Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]2C(OCC2C=CC=CC=2)=O)=[N:12][C:11]=1[C:38]([O:40][CH3:41])=[O:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)CCC1C(O)=O>CCOC(C)=O.[Pd]>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27][CH:18]1[C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:11]([C:38]([O:40][CH3:41])=[O:39])[N:12]=1
Reactant: COC(=O)c1nc(C2CCc3ccccc3N2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Agent: [Pd]
Agent: O=C(O)C1CCc2ccccc2N1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C2CCc3ccccc3N2)n(C)c(=O)c1OC(=O)c1ccccc1

Procedure:
Benzyl 2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-1,2,3,4-tetrahydroquinoline-1-carboxylate (prepared from tetrahydroquinoline-2-carboxylic acid (Robl et al, Tetrahedron Letters 1995, 36: 1593) by protection of the nitrogen and following procedures similar to those set forth in Examples 1 or 2 in combination with a deprotection step) was dissolved in EtOAc and hydrogenated at atmospheric pressure on 10% Pd/C at room temperature overnight. The title product was obtained as the residue after filtration and evaporation of the organic solvent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([NH:18]C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=1)[CH3:2].[ClH:27]>O1CCOCC1>[ClH:27].[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([NH2:18])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(NS(C)(=O)=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](N)Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(S)-Ethyl-2-tert-butyloxycarbonylamino-3-(4-methanesulfonylaminophenyl)propionate (3.00 g, 7.76 mmol) was dissolved in a solution of 4 N HCl in dioxane (10 mL). The bright orange solution was allowed to stir at room temperature overnight. The solvent was then evaporated and the residue azeotroped with toluene, furnishing the product as a bright peach solid (2.5 g, 100%).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)C.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>[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:21][CH:20]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Clc1ccc(/C=C/c2cccc3c4c([nH]c23)C2CCN(CC2)C4)cc1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A suspension of the product of Example 1B (55 mg, 0.19 mmol), trans-2-(4-chlorophenyl)vinylboronic acid (41 mg, 0.23 mmol; Aldrich), dichlorobis(triphenylphosphine)palladium (II) (6.6 mg, 9.4 μmmol; Aldrich) and 1.0 M sodium carbonate (0.47 mL) in 2-propanol (1.5 mL) was purged with nitrogen and then stirred at 110° C. for 5 hours in a sealed tube. The reaction mixture was cooled and partitioned between CHCl3/2-propanol (4:1, 2×20 mL) and 1.0 M sodium carbonate (30 mL). The combined organic extracts were dried (sodium sulfate) and concentrated under vacuum. The resulting residue was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (500 MHz, methanol-d4 ) δ ppm 2.03-2.16 (m, 4 H), 3.04-3.12 (m, 2 H), 3.12-3.18 (m, 1 H), 3.20-3.29 (m, 2 H), 4.24 (s, 2 H), 7.01 (t, J=7.6 Hz, 1 H), 7.19-7.26 (m, 2 H), 7.31-7.41 (m, 3 H), 7.55-7.67 (m, 3 H); MS (APCI) m/z 349 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>C(O)C.[Pd]>[F:1][C:2]([F:16])([F:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCCCC=CCCC(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCCCCCCCCC(F)(F)F
Reaction time: 18 h

Procedure:
Dissolve 12,12,12-trifluoro-8-dodecenoic acid (1.39g, 5.5 mmol) in ethanol (50 mL) and place in a Paar hydrogenation flask. Add 10% palladium/carbon (500 mg). Charge the vessel to 50 psi and shake for 18 hours. Filter through celite and remove the solvent in vacuo to give 12,12,12-trifluorododecanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC#N.O>C(Cl)(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[Br:18]
Reactant: COC(=O)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: COC(=O)C(Br)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a stirred solution of biphenyl-4-yl-acetic acid methyl ester (5 g., 22.1 mmol) in carbon tetrachloride (from Acros, 16772) (25 mL) was added N-bromosuccinimide (from Aldrich, 18350) (3.9 g., 22.1 mmol) and benzoyl peroxide (from Acros, 21178) (0.54 g, 2.2 mmol) and the reaction was heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate concentrated in vacuo to afford Cpd. 2 as a crude yellow oil (6.24 g., 93% yield). 1HNMR (CDCl3) δH, 3.81, 3H (s, CH3), 5.41, 1H (s, Br—CH), 7.33-7.39, 2H (m, Ar—H), 7.41-7.46, 3H (m, Ar—H), 7.54-7.63, 4H (m, Ar—H); LCMS analysis (solvent MeCN/H2O/0.1% HCO2H, 5-95% gradient/H2O 2.5 min, 95% 4 min., Phenomenex C18 reverse phase, flow rate 1 mL/min.) HPLC retention time 4.39 min.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1)[CH3:8].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.O.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>[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:13][CH:12]=1)[CH3:8]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1
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: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1
Yield: 57 %

Procedure:
Na2CO3 (228 mg, 2.16 mmol) was added to a stirred solution of 6-chloro nicotinic acid ethyl ester (200 mg, 1.08 mmol) in toluene:H2O (5:1, 6 mL). Pd (PPh3)4 (250 mg, 0.216 mmol) and phenylboronic acid (168 mg, 1.29 mmol) were then added and the reaction mixture was heated to reflux for 3 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to afford 140 mg (64.4% yield) of 6-phenyl-nicotinic acid ethyl ester. LCMS Purity %: 98.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][N:9]2[C:23]([C:22]2[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:24])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(C2NCCc3ccsc32)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCc3ccsc3C2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
7-(4-Chloro-phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin (100 mg) in toluene (20 ml), 4-methoxybenzoyl chloride (68.3 mg) and triethylamine (1 ml) were mixed and the mixture stirred at RT for 2 h. The reaction mixture was extracted once with NaOH (1 M) and once with water, the organic phase dried (MgSO4) and evaporated to dryness resulting in yellow oil which was purified on silica gel using methylene chloride/methanol 19/1 as eluent. The resulting oil was treated with abs ethanol resulting in precipitation of crystals. Yield 91%, m.p. 129.5-130.0 C. MS. M+=383.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:29])[C@@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].NN>CCO.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:29])[C@@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@H](CN1CCCC1)c1cccc(N)c1
Temperature: 55 °C

Procedure:
A mixture of 14 (1.17 g, 2.68 mmol), hydrazine (1 mL, 32 mmol), and Raney-Ni in 95% EtOH (75 mL) was heated at 55° C. Small portions of Raney-Ni and hydrazine were added until TLC indicated completion of the reaction (2.5 h). The reaction was filtered through celite, and the Raney-Ni was washed with hot MeOH. The combined filtrates were evaporated under reduced pressure to yield 15 in quantitative yield. Further purification was achieved by gravity column chromatography with CHCl3 :1% MeOH:2% NH3 :mp (15.2HCl) softens at 149° C. and melts at 223°-224° C.; [α]D25°C. +143.7° (c=0.45, 15.2HCl, MeOH); 1H NMR (15.2HCl, DMSO-d6) δ 1.9-2.0 (m, 4H, --CH2CH2 --), δ 2.82 (s, 3H, NCH3), δ 3.07-4.07 (complex, 6H, 3 --CH2N), δ 3.77 (d, J=16 Hz, 1H, ArCH2CO), δ 4.10 (d, J=16 Hz, 1H, ArCH2CO), δ 6.05 (d of d, J=12.5 Hz and 2.5 Hz, 1H, CH), δ 6.87 (br s, 2H, m-NH2C6H4), δ 6.92 (d, J=8 Hz, 1H, m-NH2C6H4), δ 7.26 (t, J=8 Hz, 1H, m-NH2C6H4), δ 7.29-7.31 (m, 1H, Cl2C6 H3 --), δ 7.55-7.59 (m, 2H, Cl2C6H3 --). MS (FAB) m/z 406.2. Anal. (C21H25N3OCl2.2HCl) calcd.: C 52.62, H 5.68, N 8.77, Cl 29.59; found: C 52.43, H 5.58, N 8.50, Cl 29.47.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[CH:15]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].[BH4-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[CH2:15][NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([Cl:17])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CNc1cccc(Cl)c1
Reaction time: 12 h
Yield: 10.3 %

Procedure:
Solution of (S)-4,4-difluoro-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 0.0042 mol) and 3-chloroaniline (0.53 mL, 0.0042 mol) in titanium tetraisopropoxide (5 mL) was allowed to stir for 12 h. The reaction was monitored by TLC. After disappearance of starting reaction on TLC, the mixture was diluted with methanol (20 mL) followed by the addition of sodium borohydride (0.33 g, 0.0084 mol) in portions. The reaction mixture was stirred for 6 h. The reaction was quenched with water and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and the volatiles were removed using a rotary evaporator to give a crude oil, which was then purified via column chromatography (5% methanol: DCM, mesh Size—100-200 silica, diameter of column—2.5 cm, height of silica—approx. 4 inch) to afford the desired (S)-2-[(3-chloro-phenylamino)-methyl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as a sticky solid (0.15 g, 12%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]C(=O)N(C)C)=[C:4]([Cl:15])[CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([SH:9])=[C:4]([Cl:15])[CH:3]=1
Reactant: CN(C)C(=O)Sc1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(S)c(Cl)c1
Temperature: 95 °C
Yield: 68.7 %

Procedure:
A solution of dimethyl-thiocarbamic acid S-(4-amino-2,6-dichloro-phenyl)ester (81) (2.0 g, 7.5 mmol) in ethanol was treated with a 3N aqueous potassium hydroxide solution. The reaction was heated to 95° C. for 2 d. At this time, the reaction was cooled to 25° C. and was then acidified to pH=2 with a 3N aqueous hydrochloric acid solution. This solution was diluted with water (500 mL) and then was extracted with ethyl acetate (2×250 mL). The organics were dried with magnesium sulfate, filtered, and concentrated under vacuum to an orange solid. The solid was slurried in chloroform, collected by filtration and washed with chloroform. The filtrate was concentrated under vacuum and purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 85:15 petroleum ether/ethyl acetate) to afford 4-amino-2,6-dichloro-benzenethiol (82) (1.0 g, 69%) as a white solid; EI(+)-HRMS m/e calcd for C6H5Cl2NS (M+) 192.9520, found 192.9519. Exact Mass=192.9520; Molecular weight=194.08
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[O:19]=[C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O.C(N(CC)CC)C>[C:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]([C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]3=[O:19])[CH:27]=2)=[O:30])=[CH:3][CH:4]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C(O)c1cccc(N2CCCCC2=O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (230 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (7 mL) were added 3-(2-oxopiperidin-1-yl)benzoic acid (169 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg), 1-hydroxybenzotriazole (125 mg) and triethylamine (128 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (53.4 mg).
Reaction SMILES: [C:1](O)(=O)/C=C\C(O)=O.[C:9]([O:16][CH3:17])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13].O>CO>[C:12]([O:14][CH3:1])(=[O:13])/[CH:11]=[CH:10]\[C:9]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)/C=C\C(=O)OC

Procedure:
This example relates to FIG. 1. In this example a 95 wt % solution of aqueous maleic acid is provided as described in Example 1. The aqueous maleic acid is fed to the mono-ester reactor column (9). Recycled methanol from the refining section (line 16a) is fed to the bottom of the column 9. More than 80% of the maleic acid is converted to mono-methyl maleate from the bottom product line (line 17) contains less than 10 mole % water. Mainly water and methanol and a small amount of maleic acid in the overhead (line 14) are fed to the methanol column (line 25). The bottom product from column (9) is fed to a reaction column (19) to react the mono-methyl maleate with methanol to produce di-methyl maleate. 300 mols per hour of methanol (line 24) are fed to the bottom of the reaction column (19). Essentially water free, fully converted di-methyl maleate is fed (line 26) to hydrogenation in reactor (20). Recycle methanol from the refining section is fed to the top of the reaction column as wash (line 16b) to minimise the di-methyl maleate and maleic acid in the overhead of the column. Methanol and water from the overhead (line 31) of the reaction column is fed to the methanol column (25) where the methanol is separated and recycled to the reaction column (line 24). Water and a small amount of recovered maleic acid and di-methyl maleate from the bottom of the methanol column are recycled to the absorber (2) in line 3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](N)=[O:7])#[N:2].N([O-])=[O:13].[Na+].CS(O)(=O)=O>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:13])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(N)=O)c1
Reactant: O=N[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
m-Cyanobenzamide (2.92 g), sodium nitrite (2.76 g), and dimethyl sulfoxide (50 ml) were mixed and stirred vigorously at room temperature. To the mixture, methanesulfonic acid (3.95 g) was added dropwise over ten minutes, and further stirred vigorously for three hours. The solvent was removed under reduced pressure, and water (50 ml) was added to the residue. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 2.57 g of m-cyanobenzoic acid (yield 88%). The obtained m-cyanobenzoic acid had a purity of 96%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:27](I)[CH:28]([CH3:30])[CH3:29]>CN(C=O)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]([CH2:27][CH:28]([CH3:30])[CH3:29])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
To a solution of 1-boc-4-(2-methanesulfonylamino-phenyl)-piperazine (1.07 g, 3.0 mmol) in 50 mL of DMF was added NaH (240 mg of a 60% dispersion in oil, 6 mmol). After stirring for about 15 minutes at r.t., isobutyl iodide (420 □L, 3.65 mmol) was added and the solution warmed to 60° C. After stirring at 60° C. overnight, the reaction was quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The solution was washed twice with water and brine, and then dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (40M Biotage column, 10-30% linear gradient EtOAc/Hex, over 45 min at 35 mL/min) afforded about 1.07 g (2.6 mmol, 87%) of the title compound as a white foam. LRMS: 412.3 (M+1)
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: O=C1NC(=O)c2c(CCCN3CCOCC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 3-morpholinylpropylphthalimide (219 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH3:22])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].CO.[ClH:25]>>[ClH:25].[CH3:22][CH:10]1[CH2:11][NH:12][CH2:13][CH2:14][N:9]1[CH:7]1[CH2:8][N:5]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:6]1
Reactant: C=CC(=O)N1CC(N2CCN(C(=O)OC(C)(C)C)CC2C)C1
Agent: Cl
Solvent: CO
Product: C=CC(=O)N1CC(N2CCNCC2C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of tert-butyl 4-(1-acryloylazetidin-3-yl)-3-methylpiperazine-1-carboxylate (62 mg, 0.199 mmol) in MeOH/HCl (20 mL, 2.9 M) was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the crude product (59 mg). The crude product was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:16]([CH:26]=1)[C:17]([NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:29]1([CH2:28][O:27][C:15]2[CH:14]=[CH:13][C:12]([CH2:10][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:26][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(CN2CCCC2)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Pyrrolidine (25 uL, 0.30 mmol) and acetic acid (17 uL, 0.30 mmol) were added to a solution of 5-formyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 66; 100 mg, 0.30 mmol) in DCE (5 ml). The solution was stirred for 4 hours at 50° C. then sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added. The reaction was stirred overnight then quenched with NaHCO3 solution (7 ml) and extracted with dichloromethane (5 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give a yellow solid. The residue purified by MDAP to yield the title compound as an opaque solid. 34 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[C:3]=1[CH2:9][O:10][CH3:11].[H-].[Na+].[CH3:14]I.Cl>O.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[N:6][N:5]([CH3:14])[C:4](=[O:8])[C:3]=1[CH2:9][O:10][CH3:11]
Reactant: COCc1c(Cl)cn[nH]c1=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1c(Cl)cnn(C)c1=O
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
Into 22 ml of an N,N-dimethylformamide solution of 2.17 g of 5-chloro-4-methoxymethylpyridazin-3-(2H)-one prepared in the above step (3), 0.55 g of sodium hydride (containing 40% of mineral oil) was added at room temperature. After the addition, the mixture was stirred for 30 minutes. Then, 2.12 g of methyl iodide was dropwise added thereto at a temperature of not higher than 20° C. After completion of the dropwise addition, the mixture was stirred at room temperature for one hour. After completion of the reaction, 70 ml of water and 4 ml of 10% hydrochloric acid were added to the reaction mixture, and the mixture was extracted with 70 ml of benzene. The benzene layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and from a fraction of n-hexane:ethyl acetate=3:1, 1.53 g of 5-chloro-2-methyl-4-methoxymethylpyridazin-3-(2H)-one having a melting point of from 47 to 49° C., was obtained.