Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.[OH-].[K+].NN.O>C(O)CO>[CH:1]1([CH2:6][C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ncccc1C(=O)C1CC=CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ncccc1CC1CC=CC1
Reaction time: 18 h
Yield: 50.9 %

Procedure:
Cyclopent-3-en-yl[2-(methyloxy)pyridin-3-yl]methanone (Preparation 29, 10 g, 49.3 mmol), potassium hydroxide (85%, 16.8 g, 0.3 mol), and hydrazine (6.33 g, 198 mmol) in ethylene glycol (100 ml) were heated to 180° C. and stirred for 18 h. Water was added and the product was extracted with hexane:ethyl acetate (50:50). The combined organic extracts were washed with brine and concentrated in vacuo. The crude oil was purified by flash chromatography eluting with ethyl acetate:hexane (10:90) to give a colourless oil (4.75 g, 51%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:17][C:18]([CH3:20])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH:18]([CH3:20])[CH3:17])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(C2CCN(C(C)C)CC2)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
A mixture of 2 g (8.3 mmol) 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester, 0.67 g acetone, 1.2 ml acetic acid and 2.47 g (11.6 mmol) sodium triacetoxyborohydride in 20 ml THF was stirred at 40° C. for 18 h. After evaporation to dryness the residue was extracted with 3×250 ml ethyl acetate and the combined organic phases were washed with 2×NaHCO3, NaCl aq., dried with MgSO4 and evaporated to yield 1.9 g (83%) of the title compound of orange solid. (m/e): 283.0 (MH+; 100%).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:11]([NH:18][CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC=Cc1ccccc1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C(=C/c1ccccc1)\CNCc1ccccc1
Reaction time: 18 h

Procedure:
Cinnamaldehyde and benzylamine were dissolved in 1% acetic acid in methanol under an atmosphere of dry nitrogen. Sodium cyanoborohydride (~1 equivalent) was added, and stirring was continued for 18 hours at which time the solvent was removed under reduced pressure. The residue was suspended in ether, washed with 5% NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18].[CH3:19][NH:20][CH3:21]>O1CCCC1.CCOCC>[CH3:19][N:20]([CH3:21])[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18]
Reactant: C#CCn1c(-c2ccccc2)nc(Cl)c(C)c1=O
Reactant: CNC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(N(C)C)c(C)c1=O
Temperature: 25 °C

Procedure:
To an ice cooled solution of 1.5 g (3.8 mmol) 6-chloro-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone in 4 mL of tetrahydrofuran, was added 22 mL (99 mmol) of 4.5M dimethylamine in ether portionwise (2-4 mL) over a period of 7 days. The reaction mixture was allowed to warm and stir at room temperature after each addition. The progress of the reaction was followed by gas chromatography and proceeded to 80% completion. The solvent was removed in vacuo and the residue was taken up in ether and washed twice with water. The organic layer was dried over MgSO4 and concentrated to yield 1.15 g crude solid product. Flash column chromatography on silica gel (gradient elution 25-30% ethyl acetate-hexane) afforded pure 6-dimethylamino-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (compound 23), as a white solid. 1H-NMR (CDCl3) δ 2.2(3H,s); 2.35(1H,t); 3.5(6H,s); 4.6(2H,d); 7.65(3H,m); 7.75(2H,m).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2Cl)n1
Yield: 22 %

Procedure:
The tide compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-chlorobenzenesulfonyl chloride according to METHOD A, giving 0.65 g (22%) of a pink solid after recrystallization from methanol: MS (Ionspray, [M+H]+) m/z 361; Anal. Calcd (found) for C13H13ClN2O4S2: C, 43.3 (43.2)%, H, 3.6 (3.5)%, N, 7.8 (7.6)%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(NC(C)C)(C)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.[Cu]I>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:16]#[C:17][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)s1
Temperature: 80 °C
Yield: 98.4 %

Procedure:
A mixture of ethyl 5-bromo-thiophene-2-carboxylate (500 mg, 2.13 mmol), trimethylsilylacetylene (0.445 mL, 3.2 mmol), Pd(PPh3)4 (15 mg) and CuI (10 mg) in diisopropylamine (10 mL) was heated at 80° C. for 2 h. After being cooled to room temperature, the mixture was filtered through CELITE, and the filtrate was poured into water. The product was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, concentrated in vacuo to give ethyl 5-(2-trimethylsilyl-ethyn-1-yl)-thiophene-2-carboxylate (529 mg). MS 253 (M+H).
Reaction SMILES: [OH-].[Na+].[N:3]1([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[C:15]([CH:20]=2)[C:16]([O:18]C)=[O:17])[CH:7]=[CH:6][N:5]=[CH:4]1>O.CO>[N:3]1([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[C:15]([CH:20]=2)[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: COC(=O)c1cc(C=CCn2ccnc2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(C=CCn2ccnc2)ccc1CCc1ccc(F)cc1

Procedure:
Sodium hydroxide (0.8 g, 20 mmol) in distilled water (3 ml) was added to a solution of methyl 5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate (E and Z isomers) (2.4 g;.6.6 mmol) in methanol (30 ml). The mixture was refluxed for 6 hours. After evaporation and acidification with 12N HCl to pH 6, the residue was extracted with dichloromethane and evaporated to dryness to give 5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoic acid (mixture of E and Z isomers).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][CH2:25][NH2:26])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][CH2:25][NH:26][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCCN)CC1
Product: CC(C)N1CCC(NS(=O)(=O)CCCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid [3-(1-isopropyl-piperidin-4-ylsulfamoyl)-propyl]-amide was prepared by an analogous procedure as described in example 5 iii) starting from 120 mg (1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 195 mg (0.74 mmol) 3-amino-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [3-(1-isopropyl-piperidin-4-ylsulfamoyl)-propyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: CN(C)C=O.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-]#N.[Na+].[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18]>O>[C:7]1([C:6](=[O:13])[CH2:18][CH2:17][C:19](=[O:20])[CH3:21])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC(C)=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CCC(=O)c1ccccc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To 1200 ml of dimethylformamide (DMF) containing 3 moles of benzaldehyde and heated at 35° C., a mixed solution of 0.3 mole of sodium cyanide and 2400 ml of DMF was added dropwise in 30 minutes, and the reaction was carried out for further 30 minutes with stirring. To the reaction solution, a mixed solution of 2.25 moles of methyl vinyl ketone and 2400 ml of DMF was added dropwise in 30 minutes, and the reaction was carried out for further 1 hour. After the reaction, water was poured into the reaction solution, followed by extraction with chloroform. The obtained chloroform solution was washed with dilute sulfuric acid, saturated aqueous solution of sodium bicarbonate, and water in this order, and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The resulting residue was distilled under reduced pressure to give a fraction of pale yellow liquid of 1-phenyl-1,4-pentanedione having a boiling point of 124°-127° C./0.15 mmHg (yield 40% ).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][C:26]([C:25]([NH:24][CH3:23])=[O:41])=[CH:27][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(-c2ccccc2-n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 90 °C

Procedure:
To a degassed solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 0.84 mmol), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (328 mg, 1.27 mmol) and K3PO4 (445 mg, 0.706 mmol), in DMF (6 mL)-water (0.6 mL) was added dichlorobis (triphenylphosphine) palladium (II) (30 mg, 0.042 mmol). The reaction mixture was heated at 90° C. for 95 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse HPLC to yield 2′-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methylbiphenyl-4-carboxamide. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.57-7.78 (m, 5H), 7.4 (dd, 1H), 7.25 (s, 1H), 6.92-7.2 (m, 4H), 4.6 (m, 1H), 4.2 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.1 (m, 1H), 2.83 (m, 6H), 2.5 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:28](=[O:30])[NH2:29])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:28](=[O:30])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cn2c3cccc(OCC(=O)O)c3c3c(C(N)=O)cccc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
A suspension of the {9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (15.8 mg, 0.039 mM) and 0.04 mL (0.04 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 24 h at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 10 mg (62%) of the {9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ7.55 (d, 1H, J=8 Hz), 7.5-7.0 (m, 9H), 6.85 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 5.6 (s, 2H), 4.35 (s, 2H), and 2.2 (s, 3H). IR (KBr, cm−1) 3390, 1656, 1613, 1595, 1573, 1498, 1455, 1408, 1325, 1332, and 719. MS (ES) m/e 387, 389.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:33]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:38][C:36]1[CH:37]=[C:32]([CH3:31])[N:33]=[C:34]([C:39]2([NH:42][C:24]([C:23]3[CH:27]=[CH:28][C:29]([CH3:30])=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:22]=3)=[O:25])[CH2:40][CH2:41]2)[N:35]=1
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (0.203 g, 1.2 mmol, 2.5 eq) (60% purity), HOBT (0.068 g, 0.5 mmol, 1.1 eq), EDC.HCl (0.105 g, 0.55 mmol, 1.1 eq) in DCM at ambient temperature under a nitrogen atmosphere was added diisopropylehtylamine (0.194 g, 1.5 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.24-1.27 (m, 2H), 1.53-1.56 (m, 2H), 2.30 (s, 3H), 2.32 (s, 6H), 2.82 (d, J=4.8 Hz, 3H), 7.00 (s, 1H), 7.38-7.44 (m, 4H), 7.59 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.82-7.84 (s and d, 2H), 7.98-8.02 (m, 2H), 8.47-8.50 (m, 1H), 9.14 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:11]([O:13][C:14](=[O:25])[C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:16][C:17]([CH3:19])=[CH2:18])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH2:11]([O:13][C:14](=[O:25])[C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:16][C:17]([C:4]1[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:19])[CH3:18])[CH3:12]
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Reactant: Brc1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)cc2c1OCC2)C(F)(F)F

Procedure:
4-(5-Bromo-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester was prepared using the procedure described in Example 1 with 5-bromo-2,3-dihydrobenzofuran and 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester in carbon disulfide with aluminum chloride.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>C1COCC1>[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH:3]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: Oc1ccc2c(c1)Nc1ccccc1S2
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(COc2ccc3c(c2)Nc2ccccc2S3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
1.08 g (5 mmol) of 2-hydroxy-10H-phenothiazine (J. Med. Chem. (1992) 35, 716) is dissolved, under argon atmosphere, in 20 ml anhydrous THF in a flask. The solution is then cooled down to 0° C. and 0.22 g (5.5 mmol) of NaH (60%) is added by portions. After agitation for 15 minutes, 1.2 g (5.5 mmol) of 4-nitrobenzyl bromide is added by portions and the reaction mixture is agitated for 15 hours at 20° C. before being poured into 50 ml of ice-cooled water. The product is extracted twice with 25 ml CH2Cl2 and the organic solution is washed successively with 25 ml of water and 25 ml of salt water. After drying over MgSO4, filtration and concentration under vacuum, the evaporation residue is purified on a silica column (eluent: CH2Cl2/EtOH: 99/1 to 98/2). After concentration of the purest fractions, a maroon solid is obtained, which is recrystallized using isopropyl acetate. A maroon solid is finally obtained with a yield of 37%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([N+:20]([O-])=O)[C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+]>O>[NH2:20][C:14]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]([O:18][CH3:19])=[CH:16][CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(N)c(C(=O)O)c1OCc1ccccc1
Temperature: 70 °C
Yield: 87 %

Procedure:
A solution of ferrous sulphate heptahydrate (99 g) in water (410 ml) that had been heated to 70° C. was added to a mixture of 2-benzyloxy-3-methoxy-6-nitrobenzoic acid (Bull. Soc. Chim. France, 1965, 1417; 15.5 g) and concentrated aqueous ammonium hydroxide (370 ml) which was heated to 70° C. The resultant mixture was heated to reflux for 30 minutes. The mixture was filtered and the basicity of the filtrate was adjusted to pH8 by the addition of 2N aqueous hydrochloric acid and then the filtrate was acidified to pH4 by the addition of 1M aqueous citric acid solution. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and with brine, dried over magnesium sulphate and evaporated to give 6-amino-2-benzyloxy-3-methoxybenzoic acid (12.15 g); NMR Spectrum: (CDCl3) 3.9 (s, 3H), 5.22 (s, 2H), 6.5 (d, 1H), 7.05 (d, 1H), 7.35-7.55 (m, 5H): Mass Spectrum: M+H+ 274.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[O:36][CH:37]([CH3:39])[CH3:38]>ClCCl>[CH:37]([O:36][C:35](=[O:40])[NH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C:22]4=[O:27])=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[CH2:4][CH2:5]1)([CH3:39])[CH3:38]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(=O)OC(C)C)CC2)c1OC

Procedure:
To a stirring solution of 4-[2-(1-Aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (150 mg, 0.272 mmol) in dichloromethane (10 mL), were added triethylamine (0.082 g, 0.811 mmol) and isopropyl carbonochloridate (66 mg, 0.544 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 183 to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH:10]([C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9](=[O:26])[CH:10]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:19]1[CH:24]=[CH:23][C:22](/[CH:28]=[CH:27]/[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(/C=C/S(C)(=O)=O)cc1
Yield: 74.8 %

Procedure:
(4-Bromo-phenyl)-tert-butoxycarbonylamino-acetic acid benzyl ester (1.5 g, 3.6 mmol), methyl vinyl sulfone (406 μL, 4.6 mmol), palladium(II) acetate (80 mg, 10 mol %), tri-o-tolylphosphine (217 mg, 20 mol %) and triethylamine (2.0 ml, 14.3 mmol) were combined in acetonitrile (18 mL), degassed and refluxed for 8 hours. Additional palladium(II) acetate (80 mg, 10 mol %) and tri-o-tolylphosphine (217 mg, 20 mol %) were added and refluxing continued overnight. The reaction was cooled, solvent removed in vacuo and the residue was purified by chromatography over silica gel gradient eluted from 20 to 90% v/v ethyl acetate in hexane to afford tert-butoxycarbonylamino-[4-((E)-2-methanesulfonyl-vinyl)-phenyl]-acetic acid benzyl ester (1.2 g, 75%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.C1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>O>[ClH:11].[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Cl:11])[CH:4]([OH:13])[CH2:3][NH:2][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1
Reactant: NCC(O)c1ccc(Cl)c(Cl)c1
Reactant: COc1cccc(C=O)c1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc(CNCC(O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
The free base obtained from 70.0 g. of rac.-α-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride is heated at reflux in 1 l. of benzene with 40.8 g. of 3-methoxybenzaldehyde using a water-separator for 2 hours until no more water is released. After concentration and dissolving in 1 l. of methanol, the product is reduced with 30 g. of sodium borohydride below 5°, evaporated and extracted with methylene chloride and water. The methylene chloride extract, acidified with ethanolic hydrogen chloride, crystallizes with ethyl acetate and, after recrystallization from methanol-ether, yields rac.-3,4-dichloro-α-{[(3-methoxybenzyl)amino]methyl}benzyl alcohol hydrochloride, m.p. 198°-200°. The free base recrystallized from methanol-petroleum ether has a m.p. of 94°-95°.