Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][OH:6].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([N:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][OH:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1CCN1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CC[C@H]1CO
Reaction time: 14 h
Yield: 69.1 %

Procedure:
Said solution of (S)-azetidine-2-methanol was adjusted to pH 10 by adding 10% sulfuric acid, sodium hydrogen carbonate (2.00 g, 24.0 mmol) was then added and benzyloxycarbonyl chloride (ZCl) (4.00 g, 24.0mmol) was added at room temperature. Thereafter, stirring was continued for 14 hours. The mixture was adjusted to pH 7 and extracted with ethyl acetate (50 mL ×1), the extract was washed with water (50 mL×1) and dried over magnesium sulfate and, after filtering off the same, the filtrate was concentrated. This was subjected to column chromatography (Wakogel C-200) using toluene/ethyl acetate (1/1) as a mobile phase for separation and purification, whereby a pale yellow oil was obtained (1.50 g). Based on its proton NMR spectrum (FIG. 3), this was identified as the desired product (S)-N-benzyloxycarbonylazetidine-2-methanol (yield 69.1%). Further, as a byproduct, there was obtained (S)-2-N-benzyloxycarbonyl-1,4-butanediol (0.27 g, yield 11.4%). Its proton NMR spectrum is shown in FIG. 4.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=1>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:64]=1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc(OC)c(-c2cccc(N)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,5′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.02 g of product in 64% yield: LCMS (ESI) m/z 486 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[N:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[CH:12]4)[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Clc1cncc(Nc2ccc3[nH]ccc3c2)n1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1cc(-c2cncc(Nc3ccc4[nH]ccc4c3)n2)ccn1
Yield: 31.1 %

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-1H-indol-5-amine (0.030 g, 0.123 mmol), pyridine-4-boronic acid (0.018 g, 0.147 mmol), sodium carbonate (0.067 g, 0.615 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield N-(6-pyridin-4-ylpyrazin-2-yl)-1H-indol-5-amine (0.011 g, 31%) as a yellow solid. 1H NMR (CD3OD) δ 8.70-8.68 (d, J=6.17 Hz, 2H), 8.47 (s, 1H), 8.15 (s, 1H), 8.14 (d, J=1.50 Hz, 2H) 7.96 (d, J=1.70 Hz, 1H), 7.45-7.43 (d, J=8.64 Hz, 1H), 7.37-7.35 (dd, J=10.46, 1.83 Hz, 1H), 7.29-7.28 (d, J=3.06 Hz, 1H), 6.49-6.48 (d, J=3.02 Hz, 1H); MS (API-ES/Positive); m/z: 288 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=O)[CH2:5][C:4]1([CH3:13])[CH3:12].[CH2:14]([NH2:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:21][CH:6]2[CH2:7][C:8]([CH3:9])([CH3:10])[N:3]([O:2][CH3:1])[C:4]([CH3:13])([CH3:12])[CH2:5]2)[CH2:5][C:4]1([CH3:13])[CH3:12]
Reactant: CON1C(C)(C)CC(=O)CC1(C)C
Reactant: NCCCCCCN
Product: CON1C(C)(C)CC(NCCCCCCNC2CC(C)(C)N(OC)C(C)(C)C2)CC1(C)C

Procedure:
The product is prepared as described in Example II-1, by reaction of 185.3 g (1 mole) of 1-methoxy-2,2,6,6-tetramethyl-4-oxopiperidine and 60.4 g (0.52 moles) of 1,6-hexanediamine.
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]2[N:7]([CH3:15])[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([OH:14])[C:13]=3[C@:5]2([CH3:16])[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[CH3:28][CH:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH3:28][C@@H:29]([NH:36][C:37](=[O:38])[O:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C@@:5]1([CH3:16])[CH2:4][CH2:3][N:2]([CH3:1])[C@H:6]1[N:7]2[CH3:15])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1CC[C@@]2(C)c3c(O)cccc3N(C)[C@@H]12
Reactant: CC(N=C=O)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](NC(=O)Oc1cccc2c1[C@@]1(C)CCN(C)[C@H]1N2C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
cis-(±)-1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo [2,3-b]indol-4-ol (2g) was dissolved in degassed THF (200 ml). DBU (0.8 ml) was added to the mixture followed by R-(+)-α-methylbenzyl isocyanate (2 g). The reaction was stirred at room temperature overnight under nitrogen. The solvent was evaporated under reduced pressure and the residue was purified using Prep 500 chromatography (4% MeOH/DCM) to yield 1.2 g of a solid. This material was combined with 600 mg of identically prepared material, which was found to be pure by thin layer analysis. The combined product was triturated with isopropyl ether and filtered to yield 1.8 g of (±)-(3aR*, 8aS*)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo [2,3-b]indol-4-yl (R)-(α-methylbenzyl)carbamate, m.p. 151°-155° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[N:19][CH:20]=1)[CH3:14].[O:22]1CCC[CH2:23]1>>[CH2:13]([C:15]1[CH:16]=[C:17]([CH:23]=[O:22])[C:18]([F:21])=[N:19][CH:20]=1)[CH3:14]
Reactant: CCc1ccc(F)nc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CCc1cnc(F)c(C=O)c1
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (1.01 mL, 7.19 mmol) in tetrahydrofuran (20 mL) was treated in ice-bath with n-butyllithium (2.5M, 2.9 mL, 7.19 mmol) and stirred for 30 min. The resulting solution was reacted at −78° C. with 5-ethyl-2-fluoropyridine (2-b, 0.75 g, 5.99 mmol), stirred for 4 h, and treated with N,N-dimethylfornmamide (482 mg, 6.59 mmol). The reaction mixture was quenched with acetic acid (1 mL), partitioned between ethyl acetate and water. The organic layer washed with 0.5N—HCl and then with brine, separated, dried (MgSO4) and concentrated in vacuo. Chromatography (30% ethyl acetate in hexanes) afforded the desired compound (2-f); 1H NMR (500 MHz, CDCl3) δ10.3 (s, 1 H), 8.29 (d, 1 H, J=2.0 Hz), 8.12 (dd, 1 H, J=9.0, 2.5 Hz), 2.73 (q, 2 H, J=7.8 Hz), 1.29 (t, 3 H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Clc1cncc(Cl)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Reaction time: 0.25 h
Yield: 32.2 %

Procedure:
A solution of 4.44 g (30 mmol) of 3,5-dichloropyridine in 40 mL of THF is added dropwise over 30 minutes to a stirred solution of 23 mL (35 mmol) of 1.5 M LDA in 30 mL THF at −78° C. After a further 15 minutes at −78° C., a solution of 6.13 g (42 mmol) of diethyl oxalate in 15 mL THF is added, and the temperature is allowed to rise slowly to −20° C. The reaction mixture is then quenched with aqueous ammonium chloride, the solvent is removed, and the residue is worked up in EtOAc. Chromatography on silica, eluting with hexane/EtOAc (9:1), gives 2.4 g (32%) of the title compound as an oil.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:25]=1)(=O)=O.CN(C)C=O>O>[CH2:39]([O:38][C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=1)[CH2:23][N:12]1[CH:13]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CS(=O)(=O)OCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium hydride (60%, oily, 2.20 g) was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (11.10 g), 3,5-dibenzyloxybenzyl methanesulfonate (21.9 g) and N,N-dimethylformamide (200 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-(3,5-dibenzyloxybenzyl)-4-phenylpyrrole-3-carboxylate (26.4 g, yield: 95%) was obtained as an oily substance from the fraction eluted with tetrahydrofuran-hexane (1:2, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[O:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:25]4[CH:26]=[CH:27][O:23][CH:24]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccoc1
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccoc4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 144 mg (1.5 mmol) of 3-furaldehyde to form 4-(3-chloro-phenylamino)-3-[(fur-3-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chloro-phenylamino)-3-[(fur-3-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p. 207-209° C.; HPLC: tRet(grad20-100/20)=8.4; MS: (M)+=340, (M−H)+=339.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CC1C=C[C:9]([O:12]C)=CC=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>Cl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:9]=[O:12])=[CH:17][CH:16]=1
Reactant: COc1ccc(C)cc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=Cc1ccc(F)cc1
Temperature: 30 °C
Yield: 241.8 %

Procedure:
220.67 g of aluminum chloride (mol. Wt. 133.34; 1,654.9 mmol), 109.00 g (4-Methylanisole (mol. Wt. 122.17; 892.2 mmol), and about 500 g of fluorobenzene (mol. Wt. 96.10; 5,202.9 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 30° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 550 psi, the pressure at which the reaction was maintained for the total reaction time of about 89 hours (the reaction temperature was maintained at 30° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a orange-brown color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, fluorobenzene, and left about 60.90 g of 4-fluorobenzaldehyde product (mol. Wt. 124.11; 490.7 mmol; yield of approximately 64.3%). The 4-fluorobenzaldehyde product may then be easily separated from any residual 4-methylanisole by conversion into its corresponding bisulfite adduct, filtration, and decomposition of the bisulfite adduct under acidic or basic conditions.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](O)[CH:12]=[CH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O>[CH3:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:13][CH:12]=[CH2:11])[CH:8]=[O:9]
Reactant: CC(C=O)c1ccccc1
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C=CCC(C)(C=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2-phenylpropionaldehyde (9.90 mL, 74.5 mmol), allyl alcohol (20.4 mL, 300 mmol) and p-toluene sulfonic acid (0.8560 g, 4.5 mmol) in benzene (37 mL) was heated to reflux for 19 hours and a Dean-Stark trap was used to collect the water formed. The mixture was cooled to room temperature and saturated aqueous NaHCO3 (5 mL) and H2O (5 mL) were added. The phases were separated and the organic layer was washed a second time with saturated aqueous NaHCO3 (5 mL) and H2O (5 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. A solution of the resultant yellow residue in p-xylene (150 mL) was heated to reflux for 24 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The resultant aldehyde (13.0 g) was used in the next reaction without further purification.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][NH2:6])#[N:2].[Cl:30][CH2:31][CH2:32][CH2:33][S:34](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:36])=[O:35]>>[Cl:30][CH2:31][CH2:32][CH2:33][S:34]([NH:6][CH2:5][CH:4]([CH2:3][C:1]#[N:2])[CH2:7][O:8][C:9](=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:36])=[O:35]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)CC#N
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CC#N)CNS(=O)(=O)CCCCl

Procedure:
The crude 2-cyanomethyl-3-n-octadecylcarbamoyloxypropylamine IVn2 which was prepared above is allowed to react by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9](N(CC)CC)[CH3:10]>C(OCC)(=O)C.BrCCBr>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:10][CH2:9]1
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1S
Solvent: BrCCBr
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)NCCS2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-aminothiophenol (5.01 g) in ethyl acetate (20 ml), 1,2-dibromoethane (4.14 ml) was added and stirred while heating at 60° C. under a nitrogen atmosphere. To the reaction mixture, triethylamine (9.72 ml) was added dropwise over 30 minutes and stirred at 60° C. for 10 hours. The reaction mixture was allowed to stand overnight at room temperature and then filtered to remove insoluble materials. The filtrate was washed sequentially with water and brine, dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 3:1) to give the titled compound, i.e., 3,4-dihydro-2H-1,4-benzothiazine (3.69 g) as a red-brown oil.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][S:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH2:20](N(CC)CC)[CH3:21].ICC>O>[C:1]([NH:4][C@@H:5]([CH2:9][S:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:20][CH3:21])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CSC(=O)c1ccc(C)cc1)C(=O)O
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: O
Product: CCOC(=O)[C@H](CSC(=O)c1ccc(C)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To a solution of 2-acetylamino-3-(4-methyl-benzoylsulfanyl)-propionic acid (1.1 g, 3.91 mmol) and triethylamine (0.68 mL, 4.89 mmol) N,N-dimethylformamide (5 mL) was added iodoethane (0.39 mL, 4.89 mmol) and the resulting solution was stirred at ambient temperature for 18 hours. The reaction mixture was added slowly to water (50 mL) with rapid stirring. After stirring for 2 hours, the resulting slurry was filtered and the solid was rinsed with water and dried under vacuum to give the product as a white solid (780 mg, 60%). 1H NMR (300 MHz, DMSO) δ=8.47 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.80-7.78 (m, 1H), 7.35 (d, J=7.6 Hz, 2H), 4.46 (dt, J=5.3, 8.1 Hz, 1H), 4.09 (q, J=6.8 Hz, 2H), 3.50 (dd, J=5.4, 13.6 Hz, 1H), 3.24 (dd, J=8.2, 13.8 Hz, 1H), 2.37 (s, 3H), 1.83 (s, 3H), 1.16 (t, J=7.0 Hz, 3H). MS (ESI) m/z 310 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH:10]([N:13]=[C:14]=S)([CH3:12])[CH3:11].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:9]=[C:14]([NH:13][CH:10]([CH3:12])[CH3:11])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N=C=S
Reactant: Nc1cccc(Cl)c1N
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)cccc2[nH]1
Yield: 57.8 %

Procedure:
3-Chloro-1,2-phenylenediamine (6.41 g, 44.95 mmol), isopropyl isothiocyanate (5.20 g, 51.6 mmol), 1cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (25.0 g, 59.02 mmol) and pyridine (300 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane afford 5.45 g (58%) of a brownish solid. MS (EI): m/z 210.1 (M+H). Anal. calcd for C10H12ClN3-(0.5 C4H8O2): C, 56.80; H, 6.36; N, 16.56. Found: C, 57.00; H, 6.34; N, 16.69.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N+]([O-])=O)=[CH:4][C:3]=1[C:21]([O:23][C:24]1C=CC=CC=1)=[O:22].C(=O)([O-])[O-].[K+].[K+].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][CH:38]=1.CN1CCCC1=O>CO>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([S:43][C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=2)=[CH:4][C:3]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: Nc1c(C(=O)Oc2ccccc2)cc([N+](=O)[O-])c2c1C(=O)c1ccccc1C2=O
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: COC(=O)c1cc(Sc2ccc(Cl)cc2)c2c(c1N)C(=O)c1ccccc1C2=O
Temperature: 80 °C

Procedure:
11.6 g of phenyl 1-amino-4-nitroanthraquinone-2-carboxylate (see Example 3a), 4.2 g of potassium carbonate (anhydrous) and 4.8 g of 4-chlorothiophenol are introduced into 50 cc of N-methylpyrrolidone, and the mixture is heated at 80° C. until the starting material has reacted completely. The mixture is then diluted at 70° C. with 50 cc of methanol and is allowed to cool. The crystals which have separated out are filtered off with suction, washed with methanol and hot water and dried. This gives 8.3 g, corresponding to 65% of theory, of methyl 1-amino-4-(4-chlorophenylmercapto)-anthraquinone-2-carboxylate, which has been formed by reacting the phenyl ester with the methanol used for the precipitation. The dyestuff can be purified by recrystallisation from dimethylformamide.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][O:49][C:50]1[C:55]([NH2:56])=[CH:54][CH:53]=[CH:52][N:51]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:56][C:55]4[C:50]([O:49][CH3:48])=[N:51][CH:52]=[CH:53][CH:54]=4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: COc1ncccc1N
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2cccnc2OC)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-methoxy-pyridin-3-ylamine (Fluorochem) to give the title compound. HR-MS (ES, m/z) calculated for C41H48Cl2N7O4 [(M+H)+] 772.314, observed 772.3138.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]([F:15])([F:14])[C:11]([OH:13])=[O:12].O>C(Cl)Cl>[N:7]([C:1]1([O:13][C:11](=[O:12])[C:10]([F:15])([F:14])[F:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(O)C(F)(F)F
Reactant: ON=C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: O=NC1(OC(=O)C(F)(F)F)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of cyclohexanone oxime (4.88 g, 43.16 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (19.14 g, 43.16 mmol) and trifluoroacetic acid (49.22 g, 431.6 mmol) in methylene chloride (200 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was purified by column chromatography to give 1-Nitroso-1-trifluoroacetoxycyclohexane as a bright blue liquid (30% yield): Rf 0.57 (pentane); 1H NMR (300 MHz, Benzene-d6) δ 1.1-1.9 (m, 10H); 13C NMR (300 MHz, Benzene-d6) δ 19.9 (2CH2), 22.9 (CH2), 27.4 (2CH2), 113.8 (q, J=286.2 Hz), 127.2 (O—C—N), 153.7 (q, J=42.5 Hz); 19F NMR (300 MHz, Benzene-d6) δ −75.7 (CF3).