The precipitated crystal is collected by filtration and washed successively with water and methanol to give 2-(1-benzyl-4-piperidinylamino)-6-fluorobenzoic acid (7.6 g) as white powders, m.p.: 233°-236° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.O=[CH:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:22][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH3:20])[CH2:16][CH2:17]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: O=C1NC[C@H](c2ccc(F)cc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](CN1CCC2(CC1)C(=O)NC[C@@H]2c1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A reaction mixture containing 0.25 g (1.0 mmol) of (R)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one, 0.25 g (1.44 mmol) of the (S)-tert-butyl 1-oxopropan-2-ylcarbamate, 2 mL of THF, 1 mL of DCM, and 1 g (2.5 mmol) of MP-sodium triacetoxyborohydride resin was rotated overnight. The reaction mixture was filtered and the solvents were removed under reduced pressure. The residue was subjected to silica gel chromatography to give 250 mg (61%) of tert-butyl (S)-1-((R)-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)propan-2-ylcarbamate as a colorless oil. 1HNMR (400 MHz, CD3OD) δ ppm 7.35-7.31 (m, 2H), 7.10-7.06 (m, 2H), 3.85 (brs, 1H), 3.73-3.68 (m, 1H), 3.55-3.51 (m, 2H), 3.39-3.27 (m, 1H), 3.10-2.87 (m, 2H), 2.78-2.59 (m, 3H), 2.01-1.72 (m, 5H), 1.42 (s, 9H), 1.32-1.20 (m, 1H), and 1.11 (d, 3H, J=2.4 Hz); LCMS m/z: 406.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7](=[S:27])[NH:8][C:9]1[S:19][C:12]2[CH2:13][O:14][C:15]([CH3:18])([CH3:17])[CH2:16][C:11]=2[C:10]=1[C:20]([O:22]C(C)(C)C)=[O:21])=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7](=[S:27])[NH:8][C:9]1[S:19][C:12]2[CH2:13][O:14][C:15]([CH3:17])([CH3:18])[CH2:16][C:11]=2[C:10]=1[C:20]([OH:22])=[O:21])=[O:5]
Reactant: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2F)sc2c1CC(C)(C)OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Cc2c(sc(NC(=S)NC(=O)c3ccccc3F)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To tert-butyl 2-(3-(2-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (36 mg, 0.077 mmol) was added a solution of 2,2,2-trifluoroacetic acid (0.75 mL, 9.76 mmol) in CH2Cl2 (1.1 mL) [40% v/v] and the mixture stirred at RT for 1 h. The solvent was evaporated in vacuo and the residue chromatographed using reversed-phase MPLC (0-100% ACN—H2O; 40 g C18 column) to yield 2-(3-(2-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (10.5 mg, 0.026 mmol, 33% yield) as a pale yellow solid. 1H NMR (500 MHz, DMSO) δ 14.70 (s, 1H), 11.94 (s, 1H), 7.72 (apparent d, J=7.3, 1H), 7.65 (s, 1H), 7.38-7.32 (m, 2H), 4.65 (s, 2H), 2.73 (s, 2H), 1.22 (s, 6H). 13C NMR (126 MHz, DMSO) δ 173.69, 165.48, 163.91, 160.34, 158.35, 146.81, 134.19, 134.12, 130.50, 129.19, 124.64, 124.61, 124.24, 122.28, 122.17, 116.60, 116.32, 116.14, 70.20, 58.87, 37.32, 26.23. LCMS retention time: 3.275 min; LCMS purity at 214 nm=99.6%. HRMS m/z calculated for C18H18FN2O4S2 [M++1]: 409.0687. found 409.0687. Melting point 202.8° C., decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccncc1
Temperature: 0 °C

Procedure:
A suspension of 4-aminopyridine (0.96 g) in dry dichloromethane (10 mL) under nitrogen was cooled to 0° C. in an ice bath. Triethylamine (1.56 mL) was added, followed by the slow addition of chloroacetyl chloride (0.89 mL). The ice bath was removed and the reaction mixture allowed to reach room temperature. The reaction mixture was diluted with water (20 mL) and dichloromethane (25 mL). The solid was filtered off, washed with pentane and dried to give the title compound as a brown solid (0.87 g). The layers of the filtrate were separated and the organic layer was washed with water, dried and the solvent was evaporated to give a dark brown glass. Trituration with pentane gave another batch of the title compound (0.91 g).
Reaction SMILES: N(OC(C)(C)C)=O.[C:8]([Cu])#[N:9].[Br:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](N)=[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=2)[CH:13]=1.Cl>CS(C)=O>[Br:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:8]#[N:9])=[C:14]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=2)[CH:13]=1
Reactant: CCc1ccc(Cc2cc(Br)c(OC)cc2N)cc1
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CS(C)=O
Product: CCc1ccc(Cc2cc(Br)c(OC)cc2C#N)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Tert-butyl nitrite (1.1 mL) is added to a 60° C.-warm solution of CuCN (0.36 g) in DMSO (3 mL). Then, a solution of 4-bromo-2-(4-ethyl-benzyl)-5-methoxy-phenylamine (1.0 g) in DMSO is added dropwise and the resulting solution is stirred for 1 h at 60° C. After cooling to room temperature, the solution is acidified by the addition of 5 N aqueous hydrochloric acid. The resulting mixture is extracted with ethyl acetate and the combined extracts are dried (Na2SO4). After removal of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/dichloromethane 3:1->1:3) to give the title compound.