Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[CH2:22](Br)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccccc2)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (1 g), phenethyl bromide (0.-67 g), anhydrous potassium carbonate (1.5 g) and acetonitrile (25 ml) was heated under reflux for 4 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (3×30 ml)--. The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.72 g, m.p. 134°-138° C., [α]D25 +13.3° (C 1.0, CH2Cl2).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][CH:11]1[CH2:16][O:15][CH2:14][CH:13]([CH3:17])[NH:12]1>>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[CH:13]([CH3:17])[CH2:14][O:15][CH2:16][CH:11]2[CH3:10])[N:7]=1
Reactant: CC1COCC(C)N1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: CC1COCC(C)N1c1nc(Cl)nc(Cl)n1
Yield: 35 %

Procedure:
The title compound was prepared by following the procedure of Example 462 step 3 using cyanuric chloride and 3,5-dimethylmorpholine. Yield 5 g, 35% yield.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[N:30]1([C:36]2[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:40]3[CH:39]=[CH:38][N:37]=[C:36]([N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[CH:41]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccnc(N2CCNCC2)c1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCNCC4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (106.5 mg, 0.214 mmol), 2-(1-piperazinyl)-pyridine-4-boronic acid, pinacol ester (93 mg, 0.322 mmol), Pd(PPh3)4 (25 mg, 0.02147 mmol) and 2M potassium carbonate (0.321 mL, 0.642 mmol) in anhydrous dioxane (1.0 mL) was sparged with nitrogen for 5 minutes, then heated in microwave for 1 h at 100° C. Reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO4), filtered, concentrated and used in next step without further purification. LCMS-ESI+: calc'd for C36H36ClN4O3S: 579.2 (M+H+); Found: 579.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.O>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.8 %

Procedure:
To a solution of 6-chloro-3-pyridinecarboxylic acid (10 g, 63.5 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (11.3 g, 69.8 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled and monoethyl malonate magnesium salt (10 g, 34.9 mmol) was added. The mixture was stirred at room temperature for 30 min. To the reaction solution was added water (200 ml) and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(6-chloro-3-pyridyl)-3-oxopropionate (9.28 g, 64%) as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl.NCCCCNC(=O)OC(C)(C)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
A solution of 6-benzyloxy-4-chloro-3-nitroquinoline (14.47 g, 46.29 mmol), prepared in Parts A-D of Example 57, and triethylamine (8.4 mL, 60.2 mmol) in dichloromethane (200 mL) was cooled to 0° C. tert-Butyl N-(4-aminobutyl)carbamate (8.71 g, 46.3 mmol) was added; the reaction was stirred for 15 minutes at 0° C. and then allowed to warm to ambient temperature and stirred for five hours. An analysis by TLC indicated the presence of starting material; therefore, additional tert-butyl N-(4-aminobutyl)carbamate (0.5 mL, 2.6 mmol) was added. The reaction was stirred overnight and then washed with water (2×200 mL). The combined washings were extracted with chloroform after the addition of sodium chloride. The combined organic solutions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate (100 mL). The crystals were isolated by filtration and washed with cold hexanes to provide 17.62 g of tert-butyl [4-(6-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate as an orange powder.
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.O>C(O)C>[Cl:1][CH:2]([Cl:17])[C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)[N:24]([C:23]2[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=2)[N:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(C(=O)CC(=O)C(Cl)Cl)cc1F
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc(C(Cl)Cl)nn2-c2ccc(S(N)(=O)=O)cc2)cc1F
Yield: 63 %

Procedure:
4,4-Dichloro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from Step (2 (2.8 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours. The mixture was cooled and water was added until crystals slowly appeared. Filtration yielded a light tan solid (2.7 g, 63%): mp 190-193°C.; 1HNMR (DMSO-d6) 7.84 (d, J=8.4 Hz, 2H), 7.53 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.47 (brs, 2H), 7.3-7.0 (m, 3H), 6.95 (s, 1H), 3.85 (s, 3H). Anal. Calc'd for C17H14N3SO3FCl2: C, 47.45; H, 3.28; N, 9.76. Found: C, 47.68; H, 3.42; N, 10.04.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Br:6][C:7]1[C:8]([O:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])=[CH:9][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[N:11][CH:12]=1.C(N(CC)CC)C>C(O)C>[Br:6][C:7]1[C:8]([O:17][C:18]2[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=2[F:24])=[CH:9][C:10]([NH:13][C:14]2[S:15][CH:2]=[C:3]([CH3:4])[N:16]=2)=[N:11][CH:12]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)Nc1cc(Oc2c(F)cccc2F)c(Br)cn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1

Procedure:
A mixture of 1-chloropropan-2-one (1.01 g, 11 mmol), 1-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)thiourea (3.24 g, 9.0 mmol), triethylamine (1.41 g, 14 mmol) and ethanol (15 mL) is heated at reflux for 16 hours. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried and concentrated. The residue is purified via chromatography to afford N-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CO.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>[F:9][C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Reactant: Nc1cnc(Br)cn1
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: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
5-[2-Fluoro-4-(methylsulfonyl)phenyl]-2-pyrazinamine (0.30 g, 50%) was prepared as a yellowish brown solid from 2-amino-5-bromopyrazine (0.4 g, 2.23 mmol), [2-fluoro-4-(methylsulfonyl)phenyl]boronic acid (0.50 g, 2.23 mmol), 2M Na2CO3 (4 mL), Pd(PPh3)4 (52 mg, 0.05 mmol) in 1,4-dioxane (8 mL) and MeOH (4 mL) in a manner similar to Example 145, Step 1. The crude product was triturated with CH2Cl2 to give 5-[2-fluoro-4-(methylsulfonyl)phenyl]-2-pyrazinamine as a yellowish brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 8.11 (t, 1H, J=8.0 Hz), 8.01 (s, 1H), 7.85-7.75 (m, 2H), 6.91 (s, 2H), 3.26 (s, 3H); LRMS (ESI), m/z 268 (M+H).
Reaction SMILES: Cl.[NH:2]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)C[C@H]1C(OCC1C=CC=CC=1)=O.[CH3:21][OH:22]>[Pd]>[NH2:2][C@H:10]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[CH2:21][OH:22]
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: N[C@H]1CCCC[C@@H]1CO

Procedure:
In yet another embodiment, (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride salt (3), is produced using a starting material of crystalline ((1S,2S)-2-(S)-1-phenylethylamino)cyclohexyl)methanol (11). The first step of the process involves reaction with a catalyst including palladium on carbon in the presence of methanol to produce ((1S,2S)-2-aminocyclohexyl)methanol (17). Compound (17) is subjected to treatment with sodium cyanide in the presence of formaldehyde to produce compound (18). Subsequently, compound (18) is first reacted with trimethylsilyl chloride, and then the product of that reaction is treated with benzyl chloride to produce compound (19). Further, compound (19) is subjected to three sequential reactions to produce compound (20) as illustrated in FIG. 3. Specifically, compound (19) is first subjected to treatment with hydrochloric acid. Subsequently, methanesulfonyl chloride is added to the reaction mixture. Thereafter, potassium hydroxide is added to the reaction to produce compound (20). After compound (20) is produced, the compound is treated with aqueous mineral acid to produce the hydrochloride salt of compound (5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[F:17])(=[O:26])=[O:25])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1F

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 2-fluoro-benzenesulfonyl chloride. 1H NMR (CDCl3): δ (ppm): 6.88-6.93 (m, 1H), 7.16-7.20 (m, 1H), 7.38 (d, J=6.4 Hz, 1H), 7.41-7.46 (m, 4H), 7.52 (m, 2H), 7.58-7.62 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.81-7.85 (m, 1H), 10.10 (s, 1H). MS: m/z 390.0 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[S:17](Cl)([CH3:20])(=[O:19])=[O:18]>C(Cl)Cl>[CH3:20][S:17]([O:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[NH:8]1)(=[O:19])=[O:18]
Reactant: O=C1CCCC(CO)N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-(Hydroxymethyl)piperidin-2-one (1.0 g, 7.8 mmol) and Et3N (1.1 ml, 7.8 mmol) in DCM (5 ml) was added into mesyl chloride (0.88 g, 7.8 mmol) in DCM (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 15 mins. The reaction mixture was washed with 1 N HCl (20 ml) and brine (40 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (6-oxopiperidin-2-yl)methyl methanesulfonate which was used in the next step without additional purification. Yield (quant.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[CH:11]([CH3:13])[OH:12].S(C1C=CC(C)=CC=1)([O-])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([O:12][CH:11]([CH3:13])[C:10]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)O
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
12.2 g of 4-hydroxybenzaldehyde, 30 g of (-)-ethyl lactate-tosylate ([α]D25 =-34.2°, optical purity: 96%), 20 g of potassium carbonate and 100 g of acetonitrile, were mixed, and the mixture was refluxed for 5 hours and then cooled to room temperature. The reaction mixture was treated in the same manner as in Reference Example 3, whereby 20.0 g of (+)-ethyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg. [α]D25 =+51.5°, optical purity: 93%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH2:10]([N:17]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1cc(O)cc(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-hydroxy-6-methyl-2-pyrone (0.2 mol, 25.2 g) and benzylamine (0.2 mol, 21.4 g) were added to water (800 mL) and heated to reflux with stirring for 2 hours. After cooling to room temperature, a light brown solid was collected by filtration. (33.4 g, 77%): 1H NMR (DMSO-d6/300 MHz) δ: 10.5 (s, 1H), 7.4-7.1 (m, 5H), 5.8-5.6 (m, 2H), 5.2 (s, 2H), 5.1 (s, 2H), 2.2 (s, 3H). ESHRMS m/z 216.100 (M+H, C12H13NO2 requires 216.102).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][CH:8]([F:12])[C:9](O)=[O:10].[CH3:13][C:14]([SH:17])([CH3:16])[CH3:15]>C(#N)C.[Co](Cl)Cl>[F:7][CH:8]([F:12])[C:9](=[O:10])[S:17][C:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)S
Reactant: O=C(O)C(F)F
Agent: Cl[Co]Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Product: CC(C)(C)SC(=O)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a solution of oxaloyl chloride (9.08 mL, 104 mmol) in acetonitrile (ACN) (50 mL) at 25° C. was added dropwise difluoroacetic acid (6.55 mL, 104 mmol). After 3 hours, 2-methyl-2-propanethiol (11.74 mL, 104 mmol) was added dropwise followed by cobalt(II) chloride (10 mg). After being stirred at room temperature for 18 hours, additional 2-methyl-2-propanethiol (4.0 mL, 35.4 mmol) was added. After 2 hours, the solution was poured onto Et2O (500 mL) and washed with saturated NaHCO3 (2×300 mL) and H2O (2×300 mL). The organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure to give a red oil. Vacuum distillation at 30 mm Hg gave S-tert butyl difluoroethane-thioate (8.26 g, 47% yield) as a colorless oil: bp 59-63° C. (30 mm Hg); 1H NMR (CDCl3) δ 1.48 (s, 9H), 5.67 (t, 1H, J=54 Hz); 13C NMR (CDCl3) δ 29.45, 49.32, 108.94 (t, J=255 Hz), 191.23 (t, J=28 Hz); 19F NMR (CDCl3) δ -123.65 (d, J=55 Hz); IR (film, cm-1) 2969, 1684, 1154, 1093, 1064. Anal. Calcd for C6H10F2OS: C, 42.84; H, 5.99. Found: C, 43.06; H, 6.15.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[Zn](CC)[CH2:14][CH3:15]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:14]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])[CH3:15]
Reactant: CC[Zn]CC
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCc1ccc(C(=O)O)cc1OC
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-3-methoxy-benzoic acid (2.49 g, 10.9 mmol) and Pd(dppf)Cl2 (158 mg, 0.216 mmol) were stirred in dioxane (25 mL) and Et2Zn (22 mL, 1M in hexanes, 22 mmol) was added. The reaction mixture was heated at 70° C. for 1 h. The mixture was cooled to room temperature and was quenched with MeOH (1.1 mL). The solution was diluted with ethyl acetate (20 mL) and was washed with 1N HCl (10 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to dryness to give 4-ethyl-3-methoxybenzoic acid. ESI-MS m/z calc. 180.1. found 179.1 (M−1)−; Retention time: 1.77 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(N)CCCCC1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Solvent: NC1CCCCC1
Solvent: O
Product: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2)cc1
Yield: 54 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-fluoro-4-biphenylyl)-4-oxo-butyric acid. Melting point of the cyclohexylamine salt: 175°-177° C. (from water). Yield 54% of theory.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2C=[CH:19][CH:18]=[CH:17]2)=[CH:12][C:11]=1[Cl:21]>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:17]=[CH:18][CH:19]=[C:2]2[CH:1]=[O:5])=[CH:12][C:11]=1[Cl:21]
Reactant: COC(=O)c1ccc(-n2cccc2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cccc2C=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of DMF (0.1 mL) in CH2Cl2 (2 mL) was added dropwise with stirring to a solution of oxalyl chloride (0.2 mL) in CH2Cl2 (16 mL) at −30° C. under N2. The mixture was stirred for 15 min and a solution of 2-chloro-4-(1-pyrrolyl)benzoic acid methyl ester (0.5 g) in DMF (4 mL) was added. The mixture was stirred at that temperature for 3 h and allowed to warm to room temperature. The mixture was stirred overnight and evaporated. The residue was partitioned between EtOAc and 0.2 M NaOAc. The EtOAc layer was separated and the aqueous solution was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 3/1) to yield 2-chloro-4-(2-formyl-1-pyrrolyl)benzoic acid methyl ester (0.41 g). ESMS: 264 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[H-].[Li+].[Cl:43][CH2:44][CH2:45][CH2:46]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:46][CH2:45][CH2:44][Cl:43])[CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: ClCCCI
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.8 g, 1.33 mmol) prepared in example 55b was reacted with LiH (0.5 g, 62.5 mmol) and 1-chloro-3-iodo-propane (3.9 g, 19.1 mmol) in N,N-dimethyl-formamide (20 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-(3-chloro-propyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white form (Yield: 0.43 g, 47.8%).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].P(=O)(O)(O)O.C(O[C:17](=[O:19])[CH3:18])(=O)C>>[CH2:1]([C:3]1[S:4][C:5]([C:17](=[O:19])[CH3:18])=[CH:6][CH:7]=1)[CH3:2]
Reactant: CCc1cccs1
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Product: CCc1ccc(C(C)=O)s1
Temperature: 80 °C
Yield: 76 %

Procedure:
In a 50 ml three-necked flask, 5 g (44.6 mmol, 1 eq) of 2-ethylthiophene are dissolved in 28 ml of acetic anhydride, 0.5 ml of ortho-phosphoric acid are added and the reaction mixture is then heated for 1 hour at 80° C. The acids are evaporated off under reduced pressure, and the oil obtained is then filtered over a silica patch (eluent: 20% ethyl acetate, 80% heptane) after evaporation of the solvents: 5.2 g of 1-(5-ethylthiophen-2-yl)ethanone are obtained in the form of a brown oil. Yield: 76%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:14])O[C:11](=[O:13])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([N:19]2[C:11](=[O:13])[CH:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:9]2=[O:14])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cccc(C2=CC(=O)OC2=O)c1
Solvent: CC(=O)O
Product: Cc1cccc(C2=CC(=O)N(c3cccc(Cl)c3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (3-methylphenyl)-furan-2,5-dione (265 mg, 1.41 mmol) in acetic acid (5 ml) at room temperature was added 3-chloroaniline (149 μl, 1.41 mmol). The reaction mixture was heated to reflux and stirred for 3 hours. The reaction mixture was cooled to room temperature. The precipitate formed was filtered, re-suspended in water (15 ml) and recovered by filtration. The precipitate was washed with water (10 ml), heptane (10 ml) and dried under air suction followed by high vacuum.