Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][NH2:6].C1(C)C=CC=CC=1.[Cl:14][C:15]1[CH:34]=[CH:33][C:18]2[O:19][C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22]3[C:26]([C:17]=2[CH:16]=1)=[CH:25][S:24][C:23]=3[CH2:27][OH:28]>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:14][C:15]1[CH:34]=[CH:33][C:18]2[O:19][C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22]3[C:26]([C:17]=2[CH:16]=1)=[CH:25][S:24][C:23]=3[CH2:27][O:28][CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: OCc1scc2c1-c1ccccc1Oc1ccc(Cl)cc1-2
Reactant: NCCCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: NCCCOCc1scc2c1-c1ccccc1Oc1ccc(Cl)cc1-2
Temperature: 25 °C

Procedure:
To a solution of 3-chloropropylamine-hydrochloride (2.2 mmoles) in 50% sodium hydroxide (3 ml), benzyltriethylammonium chloride (0.3 mmole) and toluene solution of the alcohol 13 (0.22 mmole) were added. The reaction mixture was heated under vigorous stirring and refluxing for 5 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product was isolated.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[NH:20][C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=3[F:28])=[N:11][N:10]=2)[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>ClCCl>[F:28][C:22]1[CH:23]=[C:24]([I:27])[CH:25]=[CH:26][C:21]=1[NH:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:13][C:9]([NH:8][CH2:7][CH:5]([OH:6])[CH2:4][OH:3])=[N:10][N:11]=1
Reactant: CC1(C)OCC(CNc2nnc(-c3ccncc3Nc3ccc(I)cc3F)o2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCC(O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(4-{5-[(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-amino]-[1,3,4]oxadiazol-2-yl}-pyridin-3-yl)-(2-fluoro-4-iodo-phenyl)-amine (100 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL) and TFA (3 mL) was added. The reaction mixture was stirred at RT for 4 hrs. The solvent was evaporated, and the residue was dissolved in Ethyl acetate, and washed with 1N aqueous NaOH. After solvent evaporation a residue was collected and dissolved in methanol. The product crystallized out the methanolic solution and filtered (63 mg). LC/MS (Method A) [6.61 min; 472(M+1)].
Reaction SMILES: Br[CH:2]([CH:13]([CH3:15])[CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.C(O)C.[C:19]([NH2:22])(=[S:21])[CH3:20]>C(OC(=O)C)C>[CH:13]([C:2]1[S:21][C:19]([CH3:20])=[N:22][C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:15])[CH3:14]
Reactant: COc1ccc(C(=O)C(Br)C(C)C)cc1
Reactant: CC(N)=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nc(C)sc2C(C)C)cc1
Reaction time: 22 h
Yield: 51 %

Procedure:
While 77.0 g of 2-bromo-1-(4-methoxy-phenyl)-3-methyl-butan-1-one (4) prepared in Example 2 were added to 200 ml of ethanol and stirred, 42.7 g of thioacetamide were added. Subsequently, the temperature was gradually increased and stirring under reflux was continued for 22 hr. After the reaction was completed, the resultant reaction mixture was added with 300 ml of ethylacetate, and then washed with a saturated aqueous solution of potassium carbonate. The ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, thus obtaining 35.8 g (yield: 51.0%) of a title compound as brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A suspension of 4-(4′-bromo-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (2.636 g, 0.00759 mol) in 6 M HCl was refluxed for 24 hours and cooled to room temperature. The solids were filtered and washed with 1 M HCl. The filter cake was partitioned between ethyl acetate and 1 M sodium hydroxide. The aqueous layer was washed twice with ethyl acetate and filtered to remove particulates. The filtrate was rotary evaporated to remove residual ethyl acetate. The solution was stirred and acidified to pH 2 with concentrated HCl solution. The resulting precipitate was filtered, washed with water, and dried with house vacuum (air bleed) to give 1.97 g of 4-(4′-bromo-biphenyl-4-yl)-4-oxo-butyric acid as a white solid; mp 198-200° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[C:9]([F:10])=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[NH:18][C:19](=[O:30])[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.CO.O.[OH-].[Li+]>O1CCCC1>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([CH2:20][C:19]([NH:18][C:5]3[CH:6]=[C:7]([N:11]4[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]4)[CH:8]=[C:9]([F:10])[C:4]=3[C:3]([OH:31])=[O:2])=[O:30])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: COC(=O)c1c(F)cc(N2CCN(C)CC2)cc1NC(=O)Cc1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN1CCN(c2cc(F)c(C(=O)O)c(NC(=O)Cc3ccc4c(c3)OCO4)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (0.15 g, 0.35 mmol) in a mixture of tetrahydrofuran (10 mL), methanol (1 mL) and water (2 mL), was added lithium hydroxide (0.15 g, 3.49 mmol). The reaction was stirred at room temperature overnight then the solvent was evaporated. The residue was diluted with water and 2 N HCl solution was added until pH 7. The solid precipitated was filtered and washed with water to obtain the 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid crude. 2-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid was suspended in acetic anhydride (3 mL) and the reaction mixture was heated under microwave condition at 130° C. for 10 minutes. The solvent was evaporated to obtain the 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one crude. To a solution of 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one in dry pyridine (3 mL) was added aminoguanidine hydrogencarbonate (0.05 g, 0.39 mmol) and the mixture was heated under microwave condition at 180° C. for 15 minutes. The reaction was cooled at room temperature and diluted with water to induce the precipitation of a brown solid which was washed with a mixture MeOH/H2O 8/2, to afford the title compound (0.07 g, 46% yield).
Reaction SMILES: COC(=O)[CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]2[C:8](=[C:9]([CH3:16])[N:10]([CH3:15])[N:11]=2)[C:7]=1[C:17]([O:19]C)=O.[H-].[Na+].Cl.[OH-].[Na+]>O1CCCC1.CO>[CH3:16][C:9]1[N:10]([CH3:15])[N:11]=[C:12]2[C:8]=1[C:7]1[C:17](=[O:19])[CH2:4][CH2:5][C:6]=1[CH:14]=[CH:13]2
Reactant: COC(=O)CCc1ccc2nn(C)c(C)c2c1C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c2c3c(ccc2nn1C)CCC3=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a suspension of methyl 5-(3-methoxy-3-oxopropyl)-2,3-dimethyl-2H-indazole-4-carboxylate (666 mg, 2.29 mmol) and 60% sodium hydride (183 mg, 4.59 mmol) in tetrahydrofuran (23 mL) was added methanol (1 drop), and the mixture was heated under reflux for 3 hr. The reaction solution was concentrated to dryness to give yellow-brown crystals. The obtained crystals were gradually added to 12M hydrochloric acid (12 mL) heated to 100° C., and the mixture was stirred for 1 hr. The reaction solution was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→70/30) to give the title compound (364 mg, yield 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:10]=[C:4]2[CH:3]=1.[C:17]([O:21][C:22]([N:24]1[C@H:28]([CH2:29][F:30])[C@@H:27]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[O:26][C:25]1([CH3:47])[CH3:46])=[O:23])([CH3:20])([CH3:19])[CH3:18].O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([O:21][C:22]([N:24]1[C@H:28]([CH2:29][F:30])[C@@H:27]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[CH:7]=[CH:6][N:5]4[CH:8]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:10]=[C:4]4[CH:3]=3)=[CH:35][CH:36]=2)[O:26][C:25]1([CH3:47])[CH3:46])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CS(=O)(=O)NCc1cn2ccc(Br)cc2n1
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccn4cc(CNS(C)(=O)=O)nc4c3)cc2)OC1(C)C
Yield: 60.4 %

Procedure:
To the solution of N-(7-Bromo-imidazo[1,2-a]pyridin-2-ylmethyl)-methane sulfonamide (71 mg. 0.233 mmol) and (4S,5R)-4-Fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidine-3-carboxylic acid tert-butyl ester (111 mg, 0.256 mmol) in dimethoxyethane:water (2.2 mL:0.5 mL) in a microwave tube is added Na2CO3 (62 mg, 0.583 mmol) at room temperature. The resulting reaction mixture is degassed with nitrogen for 30 minutes then added Pd(PPh3)2Cl2 (9 mg, 0.0116 mmol) and heated in microwave at 120° C. for 2 hours. The solvent is evaporated and purified by flash column chromatography eluting in 2% methanol in CH2Cl2 to afford the title compound (75 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 1.44 (s, 9H), 1.51 (s, 3H), 1.64 (s, 3H), 2.92 (s, 3H), 3.83-3.89 (m, 1H), 4.28 (d, J=6.12 Hz, 2H), 4.45-4.55 (m, 1H), 4.65-4.75 (m, 1H), 5.13 (d, J=7.2 Hz, 1H), 7.27-7.29 (dd, J1=1.6 Hz, J2=7.20 Hz, 1H), 7.56-7.58 (m, 3H), 7.82-7.88 (m, 4H), 8.61 (d, J=7.2 Hz, 1H). LC-MS (m/z): [M+H]=533.1.
Reaction SMILES: CC[Mg+].[Br-].Br[C:6]1[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=1.CON(C)[C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=1>C(Cl)Cl>[CH3:11][N:10]1[C:6]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[O:26])=[CH:7][N:8]=[CH:9]1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(C)c1
Reactant: Cn1cncc1Br
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cc(C(=O)c2cncn2C)ccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of EtMgBr (3.0 M in diethylether, 15.1 mL, 45.2 mmol) was added dropwise, to a solution of 5-bromo-1-methyl-1H-imidazole (7.28 g, 45.2 mmol) in dry DCM (40 mL) at 0° C. and stirred for 10 minutes. The mixture was then stirred at room temperature for 30 minutes, cooled in an ice-brine bath and N-methoxy-N,3-dimethyl-4-nitrobenzamide (8.45 g, 37.7 mmol, Intermediate 14: step a) dissolved in 22 mL of DCM was added dropwise. A dark brown solid mass formed. The ice bath was removed and mixture stirred at room temperature for 18 hours. Water was added to the suspension followed by 6 M aqueous HCl slowly to neutralize the mixture (pH=6-7). More DCM was added and layers separated. The organic layer was dried over MgSO4, filtered and concentrated. Et2O was added, the slurry sonicated, and precipitates were filtered and dried to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11]O)[CH2:6][CH2:5]2>C1COCC1>[CH:7]1([NH2:11])[C:8]2[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2=NO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCC2N

Procedure:
Step AS2. A mixture of crude 5-aminoindan-1-one oxime (486 mg, 3 mmol) and borane-methyl sulfide complex (1.2 g, 16 mmol) was refluxed in THF for 3 days. The excess reagent was quenched with methanol. After the solvent was removed, the residue was purified by flash chromatography with DCM, then 20% MeOH in DCM, then 50% MeOH in DCM to give 2,3-dihydro-1H-indene-1,5-diamine.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][C:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH:7]=1>C(=O)=O.CC(C)=O.C1COCC1.Cl[Cu]>[CH3:5][C:6]1([CH:1]=[CH2:2])[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1
Reactant: C=C[Mg]Br
Reactant: CC1=CC(=O)CC(C)C1
Agent: Cl[Cu]
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=CC1(C)CC(=O)CC(C)C1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A 1M solution of vinylmagnesium bromide in THF (90 ml, 90 mmol) was cooled in dry ice-acetone bath to −20° C. in an inert atmosphere and CuCl (4.45 g, 45 mmol) was added in one portion. The mixture was stirred for 30 min and a solution of 3,5-dimethyl-2-cyclohexen-1-one (41) (3.73 g, 30 mmol) in THF (40 ml) was added dropwise keeping the reaction temperature at −20° C. The cooling bath was removed and the reaction mixture was allowed to reach room temperature for 2 h. Saturated aqueous NH4Cl (50 ml) was added thoroughly while cooling with ice bath. Hexane (150 ml) was then added and the aqueous layer was separated and extracted with hexane (2100 ml). The combined organic extracts were washed with 20% aqueous acetic acid (100 ml) and with saturated aqueous NaHCO3 (3200 ml). The extract was dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 20:1) to give 42 (2.4 g, 52%) as a colorless oil. 1H-NMR (CDCl3, TMS): 0.99 (3H, d, 6 Hz, 5-CH3); 1.11 (3H, s, 3-CH3); 1.2-2.6 (7H, m, ring protons); 4.94 and 5.01 (total 2H, both d, 17 and 10.5 Hz, CH2═) and 5.64 ppm (1H, dd, 17 and 11 Hz, ═CH).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH2:12]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]>ClCCl.[Cl-].[Na+].O>[CH2:12]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Cl:1])=[CH:25][CH:24]=1)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(CO)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Solvent: O
Product: CC(C)=CCC/C(C)=C/COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of N-chorosuccinimide (1.15 g) in dichloromethane (40 ml) was added dimethylsulfide (0.72 g) while being cooled with ice. Then, a solution of 4-geranyloxybenzyl alcohol (1.50 g) in dichloromethane (10 ml) was added thereto and the resulting mixture was stirred for 3 hours at room temperature. The reaction solution, with brine added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum to yield a raw product of 4-geranyloxybenzyl chloride.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]2[S:25][CH:24]=[CH:23][C:22]=2[CH:26]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C(=O)C>[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]2[S:25][C:24]([C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=3[F:10])=[CH:23][C:22]=2[CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: c1ccc(Cc2ccc3sccc3c2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(-c2cc3cc(Cc4ccccc4)ccc3s2)c(F)c1
Temperature: 150 °C

Procedure:
A mixture of 4-bromo-3-fluorobenzaldehyde (40 mg, 0.198 mmol), 5-benzylbenzothiophene (44 mg, 0.198 mmol), potassium acetate (5 mg, 0.05 mmol), tetrakis(triphenylphosphine) palladium(0) (11 mg, 0.010 mmol) and N,N-dimethylacetamide (5 mL) was heated at 150° C. for 12 h. The solvent was evaporated in vacuo and the residue was triturated with water (50 mL) and extracted with dichloromethane (2×100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ISCO system, 5% EtOAc in hexanes) to give the desired product. 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.64-7.85 (m, 6H), 7.22-7.33 (m, 6H), 4.11 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:29][CH3:30])=[C:15]([CH:17]3[CH2:22][CH2:21][N:20](C(=O)C(F)(F)F)[CH2:19][CH2:18]3)[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:29][CH3:30])=[C:15]([CH:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1C1CCN(C(=O)C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1C1CCNCC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a suspension of 1-{4-[5-(4-chloro-benzenesulfonyl)2-methoxyphenyl]piperidin-1-yl}-2,2,2-trifluoro-ethanone (31) (77 mg) in methanol (2 mL), a solution of 6N NaOH (0.5 mL) was added. After stirring at 80° C. for 10 min, water was added (10 ml) and the mixture was extracted into ethyl acetate (20 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to give 4-[5-(4-chloro-benzenesulfonyl)2methoxy-phenyl] piperidine (301) as a white solid (0.054 g ), MS, MH+ 365. The hydrochloride salt was prepared from ethanol-hydrogen chloride, m.p. 235.5-236.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30]1[CH:31]=[N:32][N:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:29][C:30]2[CH:31]=[N:32][N:33]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:34]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: ClCc1cnn(-c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2cnn(-c3ccccc3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (7.0 g) synthesized in Example 265-1 and 4-(chloromethyl)-1-phenyl-1H-pyrazole (3.47 g) synthesized in Reference Example 18 were dissolved in N,N-dimethylformamide (80 mL), potassium tert-butoxide (2.32 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1 to 3:1) to give the title compound (7.30 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[O:18][CH3:19])=[N:9][N:10]=2)[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:23]4[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([F:20])[CH:22]=4)[CH:3]=[CH:4][C:5]3=[N:10][N:9]=2)=[C:12]([O:18][CH3:19])[CH:13]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: COc1cc(Cl)ccc1-c1nnc2ccc(Cl)cn12
Product: COc1ccc(-c2ccc3nnc(-c4ccc(Cl)cc4OC)n3c2)cc1F

Procedure:
The title compound was prepared form 6-chloro-3-(4-chloro-2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine and 3-fluoro-4-methoxyphenylboronic acid using a procedure similar to those described for the synthesis of Example 1d, and was isolated as white solids. 1H NMR (DMSO-d6): 8.29 (m, 1H), 7.92 (dd, J=9.6 and 0.9 Hz, 1H), 7.80 (dd, J=9.6 and 1.8 Hz, 1H), 7.71-7.62 (m, 2H), 7.56 (m, 1H), 7.54 (t, J=1.2 Hz, 1H), 7.40-7.23 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H). MS: m/z 384.2 [M+H+].
Reaction SMILES: Cl.[C:2]([N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH3:6])(=O)C.N(CC(O)=O)C.C=O.[OH:19][PH:20]([OH:22])=[O:21].P(Cl)(Cl)Cl>C(O)(=O)C.O>[P:20]([CH2:2][N:5]([CH3:6])[CH2:7][C:8]([OH:10])=[O:9])([OH:22])([OH:21])=[O:19]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: O=[PH](O)O
Agent: C=O
Agent: CNCC(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: ClP(Cl)Cl
Product: CN(CC(=O)O)CP(=O)(O)O

Procedure:
As depicted, one equivalent of N-methylacetamide IX is reacted with one equivalent each of carbon monoxide and formaldehyde in the presence of a carboxymethylation catalyst precursor and solvent to yield N-acetylsarcosine XX. In the presence of water and an acid such as hydrochloric acid, N-acetylsarcosine XX is hydrolyzed to sarcosine XXIII and acetic acid. Sarcosine XXIII is reacted with formaldehyde and H3PO3, PCl3 or other H3PO3 source to produce N-(phosphonomethyl)-N-methyl-glycine XXI which is oxidized in the presence of a platinum catalyst and oxygen to glyphosate I.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:12]Br>Br.C(Cl)Cl.[OH-].[Na+]>[Br:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cc2ccccc2cn1
Reactant: BrBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ncc2ccccc2c1Br
Temperature: 110 °C
Yield: 34.8 %

Procedure:
In a 40 mL screw-top vial with a stirbar was added 3-methyl-isoquinoline (6.00 g, 41.9 mmol) in hydrobromic acid (6 mL), followed by the dropwise addition of bromine (2.2 mL, 42.7 mmol, 1.02 eq). The entire suspension was heated at 100-120° C. for 24 hr. The reaction mix was cooled and diluted with DCM (100 mL) and 1N NaOH added slowly to neutralize the reaction. The organic layer was collected and dried over Na2SO4 and concentrated to a dark orange oil. The crude reaction was purified using Biotage MPLC system (40M column size, 0-15% Ethyl Acetate/Heptane over 30CV) giving a tan crystalline solid as the desire product (3.48 g, 14.57 mmol, 34.8%). 1H NMR (CDCl3, 400 MHz): δ 9.01 (s, 1H), δ 8.12-8.10 (d, 1H), δ 7.87-7.85 (d, 1H), δ7.72-7.68 (dt, 1H), δ 7.54-7.50 (dt, 1H), δ 2.80 (s, 3H); LRMS (m/z): 224, 222 (M+H).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][NH:9][CH3:10].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19](Cl)=[O:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][N:9]([CH3:10])[C:19](=[O:20])[O:18][CH2:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: CNCC1COCCO1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC1COCCO1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride (4.83 g, 29 mmol) was dissolved in 100 mL dichloromethane. Benzyl chloridocarbonate (4.9 mL, 35 mmol) and triethylamine (10 mL, 72 mmol) were added. The solution was stirred at ambient temperature. After 12 hours, the solution was concentrated, then diluted with ethyl acetate, and washed with saturated sodium bicarbonate and water. The organic layer was separated, dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by silica chromatography (0-100% ethyl acetate/hexanes gradient) to afford the title compound (racemic mixture).