Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:18]N(C)C=O.CO.C[O-].[Na+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[CH2:18])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: CN(C)C=O
Agent: C[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CO
Solvent: O
Product: C=Cc1ccc2c(c1)c1ccccc1n2CC
Temperature: -5 °C

Procedure:
A three-necked flask having an inner volume of 500 ml equipped with a thermometer and a reflux condenser was charged with 22.3 g (0.1 mol) of N-ethylcarbazole-3-carboxaldehyde, 39 g (0.11 mol) of methyltriphenyl phosphonium bromide and 150 ml of N,N-dimethylformamide. This mixture was cooled by an ice-methanol bath to −5° C. under nitrogen gas stream while stirring the mixture by a magnetic stirring bar. To the mixture was gradually added 30 ml of 28% sodium methoxide methanol solution dropwise while maintaining the temperature of the mixture below 5° C. Then, the resultant mixture was stirred for 1 hour at 10° C., stirred for 2 hours at room temperature, poured into 3 L of cold water to deposite a crude solid, and filtered to obtain the crude solid. The crude solid was washed with water and dried, and the residue was purified by a silica gel column chromatography (dissolution medium: hexane/ethyl acetate=5/1). The dissolution medium was distilled off from the fraction containing the desired product and the resultant oil was subjected to crystallization using iso-propanol, to obtain 21 g of N-ethyl-3-vinylcarbazole as a crystal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([OH:20])=[CH:10][N:9]=1.Br[CH2:22][CH2:23][O:24][CH3:25]>O>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([O:20][CH2:22][CH2:23][O:24][CH3:25])=[CH:10][N:9]=1
Reactant: COc1ccc2c(Cl)ncc(O)c2c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1cnc(Cl)c2ccc(OC)cc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
Potassium carbonate (659 mg, 4.77 mmol) was added to a solution of 1-chloro-6-methoxyisoquinolin-4-ol (500 mg, 2.385 mmol) and 1-bromo-2-methoxyethane (663 mg, 4.77 mmol) and stirred for 3 hrs at 50° C. After 3 hrs, the reaction was diluted with water and extracted with EtOAc. The organic layer was washed with water (2×) followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude product 1-chloro-6-methoxy-4-(2-methoxyethoxy)isoquinoline (560 mg, 88% yield) as an orange solid. Crude material used as is in next step. MS: MS m/z 268.15(M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[I-].[K+].Br[CH2:29][CH:30]1[O:34][CH2:33][CH2:32][O:31]1>CS(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:29][CH:30]3[O:34][CH2:33][CH2:32][O:31]3)[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: BrCC1OCCO1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2cccnc2sc(=Nc2ccc(Cl)cc2)n1CC1OCCO1
Yield: 9.6 %

Procedure:
In an atmosphere of argon, a mixture of 290 mg (1.0 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 1.4 ml of DMSO was put in a 30 ml flask. To the mixture was then added 113 mg (1.0 mmol) of potassium t-butoxide with stirring. The mixture was then stirred for 1 hour. To the mixture was then added 10 mg (0.06 eq) of potassium iodide. To the mixture was then added 484 mg of 2-bromomethyl-1,3-dioxolane. The mixture was then stirred for 15 hours. After the termination of reaction, the reaction mixture was extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/2 mixture of ethyl acetate and normal hexane). As a result, 36 mg of 2-[(4-chlorophenyl)imino]-3-([1,3]dioxolan-2-ylmethyl)-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 20 mg of 2-[N-(4-chlorophenyl)-N-([1,3]dioxolan-2-ylmethyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1)C1CC1

Procedure:
Example 17 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 9.26–9.09 (br, 1H), 8.12–7.91 (br, 1H), 7.69 (d, 1H, J=7.2 Hz), 7.63–7.42 (br, 1H), 7.43–7.12 (m, 11H), 6.88 (d, 1H, J=7.2 Hz), 5.03 (s, 1H), 3.53–3.27 (m, 4H), 2.99–2.84 (m, 2H), 2.84–2.58 (m, 3H), 2.40–2.16 (m, 2H), 2.16–1.98 (m, 2H), 1.98–1.83 (m, 2H), 1.78–1.64 (m, 1H), 1.10–0.97 (m, 2H), 0.90–0.76 (m, 2H); ESMS m/e: 496.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[CH2:14]3)[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:37]([O:38][CH3:39])=[CH:36][C:25]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[C:24]([Cl:40])[CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1.C1(C)C=CC=CC=1>[Cl:40][C:24]1[CH:23]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:17]=3[C:16](=[O:18])[N:15]([CH3:19])[CH2:14]4)[C:5]([Cl:20])=[CH:4][N:3]=2)[C:37]([O:38][CH3:39])=[CH:36][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27]
Reactant: CN1Cc2cccc(Oc3nc(Cl)ncc3Cl)c2C1=O
Reactant: COc1cc(C(=O)OCc2ccccc2)c(Cl)cc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: COc1cc(C(=O)OCc2ccccc2)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
7-(2,5-dichloro-pyrimidin-4-yloxy)-2-methyl-2,3-dihydro-isoindol-1-one (0.10 g), benzyl 4-amino-2-chloro-5-methoxy-benzoate (0.28 g), Pd2dba3 (18 mg), X-Phos (37 mg) and Cs2CO3 are weighed into a microwave vial and argon flushing is carried out. Then toluene (1 mL) and NMP (50 μL) are added, argon flushing is carried out again and the mixture is stirred for 5 min at 150° C. in the microwave. For working up the mixture is diluted with ACN (20 mL) and combined with Isolute (Separtis GmbH). The solvent is eliminated in vacuo and then purified by preparative HPLC. (IC50=53 nmol)
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:28]1([S:34]([Cl:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>C(Cl)Cl.C(OCC)C>[C:28]1([S:34]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:6][CH2:5]2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[ClH:37]
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCCN1CCC(NS(=O)(=O)c2ccccc2)CC1)c1ccccc1
Reaction time: 24 h

Procedure:
To a stirred solution of 4-amino-1-(4-phenyl-4-oxobutyl)-piperidine dihydrochloride (1.752 g. 0.005 mole) and triethylamine (2 ml.) in CH2Cl2 (10 ml.) was added dropwise a solution of benzenesulphonyl chloride (0.883 g. 0.005 mole) in CH2Cl2 (5 ml.). The mixture was stirred for 24 hours and extracted with water (3× 10 ml.). The organic phase was separated, dried (MgSO4) and evaporated to give a crystalline residue. Treatment of this with ethanolic HCl followed by diethyl ether afforded the title compound as the monohydrochloride, buff solid (1.961 g.), m.p. 195.2° C.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH3:6]/[C:7](=[CH:12]\[CH2:13][CH2:14]/[C:15](/[CH3:25])=[CH:16]/[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)/[CH2:8][CH2:9][CH:10]=[O:11].[Cl-].[NH4+]>CCOCC.[Hg](Cl)Cl.O1CCCC1>[CH3:6][C:7](=[CH:12][CH:13]=[CH:14][C:15]([CH3:25])=[CH:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)/[CH:8]=[CH:9]/[C:10](/[OH:11])=[CH:4]\[C:3]#[CH:2]
Reactant: C/C(=C\CC/C(C)=C/COC1CCCCO1)CCC=O
Reactant: C#CCBr
Agent: Cl[Hg]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#C/C=C(O)\C=C\C(C)=CC=CC(C)=CCOC1CCCCO1
Reaction time: 0.25 h

Procedure:
4.86 g of magnesium shavings, 100 mg of mercury(II) chloride and 100 ml of ether are placed under an argon atmosphere in a 500 ml sulfonation flask provided with a mechanical stirrer, a dropping funnel and a thermometer. The dropping funnel is charged with a solution of 23.8 g (15.1 ml) of propargyl bromide in 50 ml of ether and 1.0 ml of this solution is added dropwise to the above mixture at room temperature. After the reaction has begun the mixture is cooled to -20° and the remainder of the propargyl bromide solution is added dropwise within 3 hours so that the reaction temperature does not exceed -15°. After completion of the addition the mixture is stirred at -20° for a further 15 minutes. A solution of 28.0 g of (E,E)-4,8-dimethyl-10-[(tetrahyro-2H-pyran-2-yl)-oxy]-4,8-decadienal in 50 ml of ether is then added dropwise at 0°. After the addition of half of this solution a precipitate results, whereupon 100 ml of ether and 100 ml of tetrahydrofuran are added in order to facilitate the stirring. The remainder of the mentioned solution is subsequently added dropwise at 5°-10° and the resulting grey suspension is stirred overnight in a melting ice-bath and then poured into a mixture of ice and saturated ammonium chloride solution. The organic phase is separated and the aqueous phase is extracted twice with hexane. The combined organic phases are washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on 1.0 kg of silica gel with hexane-ethyl acetate 10%→25%. There is obtained (E,E)-7,11-dimethyl-13-[(tetrahydro-2H-pyran-2-yl)oxy]-7,11-tridecadien-trien-1-yn-4-ol as a yellow oil. IR (film): 3450 (OH); 3307, 2118 (--C≡C--H); 1667 (C=C). MS: 236 (1, (M-dihydro-pyran, C5H8O)+); 218 (0,5, (M-(2-hydroxytetrahydro-pyran, C5H10O2))+); 85 (100, C5H9O+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:10]=1[CH2:11][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C=O)c1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NCc2cc(S(C)(=O)=O)ccc2OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
A suspension of 2-benzyloxy-5-methanesulphonylbenzaldehyde (10 g) and methyl 4-aminobenzoate (5.2 g) in toluene (100 mL) was heated on a steam bath for 18 hours and evaporated to dryness. The residue was dissolved in a mixture of methanol (100 mL) and tetrahydrofuran (100 mL) and the first portion of sodium borohydride (1.3 g) was added. The mixture was stirred for 1 hour and the second portion of sodium borohydride (1.3 g) was added. The mixture was stirred for 30 minutes and evaporated to dryness. The residue was dissolved in dichloromethane (250 mL) and was washed with water and dried (MgSO4). The solvent was evaporated and the residue subjected to chromatography on silica eluting initially with dichloromethane and then with a mixture of ethyl acetate and dichloromethane (3/7 v/v) to give methyl 4-[N-(2-benzyloxy-5-methanesulphonylbenzyl)amino]benzoate, yield 10.2 g, mp 124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2.C1([C@H](N)C)C2C(=CC=CC=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH2:13][C:14]([CH3:17])([CH3:15])[CH3:16])[O:8][C@H:7]([C:18]([F:21])([F:19])[F:20])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2
Reactant: CC(C)(C)CCc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: C[C@@H](N)c1cccc2ccccc12
Product: CC(C)(C)CCc1cc2c(cc1Cl)C=C(C(=O)O)[C@@H](C(F)(F)F)O2

Procedure:
A racemic mixture of the compound prepared in Example 9b, Step 3 was chirally resolved using the same protocol as for Example 609e, Step 1, S-enantiomer was identified as peak 2 with retention time 10.35 min: ESHRMS m/z 361.0848 (M−H, C17H17ClF3O3 Calc'd 361.0813). 1HNMR (DMSO-d6/400 MHz) 13.23 (brs, 1H, 7.80 (s, 1H), 7.55 (s, 1H), 7.01 (s, 1H), 5.89 (q, 1H, J=7.1 Hz), 3.30 (m, 2H), 2.56-2.60 (m, 2H), 1.31-1.37 (m, 2H), 0.91 (s, 9H). 19FNMR (d6-benzene; 6 eq of (R)-(+)-1-(1-naphthyl)ethylamine) d−77.80 (d, 3F, J=6.8 Hz, R-enantiomer), −77.77 (d, 3F, J=6.8 Hz, S-enantiomer).
Reaction SMILES: N[C:2]1[C:3]([O:29][CH3:30])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH:7]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.N([O-])=O.[Na+].[OH-].[Na+].[ClH:37]>O>[CH2:12]([N:9]1[CH2:8][CH:7]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:6]2[C:11](=[C:2]([Cl:37])[C:3]([O:29][CH3:30])=[CH:4][CH:5]=2)[CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cl
Reactant: COc1ccc(C2CN(Cc3ccccc3)Cc3c2ccc(OC)c3N)cc1OC
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C2CN(Cc3ccccc3)Cc3c2ccc(OC)c3Cl)cc1OC

Procedure:
2.02 g of 8-amino-2-benzyl-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 20% hydrochloric acid; and to the solution was added dropwise a solution of 0.38 g of sodium nitrite in 1.9 ml of water, under cooling. To the mixture was added dropwise a solution of 0.55 g of cuprous chloride in 11 ml of 20% hydrochloric acid. After the reaction was over, 4.84 g of sodium hydroxide was added to the mixture, and the mixture was extracted with chloroform 2 times. The chloroform layer was collected, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol, giving 1.23 g of 2-benzyl-8-chloro-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (m.p. 88°-91° C.). ##STR58##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([NH:15][CH:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12][C:13]=1[CH3:14].BrC(C)C([C:28]1[CH:33]=[CH:32][C:31](Cl)=CC=1Cl)=O.[H-].[Na+]>O1CCCC1.C1(CBr)CC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:15]([CH:16]([CH3:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:31][CH:32]2[CH2:28][CH2:33]2)[S:12][C:13]=1[CH3:14]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1sc(NC(C)c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Agent: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1sc(N(CC2CC2)C(C)c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., add 0.5 g of 4-(2,4-dichlorophenyl)-5-methyl-2-[N-(α-methylbenzyl)amino]thiazole (prepared from Compound 92 and Compound 15 according to the process described in Example 1), dissolved in 5 ml of anhydrous tetrahydrofuran, and 66 mg of sodium hydride. After 30 minutes of stirring at room temperature, run in 0.67 ml of cyclopropylmethyl bromide dropwise. Leave for eight hours under reflux, cool and dilute the reaction medium with methylene chloride, then pour it onto ice.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[C:5](=[CH:10][C:11]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[CH:13]=1)[C:6]([O:8]C)=[O:7].CO.[Li].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=1[NH:25][C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[CH:13][C:12]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])[C:3]([OH:36])=[O:2]
Reactant: COC(=O)c1cc(Nc2ccc(OC)cc2OC)c(Nc2ccc(OC)cc2OC)cc1C(=O)OC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Li]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2cc(C(=O)O)c(C(=O)O)cc2Nc2ccc(OC)cc2OC)c(OC)c1
Temperature: 25 °C

Procedure:
A steady stream of argon is passed through a suspension of 260 mg (0.6 mmol) of 4,5-bis(2,4-dimethoxy-anilino)phthalic acid dimethylester in 2 mlof methanol, and a solution of 101 mg (2.4 mmol, 4 eq) of lithium hydroxidemonohydrate and 10 mg sodium ascorbate in 1 ml of water is added. The reaction mixture is heated to reflux for 10 hours, cooled to RT, and the methanol is removed by evaporation. The resulting mixture is poured onto 20 ml of 4N hydrochloric acid, the red suspension is filtered and the crystals are washed with washed with isopropanol/hexane 1:5 to yield the title compound in the form of red crystals, FAB-MS: 469 [M+ +H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH3:13][S:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:6][O:8][C:9]([C:4]1[N:22]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([S:14]([CH3:13])(=[O:15])=[O:16])=[CH:18][CH:19]=2)[C:6](=[O:8])[C:5]2[C:4]([C:9]=1[OH:10])=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)=[O:10]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Product: COC(=O)c1c(O)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The present compound was synthesized according to the method shown in Reference Example 8 and using 4-chloro phthalic anhydride and 4-(methanesulfonyl)benzylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([NH2:21])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[C:19]([C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]1[C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])#[N:21]
Reactant: COc1ccc([C@@H]2CCCC[C@H]2C(N)=O)c(OC)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2CCCC[C@H]2C#N)c(OC)c1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a stirred solution of 1.05 g (3.58 mmol) of trans-2-(2,3,4-trimethoxyphenyl)-cyclohexane-1-carboxamide in 5 mL of THF and 5 mL of CCl4 was added 1.88 g (7.17 mmol) of triphenylphosphine. The mixture was stirred at 50° C. for 2 h. The mixture was diluted with 70 mL of ethyl acetate, washed with 50 mL of 5% aqueous HCl and 50 mL of saturated aqueous NaHCO3, and dried over MgSO4. Removal of the solvent left 2.38 g of a tan solid which was purified by flash chromatography on a column of 30 g of silica gel eluted successively with 100 mL portions of 0, 10, 20, 30, 40, 50 and 60% ether in hexanes to afford 0.77 g of trans-1-cyano-2-(2,3,4-trimethoxyphenyl)cyclohexane (Example 42) as a white solid, mp 69°-72° C.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][CH2:10][C@@H:9]([C:19]([OH:21])=[O:20])[NH:8][C:7]1=[O:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[C:1]([S:4][CH2:5][CH:6]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][CH2:10][C@@H:9]([C:19]([O:21][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20])[NH:8][C:7]1=[O:22])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)SCC1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(=O)SCC1CCCCCCCSC[C@@H](C(=O)OCc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R)-6-(Acetylthiomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid (0.62 g, 1.78 mmol) is dissolved in dimethylformide (8 ml) and cesium carbonate (0.64 g, 1.96 mmol) is added, followed by benzyl bromide (0.31 g, 1.78 mmol). The mixture is stirred overnight at room temperature, poured into water (300 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers are washed with water (2×100 ml), brine (1×200 ml), dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (5% ethyl acetate/hexane) gives benzyl (3R)-6-(acetylthiomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylate, m.p. 192°-193° C.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:19][C:17]([CH3:20])([S:21]([NH:23][CH:24]([C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11])[CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])[CH3:18]
Reactant: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Reactant: CCOc1cccc(F)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(F)cccc1OCC
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of 2-bromo-1-ethoxy-3-fluorobenzene (3.520 g; 16.10 mmol) in anh. THF (60 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (10.05 ml; 16.10 mmol). The resulting solution was further stirred at −78° C. for 5 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (2.650 g; 10.70 mmol) in anh. THF (20 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 30 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (75 ml), Et2O (250 ml) and water (75 ml). The separated organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate as a yellow oil. LC-MS (conditions A): tR=0.85 min. and [M+H]+: 388.35 g/mol; tR=0.88 min. and [M+H]+: 388.37 g/mol (mixture of diastereoisomers).