Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:15])=[N:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11])=[O:4].B.C1COCC1.CC(O)=O.O.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[OH:11][CH2:10][C:9]1[C:8]([CH3:14])=[N:7][C:6]([CH3:15])=[C:5]([CH:13]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)c(C)nc1C
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(CO)c(C)nc1C
Yield: 70.6 %

Procedure:
A solution of 686 mg of 5-(methoxycarbonyl)-2,6-dimethylnicotinic acid and 8.0 mL of BH3.THF (1.0 M in THF) in 10 mL of THF was heated to 75° C. for 2.5 h. An aqueous solution of 3 mL of AcOH:H2O (1:1) was added, and the solution was stirred until the bubbling ceased. Saturated NaHCO3 was added to a pH=7, and the solution was stirred overnight. EtOAc and H2O were added, and the layers were separated. The aqueous layer was extracted with 30 mL of EtOAc, and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (3% MeOH/CHCl3) provided 452 mg of methyl 5-(hydroxymethyl)-2,6-dimethylnicotinate as a pale yellow solid in 71% yield.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[C:6]2[C:14]([F:17])([F:16])[F:15].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][C:8]1[CH:7]=[C:6]([C:14]([F:16])([F:15])[F:17])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2nc(C)cc(C(F)(F)F)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)c2cc(O)ccc2n1
Temperature: -78 °C
Reaction time: 22 h

Procedure:
6-Methoxy-2-methyl-4-trifluoromethyl-quinoline (0.894 g, 3.71 mmol) was dissolved in Methylene chloride (60 mL), and cooled to −78° C. A solution of 1.0 M of Boron tribromide in Methylene chloride (11.0 mL, 11.0 mmol) was then added dropwise. The reaction mixture was then warmed up to 23° C. The reaction was allowed to stir 22 h at room temperature. After cooling in an ice bath, saturated sodium bicarbonate solution was added with stirring. The mixture was extracted with methylene chloride and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using 0-15% methanol in methylene chloride to give the product (Rf=0.49 in 10% methanol in methylene chloride) in 771 mg yield (92%). ESI-MS (M+H+): 228.10.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C>C1COCC1>[Cl:8][C:4]1[C:3]([CH3:9])=[C:2]([B:10]([OH:15])[OH:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(Cl)cccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1B(O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.2 %

Procedure:
To a solution of 10.0 g (48.7 mmol) 2-bromo-6-chlorotoluene and 11.3 ml (48.7 mmol) triisopropyl borate in 90 ml dry THF were added dropwise 30 ml (49 mmol) of a 1.6 M solution on n-butyllithium in hexanes at −78° C. under argon. After 45 min the reaction mixture was allowed to warm to room temperature. The reaction was quenched by addition of 5 ml water and the solvent was evaporated in vacuo. Addition of 1 M aqueous hydrochloric acid solution was followed by extraction with four portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Crystallisation from heptane gave 5.08 g (61%) of the title compound as a white solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([NH:29][C:30](=[O:40])[C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37]CO)=[O:32])[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[Br:5][CH2:1][CH2:37][CH2:36][CH2:35][CH2:34][NH:33][C:31](=[O:32])[C:30]([NH:29][CH2:25][CH2:26][CH2:27][CH3:28])=[O:40]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCNC(=O)C(=O)NCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCNC(=O)C(=O)NCCCCCBr
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of carbon tetrabromide (51 mg, 0.15 mmol) in CH2Cl2 (5 mL) was stirred into a 0° C. solution of triphenylphosphine (48 mg, 0.18 mmol) and N1-n-butyl-N2-(5-hydroxypentyl)oxalamide (30 mg, 0.130 mmol) in dry CH2Cl2 (5 mL) under an argon atmosphere. After 2 h, the reaction mixture was washed with water (5 mL), brine (10 mL), dried over anhydrous Na2SO4, and all volatiles were removed under reduced pressure. The residue was purified by SiO2 column chromatography using EtOAc/hexane (1:4) to give compound the title compound (32 mg, 84%) as a colorless solid, mp 109-110° C. TLC: 50% EtOAc/hexanes, Rf˜0.50; 1H NMR (300 MHz) δ 7.55 (br s, NH, 1H), 7.50 (br s, —NH, 1H), 3.40 (t, J=6.0 Hz, 2H), 3.25-3.35 (m, 4H), 1.80-1.85 (m, 2H), 1.40-1.60 (m, 6H), 1.25-1.35 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz) δ 160.30, 160.15, 39.65, 33.65, 32.45, 31.40, 28.60, 25.60, 20.20, 13.90. HRMS calcd for C11H22BrN2O2[M+1]+ 293.0865. found 293.0870.
Reaction SMILES: CN(C)[C:3](=[CH:9][CH:10]=[C:11]([S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.C([OH:36])C>>[OH:36][C:3](=[CH:9][CH:10]=[C:11]([S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCO
Reactant: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1cccc(Oc2ccccc2)c1
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SCc1cccc(Oc2ccccc2)c1)C(=O)OCC
Temperature: 20 °C
Reaction time: 0.02 h

Procedure:
The procedure is as in Example 2, starting with diethyl 2-dimethylamino-5-(3-phenoxybenzylthio)-2,4-hexadienedioate (7 g), 12N aqueous hydrochloric acid solution (23 cc) and ethanol (46 cc). The mixture is heated to boiling for 1 minute, and is then cooled to a temperature of approximately 20° C. After purification by chromatography on a silica column with dichloromethane as eluent, diethyl 2-hydroxy-5-(3-phenoxybenzylthio)-2,4-hexadienedioate (4.5 g) is obtained in the form of a yellow oil (Rf=0.2; thin layer chromatography on silica gel; eluent: dichloromethane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)CC(c1cccc(Br)c1)c1ccccc1C
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 5, from 3-(3-bromo-phenyl)-N-methoxy-N-methyl-3-o tolyl-propionamide and 4-bromo-2-methylpyridine was prepared the title compound as a colorless oil, MS (ESI+): m/z=394.08 ([M+H]+, 1 Br).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([CH2:30][C:31]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:19])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(adamantan-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.18-11.35 (bs, 1H), 8.39-8.42 (m, 1H), 7.89-8.02 (m, 2H), 7.70-7.73 (m, 1H), 7.56-7.68 (m, 4H), 2.04 (s, 2H), 1.92-1.95 (m, 3H), 1.66-1.69 (m, 6H), 1.63-1.70 (m, 3H), 1.57-1.62 (m, 3H); MS (ESI+) m/z 448 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH3:19][C@H:20]([C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[C:21](Cl)=[O:22]>C1COCC1>[CH2:17]([O:16][C:13](=[O:15])[CH2:14][C:21](=[O:22])[C@H:20]([CH3:19])[C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[CH3:18]
Reactant: CCOC(C)=O
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)OCC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution containing 2.0 g (13.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was added 2.1 g (16.6 mmol) of chloromethylene dimethyl-ammonium chloride. After stirring the resulting solution under nitrogen for 1.5 hours, the solvent was evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml, 52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5 mmol) in dry THF (20 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. and 4.3 g (48.5 mmol) of ethyl acetate was added. The solution was stirred at that temperature for 45 minutes. (2R,3R)-2,3-Dimethyl-hexanoyl chloride in dry THF (20 mL) was slowly added to the ethyl acetate enolate at −78° C. and the resulting reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and was cooled to 0° C. The reaction was quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 2.7 g (89.2% yield) of the titled compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9].[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1.O>CN1C(=O)N(C)CC1>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: CC(C)NS(=O)(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CC(C)NS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
To a solution of 2-amino-N-isopropyl-benzenesulfonamide (16.1 g, 75.1 mmol) in DMI (150 mL) is added sodium hydride (6.6 g, 165.3 mmol) portionwise at 0° C. After the mixture is stirred at room temperature for one hour, 2,4,5-trichloropyrimidine (20.7 g, 112.7 mmol) is added at 0° C. After further stirring at room temperature for 5 hrs, water is added and the mixture is extracted with AcOEt three times. Organic layer is washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by silica gel column chromatography (Hexane to Hexane:AcOEt=4:1) to afford the title compound as pale brown solid (10.2 g, 38%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([NH:19]C(=O)C(F)(F)F)[CH:10]=1)#[N:8]>CO>[NH2:19][C:11]1[CH:10]=[C:9]([C:7]#[N:8])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(C#N)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(C#N)cc1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Potassium carbonate (60.3 g, 436 mmol) was added to a methanol suspension (850 mL) of methyl 4-cyano-2-[(trifluoroacetyl)amino]benzoate (108 g, 397 mmol) and the mixture was stirred at 50° C. for 2 hours. After cooling, methanol was distilled off under reduced pressure and water was added to the residue. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with 0.5M hydrochloric acid and then saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (53.9 g, 76%).
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:17])[C:3]=1[C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19].C(O)(C(F)(F)F)=O>>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:17])[C:3]=1[C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccccc2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2ccccc2C2(CCOCC2)C1=O
Yield: 0.1 %

Procedure:
1,1-Dimethylethyl N-((4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (270 mg, 697 mmol) was reacted with TFA (2 mL) for 30 minutes and then concentrated, precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (193 mg) as a white solid. MS m/e=332 (M+H)+. Calculated for C17H17NO6 331.11.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH:28]=[CH2:29]>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][NH:30][CH2:27][CH:28]=[CH2:29])[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C=CCN
Solvent: CC#N
Product: C=CCNCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), prop-2-en-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 281 (M+, 6), 131 (8), 77 (6), 71 (5), 70 (bp).
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH3:8][C:9]1[S:33][C:12]2[N:13]([C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=3)=[O:20])[CH2:14][CH2:15][CH2:16][CH:17](O)[C:11]=2[C:10]=1[CH3:34]>CCCCCC.C(#N)C.C(OCC)(=O)C>[CH3:8][C:9]1[S:33][C:12]2[N:13]([C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=3)=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=2[C:10]=1[CH3:34]
Reactant: COC(=O)c1ccc(C(=O)N2CCCC(O)c3c2sc(C)c3C)cc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)N2CCCCc3c2sc(C)c3C)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.2 %

Procedure:
A solution of sodium iodide (462 mg), chlorotrimethylsilane (335 mg) and acetonitrile (0.2 ml) in hexane (0.5 ml) was cooled to 0° C. To the solution was added methyl 4-(2,3-dimethyl-4-hydroxy-5,6,7,8-tetrahydro-4H-thieno[2,3-b]azepin-8-yl)carbonyl-2-methoxybenzoate (200 mg) in acetonitrile (1.0 ml). The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (SiO2; 30 g, CHCl3) to give methyl 4-(2,3-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-b]azepin-8-yl)carbonyl-2-methoxybenzoate (150 mg).
Reaction SMILES: [CH3:1][C@:2]12[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][C@H:15]([OH:22])[C:13](=[O:14])[C@@H:12]1[C@:11]1([CH3:23])[C@H:5]([C:6]([O:8][C@H:9]([C:24]3[CH:25]=[CH:26][O:27][CH:28]=3)[CH2:10]1)=[O:7])[CH2:4][CH2:3]2.C1(=O)O[C:32](=[O:33])[CH2:31]C1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:31][C:32]([O:22][C@@H:15]1[C:13](=[O:14])[C@H:12]2[C@@:2]([CH3:1])([CH2:3][CH2:4][C@@H:5]3[C@:11]2([CH3:23])[CH2:10][C@@H:9]([C:24]2[CH:25]=[CH:26][O:27][CH:28]=2)[O:8][C:6]3=[O:7])[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16]1)=[O:33]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@@H]1C[C@H](OC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To Salvinorin B (190 mg, 0.487 mmol) and succinic anhydride (112 mg, 2.5 eq) suspended in dichloromethane (5 ml) at 0° C. was added DBU (218 pl, 3 eq) dropwise. The mixture was stirred at 0° C. for 15 mins, washed with 3% citric acid (5 ml), saturated NaHCO3 solution (5 ml) and brine (5 ml). The mixture was dried over sodium sulfate, filtered and evaporated to dryness. The crude residue was purified by column chromatography (silica gel: CH2Cl2 to 5% MeOH in CH2Cl2) to give salvinorin hemisuccinate (130 mg, 54%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[Br:11][C:12](Br)([F:14])[F:13]>CN1C(=O)CCC1>[Br:3][C:4]1[C:9]([O:10][C:12]([Br:11])([F:14])[F:13])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: FC(F)(Br)Br
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: FC(F)(Br)Oc1cccnc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
To a suspension of sodium hydride (1.72 g, 43.1 mmol) in NMP (50 mL) was added a solution of 2-bromo-3-hydroxypyridine (5 g, 28.74 mmol) in NMP (50 mL). This mixture was stirred at room temperature for 30 minutes followed by heating at 50° C. for 45 minutes before cooling to room temperature. Dibromodifluoromethane (3.15 mL, 34.5 mmol) was slowly added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was slowly quenched into saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with water (3×100 mL), brine (2×100 mL), dried over MgSO4 and concentrated in vacuo to afford a brown gum. This residue was purified using silica gel column chromatography eluting with 70/30 Heptane/EtOAc to give the title compound as a colourless oil (1.2 g, 14%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>O1CCCC1>[CH3:13][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCOCC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCOCC1
Reaction time: 3 h
Yield: 91.8 %

Procedure:
Into a 500-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl tetrahydro-2H-pyran-4-carboxylate (8 g, 50.6 mmol) in tetrahydrofuran (100 mL). This was followed by the addition of LDA (50 mL, 101.1 mmol, 2M in THF) dropwise at −78° C. and stirred for 3 h. To this was added a solution of CH3I (9.5 mL, 151.9 mmol) in tetrahydrofuran (50 mL) dropwise at −78° C. The reaction mixture was stirred for 3 h at −78° C., then carefully quenched with 400 mL of NH4Cl (sat.). The aqueous phase was extracted with 300 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 8 g (92%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]([O:18]CC)=O.C([O-])(=O)C.[NH4+:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:26][C:16](=[O:18])[C:12]2[N:11]([CH:15]=[CH:14][N:13]=2)[CH:10]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nccn1CC(=O)c1ccc(Cl)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Temperature: 0 °C

Procedure:
920 mg (2.8 mmol) of ethyl 1-[2-(2,4-dichlorophenyl)-2-oxoethyl]-1H-imidazol-2-carboxylate (Example 3A) were dissolved in 45 ml of glacial acetic acid, and 2.17 g (28 mmol) of ammonium acetate were added. The mixture was stirred under reflux for 12 h. The reaction mixture was added to ice-water and neutralized and with sodium carbonate. The precipitate was filtered off and dried under high vacuum. This gave 650 mg (82% of theory) of the product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>C(OCC)(=O)C>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: CO
Reactant: Cc1ccc(Br)cc1C(=O)O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The compound of example 1 (20.3 g, 0.0944 mol) was dissolved in 150 mL methanol and cooled to 0° C. To this reaction mixture, thionyl chloride (28.07 g, 0.236 mol) was added slowly within 15-20 min. The reaction mixture was stirred at room temperature for 2-3 h. After completion of the reaction, MeOH was removed under vacuum. The oily material obtained was dissolved in ethyl acetate and washed with sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain the title compound.
Reaction SMILES: O.O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Na+].[C:14](#[N:17])[CH:15]=[CH2:16].C(O)(=O)C>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:16][CH2:15][C:14]#[N:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: C=CC#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a suspension of sodium 4-bromophenylsulfinate dihydrate (130 g, 0.53 mol) in water (600 mL) was added acrylonitrile (70 mL, 1.07 mol) and acetic acid (62 mL, 1.07 mol). The reaction was stirred for 1.5 h at 100° C. then cooled to room temperature. The solid was filtered off, washed thoroughly with water and dried over P2O5 to give 3-[(4-bromophenyl)sulfonyl]propanenitrile (125 g). δH (400, CDCl3): 7.27-7.22 (4H, m), 2.85 (2H, t, J 7.6), 2.30 (2H, t, J 7.6).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:30])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:27]([O-])=O)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]>[Pd]>[CH3:1][CH:2]([CH3:31])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:30])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH2:27])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3[N+](=O)[O-])CC2)nn1
Agent: [Pd]
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3N)CC2)nn1
Yield: 83 %

Procedure:
6-[4-(2-Nitrobenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (3-methyl-butyl)amide (100 mg, 0.235 mmol) was hydrogenated with 10 mg 10% Pd/C as catalyst at ambient temperature under 1 atm for 24 hours. The mixture was filtered through a celite cake. The filtrate was concentrated and purified by flash chromatography (ethyl acetate) to give a white solid (83% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 7.86, 7.19-7.23, 7.10-7.13, 6.99, 4.40, 3.74-3.88, 3.50, 1.65-1.75, 1.52, 0.94. MS (ES+) m/z 397 (M+1).