Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.OS(O)(=O)=O.[CH3:18]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:18])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Br)cc1F
Yield: 94 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (260 g, 1.13 mol) in MeOH (2 L) was added H2SO4 (30 mL) at rt. The solution was heated to reflux overnight. Then the solvent was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. Another batch was repeated using the same procedure. Then the two batches were combined to provide methyl 2-(4-bromo-2-fluorophenyl)acetate (520 g, 94%). TLC (PE/EA=10:1, Rf=0.7). 1H NMR (400 MHz, CDCl3) δ 7.25-7.20 (m, 2H), 7.14 (t, J=8.0 Hz, 1H), 3.70 (s, 3H), 3.62 (s, 2H).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[C:46]([F:49])([F:48])[F:47]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:42]2[CH:43]=[CH:44][C:45]([C:46]([F:48])([F:49])[F:47])=[C:40]([Cl:39])[CH:41]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)c(Cl)c2)c1

Procedure:
5-(tert-Butyl)-3′-chloro-2-hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3-chloro-4-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:25][C:19]=2[CH:18]=1)=[O:16])(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:25][C:19]=2[CH:18]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(OCc3ccccn3)ccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1cc2cc(OCc3ccccn3)ccc2s1
Yield: 582.8 %

Procedure:
A solution of 72 mg (0.151 mmol) of (2-{[5-(Pyridin-2-ylmethoxy)-benzo[b]thiophene-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (52) in 1.0 ml trifluoroacetic acid was stirred for 45 min at room temperature and then added to an aqueous solution of sodium bicarbonate. After extraction with ethyl acetate and removal of the solvent the residue was recrystallized from ethyl acetate to yield 33 mg (0.88 mmol) 5-(Pyridin-2-ylmethoxy)-benzo[b]thiophene-2-carboxylic acid (2-amino-phenyl)-amide (51) as white solid, mp. 205–207° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.CS[C:22]1[NH:23][CH2:24][C:25](=[O:27])[N:26]=1.C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:22]2[NH:23][CH2:24][C:25](=[O:27])[N:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSC1=NC(=O)CN1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CNC(NCCCOc2cccc(CN3CCCCC3)c2)=N1

Procedure:
3-(3-Piperidinomethylphenoxy)propylamine (3.01 g), 2-methylthio-imidazolin-4-one hydroiodide (2.60 g) and triethylamine (2.18 g) were refluxed in ethanol (20 ml) for 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].N1C=CC=CC=1.Cl[C:18]([O:20][CH3:21])=[O:19].Cl>ClCCl.CN(C1C=CN=CC=1)C>[C:18](=[O:19])([O:20][CH3:21])[O:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)ccc1O
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Oc1ccc(C)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
2-methoxy-4-methylphenol (250 mmol) was dissolved in dry dichoromethane (500 ml) with pyridine (392 mmol) and DMAP (N,N-dimethyl-4-aminopyridine, 4.26 mmol). Methyl chloroformate (317 mmol) was added slowly to this solution and the reaction was stirred at room temperature for 3 hours. The reaction mixture was then poured onto a 2M HCl solution (120 ml), and the aqueous layer was extracted twice with dichloromethane (50 ml). Then the combined organic layers were washed twice with water (100 ml), dried over MgSO4 and filtered. The solvent was evaporated and the residue distilled under reduced pressure (120-140° C., 0.4 mbar) to give 38 g (186 mmol, 74% yield) of pure 2-methoxy-4-methyl-phenyl methyl carbonate.
Reaction SMILES: C[O:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2CC2C=CC(OC)=CC=2)[CH2:8][C@H:7]([NH:9][C:10](=[O:18])/[CH:11]=[C:12](/[CH3:17])\[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:6][C@@H:5]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[O:4]1.COC1C=CC(CN2CCSC2=O)=CC=1>>[OH:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[NH:25]2)[CH2:8][C@H:7]([NH:9][C:10](=[O:18])/[CH:11]=[C:12](/[CH3:17])\[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:6][C@@H:5]([CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])[O:4]1
Reactant: C=CCCC[C@@H]1C[C@@H](NC(=O)/C=C(/C)CCC=C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2CCSC2=O)cc1
Product: C=CCCC[C@@H]1C[C@@H](NC(=O)/C=C(/C)CCC=C)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (Z)-N-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin4-yl)-6-(pent-4-enyl)-tetrahydro-2H-pyran-4-yl)-3-methylhepta-2,6-dienamide was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadexa-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH:21]([CH3:24])[CH2:22][NH2:23].CCN(C(C)C)C(C)C>>[OH:20][CH:21]([CH3:24])[CH2:22][NH:23][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CC(O)CN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-hydroxy-propylamine and DIEA to give 2-(2-hydroxy-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 314 (MH+).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>[Ni]>[CH3:4][C:3]1[CH:6]=[CH:7][C:8]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:9][CH:2]=1
Reactant: N#Cc1ccccc1Cl
Agent: [Ni]
Product: Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
In one practical embodiment, 4-methylphenylchloride in tetrahydrofuran solvent is reacted with magnesium to form 4-methylphenylmagnesium chloride. An equivalent of zinc chloride is added to this mixture to form 4-methylphenylzinc chloride. This mixture is then combined with the 2-chlorobenzonitrile and the nickel catalyst components and reacted to form the 2-(4′-methylphenyl)benzonitrile.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>CN(C)C=O>[CH2:27]([C@:25]1([OH:26])[C:15]2[CH:14]=[C:13]3[N:18]([C:17](=[O:21])[C:16]=2[CH2:22][O:23][C:24]1=[O:29])[CH2:19][C:20]1[C:8]([CH2:7][CH2:6][Si:5]([CH2:4][CH2:3][CH2:2][N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)([CH3:34])[CH3:35])=[C:9]2[CH:33]=[CH:32][CH:31]=[CH:30][C:10]2=[N:11][C:12]3=1)[CH3:28]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCBr
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCn1ccnc1
Yield: 77 %

Procedure:
A solution of Compound 11 (60 mg) and imidazole (37 mg) in dry N,N-dimethylformamide (1 mL) was heated at 70° C. for 16 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and the residue was directly eluted on a silica gel column using 3% ethanol in dichloromethane to obtain the required product in 77% yield (45 mg).
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.CCCCCC.C([Li])CCC.[N:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([C:21]3=[O:28])[CH2:19]1)[CH2:25]2>O1CCCC1.CO>[C:22]([C:21]1([OH:28])[CH:20]2[CH2:19][N:18]3[CH2:25][CH:24]([CH2:5][CH:6]1[CH2:27]3)[CH2:26]2)#[CH:23]
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: C#CC1(O)C2CC3CC1CN(C3)C2
Reaction time: 0.5 h

Procedure:
To a solution of 0.2 ml of trimethylsilylacetylene in 2 ml of tetrahydrofuran was added dropwise 0.64 ml of a 1.56 mol hexane solution of n-butyllithium in a dry ice-acetone bath. After stirring for 30 minutes, a solution of 50 mg of 1-azaadamantane-4-one in 1 ml of tetrahydrofuran was added dropwise to the mixture. After further stirring for 30 minutes, 1 ml of methanol was added to the mixture and the temperature was elevated to room temperature. The solvent was removed and water was added to the resulting solid. Crystals that remained were collected by filtration, to give 17 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH2:6][N:7]=1.[Cl:8][C:9]1[N:10]([CH2:15][C:16](OC)=[O:17])[C:11]([Cl:14])=[CH:12][CH:13]=1>>[Cl:8][C:9]1[N:10]([CH2:15][C:16]([N:1]=[C:2]2[NH:3][CH2:4][CH2:5][CH2:6][NH:7]2)=[O:17])[C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: NC1=NCCCN1
Reactant: COC(=O)Cn1c(Cl)ccc1Cl
Product: O=C(Cn1c(Cl)ccc1Cl)N=C1NCCCN1

Procedure:
By a procedure analogous to Example 8, 2-amino-1,4,5,6-tetrahydropyrimidine is reacted with methyl (2,5-dichloro-1H-pyrrol-1-yl)acetate to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:4]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C(=O)C>[N:15]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:4]=1)=[N+:16]=[N-:17]
Reactant: FC(F)(F)COc1cccc(CCl)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: [N-]=[N+]=NCc1cccc(OCC(F)(F)F)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 122.3 %

Procedure:
A mixture of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.35 g, 1.55 mmol, Step-4) and sodium azide (0.20 g, 3.10 mmol) in N,N-dimethylacetamide (8 mL) is stirred 90° C. for 1 hour. The reaction mixture is poured into water (50 mL), and extracted with n-hexane/ethyl acetate (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. The organic fraction is concentrated in vacuo to give 0.44 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-6) without further purification.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29][CH2:30][CH3:31])[N:10]=1.CN(C=O)C>O>[CH2:30]([S:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:11]1[N:10]=[CH:9][C:18]2[C:13](=[CH:14][C:15]([C:19]([F:21])([F:22])[F:20])=[CH:16][CH:17]=2)[N:12]=1)[CH3:31]
Reactant: CCSc1ccccc1-c1nc(N)c2ccc(C(F)(F)F)cc2n1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccccc1-c1ncc2ccc(C(F)(F)F)cc2n1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 15.3 %

Procedure:
324 mg of t-butyl nitrite was added to a mixture of 506 mg of 4-amino-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline and 10 ml of DMF at 100° C., and the mixture was stirred at 100° C. for 45 minutes. Water was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 74 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 11).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:24]1[C:37]2[C:28](=[CH:29][C:30]3[C:35]([C:36]=2[C:38](Cl)=[O:39])=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][CH:25]=1>>[CH2:2]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:38]([C:36]3[C:37]4[C:28]([CH:29]=[C:30]5[C:35]=3[CH:34]=[CH:33][CH:32]=[CH:31]5)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:39])[CH2:20][CH2:19]2)[CH2:13]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Reactant: O=C(OCc1ccccc1)C1CCCN(C2CCNCC2)C1
Agent: Cl
Product: O=C(OCc1ccccc1)C1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1

Procedure:
[1,4′]Bipiperidinyl-3-carboxylic acid benzyl ester hydrochloride and anthracene-9-carbonyl chloride were reacted using a procedure analogous to that described above for Example 1 to give the title compound.
Reaction SMILES: O[N:2]1[C:6]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)[N:33]2[CH2:36][CH:35]([CH2:37][S:38]([NH:41][C:42]3[CH:43]=[C:44]([CH:53]=[CH:54][CH:55]=3)[C:45]([NH:47][C@@H:48]([CH3:52])[C:49](O)=[O:50])=[O:46])(=[O:40])=[O:39])[CH2:34]2)=[CH:28][CH:27]=1>O1CCCC1.C(N(CC)CC)C>[Cl:62][C:59]1[CH:58]=[CH:57][C:56]([CH:32]([C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=2)[N:33]2[CH2:36][CH:35]([CH2:37][S:38]([NH:41][C:42]3[CH:43]=[C:44]([CH:53]=[CH:54][CH:55]=3)[C:45]([NH:47][C@H:48]([C:49](=[O:50])[NH:2][CH3:6])[CH3:52])=[O:46])(=[O:40])=[O:39])[CH2:34]2)=[CH:61][CH:60]=1
Reactant: C[C@H](NC(=O)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)[C@H](C)NC(=O)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Temperature: 20 °C
Yield: 111.9 %

Procedure:
60 mg of 1-hydroxybenzotriazole, 200 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.700 cm3 of a 2M solution of methylamine in tetrahydrofuran, 0.370 cm3 of triethylamine and 8 cm3 of tetrahydrofuran are added successively to a solution of 0.5 g of (S)-2-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)benzoyl-amino]propionic acid in 15 cm3 of tetrahydrofuran, stirred at a temperature in the region of 20° C. under an inert atmosphere. The reaction medium is stirred at a temperature in the region of 20° C. for 18 hours. After concentration to dryness under reduced pressure, the residue is dissolved in a mixture consisting of 30/15 cm3 of dichloromethane/water. After separation by settling out, the aqueous phase is extracted twice with 15 cm3 of dichloromethane. The organic phases are combined, washed with 15 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and then concentrated to dryness, to give 0.415 g of a crude product which is purified by flash chromatography on a Merck 25 g silica cartridge (particle size: 15-40 μm; eluent: 100 ethyl acetate). After concentration of the fractions under reduced pressure, 0.293 g of a product is obtained which is triturated in a minimum amount of pentane. After filtration, concentration to dryness under reduced pressure and drying, 0.247 g of a solid cream is obtained. 147 mg of this solid cream are injected onto a column 6 cm in diameter containing 700 g of Chiralpak IA 20 μM chiral stationary phase. The elution is carried out at 80 cm3 per minute with a mobile phase composed of 95% acetonitrile and 5% dichloromethane. The dextrorotatory enantiomer is eluted in the second position. After concentration of the mobile phase, 105 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N—((S)-1-methyl-carbamoylethyl)benzamide are obtained in the form of an amorphous white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:35].CO>CC#N>[Cl:35][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OC(c1ccccn1)c1ccccn1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CC#N
Product: ClC(c1ccccn1)c1ccccn1
Reaction time: 8 h
Yield: 56 %

Procedure:
To di(2-pyridinyl)methanol (8.73 g, 46.94 mmol) in CH3CN (100 ml) at 0° C. was added a solution of PPh3 (14.77 gram, 56.32 mmol) in of CCl4 (80 mL) in 1.5 h. The solution was left standing overnight. After addition of MeOH (10 ml) and stirring for 15 min the mixture was concentrated in vacuum to ca 50 ml. To the residue was added of water (100 ml) and the mixture was acidified with 2M HCl to pH=1, and washed twice with 100 ml of CHCl3, the aqueous layer was neutralized with K2CO3 and extracted 4 times with 75 ml of ether. Drying and evaporation of the solvent yielded 2-[chloro(2-pyridinyl)methyl]pyridine (5.41 gram, 56%) as a pale brown solid. Analytically pure material was obtained by column chromatography on silica (ether). 1H-NMR (200 MHz, CDCl3) δ 6.20 (s, 1H), 7.14-7.20 (m, 2H), 7.60-7.73 (m, 4H). 8.51-8.54 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 62.84 (d), 121.3 (d), 121.5 (d), 135.7 (d), 147.7 (d), 156.9 (s). Anal. Cald. for C11H9ClN2: C 64.56, H 4.43, Cl 17.32, N 13.69; Found: C 64.48, H 4.45, Cl 17.29, N 13.49.
Reaction SMILES: [CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[N:30]1[C:37]([Cl:38])=[N:36][C:34](Cl)=[N:33][C:31]=1[Cl:32].C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:34]3[N:36]=[C:37]([Cl:38])[N:30]=[C:31]([Cl:32])[N:33]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(Nc4nc(Cl)nc(Cl)n4)ccc3c2O)cc1
Reaction time: 3 h
Yield: 82 %

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester Example 6, 10 g, 24 mmol) was suspended in acetone (120 mL) and cyanuric chloride (6.65 g, 36 mmol) was added. Saturated sodium bicarbonate (3 mL) was then added to the suspension. After 3 h, the reaction mixture was filtered, to provide the title compound (11.1 g, 19.7 mmol, 82%) as a red solid: NMR (DMSO-d6): δ 16.30 (s, 1H), 11.86 (s, 1H), 8.25 (d, J=9 Hz, 1H), 8.08 (s, 1H), 7.96 (d, J=9 Hz, 1H), 7.87 (s, 1H), 7.76 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 4.61 (m, 1H), 3.92 (s, 3H), 1.31 (d, J=3 Hz, 6H); MS (° FAB): 2 chlorine isotope pattern, [M+Na+] 585, [M+H+] 563; Anal. Calc. for C23H20Cl2N6O5S: C, 49.03, H, 3.58, N, 14.92. Found: C, 47.66, H, 3.29, N, 14.31.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([C@@H:14]([OH:26])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:16])[C:9]2=[O:27])=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][O:31][CH2:32][C:33](O)=[O:34].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C@H:14]([OH:26])[C@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]4[CH2:29][CH2:30][O:31][CH2:32][C:33]4=[O:34])=[CH:3][CH:4]=3)[C:9]2=[O:27])=[CH:19][CH:20]=1)#[N:25]
Reactant: O=C(O)COCCCl
Reactant: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(N)cc3)C2=O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(N4CCOCC4=O)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a suspension of compound 26-5 (0.1 g) and 2-chloroethoxy acetic acid (45.4 mg) in DMF (2 mL), was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM; 87.7 mg). The reaction mixture was stirred at room temperature overnight. Then, according to the Step 29-1 in synthetic method for EXAMPLE 29, cyclization reaction was pursued to obtain compound 30-1 (90 mg) as a colorless amorphous solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2OC)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])C.[CH3:25][OH:26]>[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:26][CH3:25])=[CH:19][CH:18]=2)(=[O:15])=[O:16])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]1)[CH3:13]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccccc2OC)CCN(CC)CC1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(OC)cc2)CC1

Procedure:
1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-ethyl4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (2.42 g, 6.8 mmol) dissolved in methanol (100 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.29 g (58%); white solid; mp 209° C.; MS: 328 (M+H)+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][CH2:22][C:23]1[CH2:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25][N:24]=1>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH3:31][O:30][C:26]1[C:27](=[O:29])[CH2:28][C:23]([CH2:22][O:21][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:24][CH:25]=1
Reactant: COC1=CN=C(CO)CC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COC1=CN=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
Trityl chloride (9.43 g) is added in one portion to a solution of 2-hydroxymethyl-5-methoxy-4-pyridone (5 g) and 4-dimethylaminopyridine (4.2 g) in dry dimethylformamide (80 mL) and the solution stirred at room temperature for 12 hours. The mixture is then heated on a steam bath for 3 hours and diluted with iced water (300 mL) to give a light brown solid. The solid is collected, washed with water and sucked dry. The solid is dissolved in hot ethyl acetate to give a clear solution which immediately deposits a granular off-white solid. The solid does not redissolve on further heating. After cooling the solid is collected, washed with ethyl acetate and diethyl ether and dried to give 5-methoxy-2-trityloxymethyl-4-pyridone (7.5 g) as an off-white solid, m.p. 185–7° C.