Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:20])=O.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:20][C:3]1[N:2]([CH3:1])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2[nH]c(=O)n(C)c(=O)c2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1ccc2nc(Cl)n(C)c(=O)c2c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 26.9 %

Procedure:
Into a round bottom flask was added methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate (1.3 g, 5.3 mmol) dissolved in phosphoryl chloride (20.0 mL, 214 mmol). N,N-diethylaniline (2.6 mL, 16.0 mmol) was added followed by phosphorus pentachloride (0.56 g, 2.7 mmol). The reaction mixture was heated to 120° C. and stirred for 1 d. The mixture was then cooled to rt and concentrated. The residue was poured over ice and extracted with DCM (3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.36 g, 26%). LC-MS: (FA) ES+ 253; 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J=2.0 Hz, 1H), 8.38 (dd, J=8.5, 2.0 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 3.97 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([C:8](=[O:14])[CH2:9]CSSC)[C@H:3]([C:5]([OH:7])=[O:6])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:30][CH:31]1[CH:56]2[O:57][C:55]2([CH3:58])[CH:54](O)[CH2:53][C:51](=[O:52])[N:50]([CH3:60])[C:43]2=[C:44]([Cl:49])[C:45]([O:47][CH3:48])=[CH:46][C:41](=[CH:42]2)[CH2:40][C:39]([CH3:61])=[CH:38][CH:37]=[CH:36][CH:35]([O:62][CH3:63])[C:34]2([OH:68])[NH:64][C:65]([O:67][CH:32]1[CH2:33]2)=[O:66]>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:30][C@H:31]1[C@@H:56]2[O:57][C@@:55]2([CH3:58])[C@@H:54]([O:7][C:5]([C@@H:3]([N:2]([C:8]([CH3:9])=[O:14])[CH3:1])[CH3:4])=[O:6])[CH2:53][C:51](=[O:52])[N:50]([CH3:60])[C:43]2=[C:44]([Cl:49])[C:45]([O:47][CH3:48])=[CH:46][C:41](=[CH:42]2)[CH2:40][C:39]([CH3:61])=[CH:38][CH:37]=[CH:36][C@@H:35]([O:62][CH3:63])[C@:34]2([OH:68])[NH:64][C:65]([O:67][C@H:32]1[CH2:33]2)=[O:66]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Reactant: CSSCCC(=O)N(C)[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)[C@H](C)N(C)C(C)=O)[C@]1(C)O[C@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)/C=C/C=C(\C)C2
Solvent: ClCCl
Product: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)[C@H](C)N(C)C(C)=O)[C@]1(C)O[C@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)C=CC=C(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-methyl-N-(methyl dithiopropanoyl)-L-alanine (26 mg) prepared by a different process in accordance with a reference was dissolved in 3 ml of CH2Cl2, 30 mg of dicyclohexylcarbodiimide (2 equivalent amounts) and 20 μl of 1M zinc chloride (1 equivalent amount) were added thereto, and the mixture was stirred at room temperature for 30 minutes. Since the reaction did not proceed under this condition, the amount of 1M zinc chloride added was changed to 100 μl (5 equivalent amounts), and the mixture was stirred at room temperature for 30 minutes. A solution of 11.8 mg of maytansinol in 1 ml of CH2Cl2 was added thereto for esterification. The reaction solution was concentrated to dryness 3 hours later, the main product was purified by preparative TLC (CH2Cl2:MeOH=10:1) and then by preparative HPLC (ODS column, eluent: 60% CH3CN). As a result, 2.5 mg of maytansine derivative (May-SS-Me) was obtained. FIG. 6 shows the resulting May-SS-Me by 500 MHz 1H NMR. In the test for assaying the cellular cytotoxicity of the human myeloma cell strain IM9 as described in Example 19, IC50 of the obtained May-SS-Me was 10 nM, which was 1/1000 or less than that of ansamitocin P-3.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([B:17]([OH:19])[OH:18])[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:5]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([B:17]([OH:19])[OH:18])[CH:14]=[CH:15][CH:16]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccc(B(O)O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCc1cccc(B(O)O)c1
Reaction time: 1 h
Yield: 23.3 %

Procedure:
Acetic anhydride (76 μL, 0.80 mmol) was added dropwise to a stirred solution of (3-aminomethylphenyl)boronic acid, hydrochloride (150 mg, 0.80 mmol) and DIEA (560 μL, 3.2 mmol) in CH2Cl2 (5 mL) at 0° C. After 1 h, the solution was concentrated in vacuo and purified by preparatory HPLC to give 36 mg (23%) of the title compound as a white solid. [M+H] calc'd for C9H12BNO3, 194; found, 194.
Reaction SMILES: C=O.[CH2:3]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[CH3:4].[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[OH-].[NH4+]>ClCCCl>[CH2:3]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)CCc1ccc(NCCc2ccccc2)cc1
Agent: C=O
Agent: C[N+](C)(C)C
Agent: [NH4+]
Solvent: ClCCCl
Product: CCOC(=O)CCc1ccc(N(C)CCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Paraformaldehyde (0.89 g, 30.5 mmol) was added to a solution of 3-[4-(Phenethyl-amino)-phenyl]-propionic acid ethyl ester (1.3 g, 4.37 mmol) in 1,2-dichloroethane (25 mL). The resultant suspension was stirred at room temperature for 15 minutes. Tetramethylammonium triacetoxyborohydride (2.0 g, 8.74 mmol) was added, and the suspension was heated at reflux for 6 hours. The mixture was cooled to room temperature and treated with ammonium hydroxide (20 mL). The organic layer was separated and applied to a silica gel column. The product was eluted with ethyl acetate/hexane (1/20) to give an oil, 0.80 g (59%). MS: m/z 312 (MH+). 1H NMR (CDCl3): δ 1.23 (t, 3 H), 2.55 (t, 2 H), 2.90 (t, 2 H), 3.37 (t, 2 H), 3.59 (br s, 1 H), 4.11 (q, 2 H), 6.55 (d, 2 H), 7.01 (d, 2 H), 7.20-7.37 (m, 5 H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:15]2=[O:26])=[O:12])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[BH4-].[Na+]>CO>[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:12])[CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:15]2=[O:26])=[CH:7][CH:6]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)CCCN1CCN(CC(=O)c2ccc(C(=N)N)cc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCN1CCN(CC(O)c2ccc(C(=N)N)cc2)C1=O

Procedure:
Prepared by reduction of 1-[(4-amidino-phenyl)-carbonylmethyl]-3-(3-methoxycarbonyl-propyl)-imidazolidin-2-one hydrochloride with sodium borohydride in methanol at 0°-5° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=1)[CH3:11]
Reactant: Cc1nccc(C=O)n1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1ccnc(C)n1

Procedure:
prepared by reaction of 2-methyl-pyrimidin-4-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:6]=[CH:5]2
Reactant: OCCCCCCCl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: OCCCCCCOc1ccc2cc(Br)ccc2c1
Temperature: 65 °C

Procedure:
A mixture of 5 g of 6-bromo-2-naphthol, 50 ml of dimethyl sulphoxide, 3.3 ml of 6-chlorohexanol, 7.1 g of potassium iodide and 7.1 g of potassium carbonate (ground and activated at 80° C. in a high vacuum) was heated to 65° C. for 16 hrs. Then, the mixture was cooled, partitioned between ethyl acetate and water, and the organic phase was washed several times with water, dried over magnesium sulphate, filtered and evaporated. Chromatography of the residue on 200 g of silica gel with toluene/ethyl acetate (3:1) and subsequent crystallization form toluene/hexane (8:1) gave 5.2 g of 6-bromo-2-(6-hydroxyhexyloxy)naphthalene as a colorless solid.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].C[S-].[Na+]>CN(C)C(=O)C.O>[OH:2][C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(OC)c(C=O)c([N+](=O)[O-])c1
Agent: C[S-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1c(O)cc(O)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
2,4-dimethoxy-6-nitro-benzaldehyde (135 mg, 0.638 mmol) and sodium methanethiolate (125 mg, 1.78 mmol) are dissolved in 4 ml of N,N-dimethylacetamide and heated at 80° C. for 26 h. The reaction mixture is diluted to 50 ml with water and extracted with dichloromethane. The aqueous layer is then acidified with 5% HCl and extracted again with dichloromethane. All of the organic layers are dried over Na2SO4, concentrated, and purified using silica gel chromatography (100% dichloromethane to 30% acetone in dichloromethane) to yield 2,4-dihydroxy-6-nitro-benzaldehyde.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH:12]=[CH:11]2.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH2:34][C@@H:33]([NH2:38])[CH2:32][CH2:31]3)[CH2:23][CH2:22]1>CN1C(=O)CCC1>[CH3:19][O:20][CH:21]1[CH2:22][CH2:23][N:24]([CH2:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH2:34][C@@H:33]([N:38]2[CH:12]=[CH:11][C:10]4[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@@H:2]5[CH2:3][CH2:4][CH2:5][O:1]5)[CH:9]=4)[C:14]2=[O:18])[CH2:32][CH2:31]3)[CH2:25][CH2:26]1
Reactant: O=c1occc2cc(OC[C@@H]3CCCO3)ccc12
Reactant: COC1CCN(Cc2ccc3c(c2)CC[C@H](N)C3)CC1
Solvent: CN1CCCC1=O
Product: COC1CCN(Cc2ccc3c(c2)CC[C@H](n2ccc4cc(OC[C@@H]5CCCO5)ccc4c2=O)C3)CC1
Temperature: 220 °C

Procedure:
A mixture of 6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]isochromen-1-one (50 mg), NMP (0.2 ml) and (S)-6-(4-methoxypiperidin-1-ylmethyl)-1,2,3,4-tetrahydro-naphthalen-2-ylamine (55 mg) was heated to 220° C. in a microwave reactor for 3×30 minutes. The cooled reaction mixture was purified by preparative HPLC. The product was thus obtained with the molecular weight of 502.66 (C31H38N2O4); MS (ESI): 503 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:25]4[CH:26]=[C:27]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:28]=[CH:29][CH:24]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(3,4-dichloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.8) (82 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (37 mg, 30%). MS (ISP) 483.5 [(M+H)+]; mp 200–202° C.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[CH2:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][C:17]#[N:18])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>CO>[OH:6][N:5]=[C:17]([NH2:18])[CH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[CH2:7][CH2:8][CH2:9]2
Reactant: NO
Reactant: N#CCc1ccc2c(c1)CCC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(Cc1ccc2c(c1)CCC2)=NO
Reaction time: 18 h
Yield: 54.2 %

Procedure:
A stirred mixture of NaOMe (25 wt % in MeOH, 16.0 mL, 0.070 mol), hydroxylamine hydrochloride (4.9 g, 0.070 mol), and MeOH (60 mL) was heated under reflux for 30 minutes. 5-Indanylacetonitrile (10.0 g, 0.063 mol) was added and heating was continued for 18 hours. The mixture was cooled, concentrated, and partitioned between H2O and ether. The organic phase was dried (MgSO4) and concentrated to give a yellow oil: 11.4 g. The crude product was purified by flash chromatography (eluant 20% EtOAc/hexane; 60% EtOAc/hexane) and recrystallized from ether/hexane to give 6.5 g (54%) of a pale yellow solid, m.p. 60° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].O>CC(O)CC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: ClCCNCCCl
Reactant: COc1ccc(N)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)O
Solvent: O
Product: COc1ccc(N2CCNCC2)cn1
Yield: 98.3 %

Procedure:
A mixture of 6-methoxy-3-pyridinamine (0.2 mol) and 2-chloro-N-(2-chloroethyl)-ethanamine hydrochloride (0.3 mol) in 2-butanol (500 ml) was stirred and refluxed. Potassium carbonate (0.7 mol) was added portionwise (20 g/h), the mixture was refluxed for 48 hours, an additional amount of potassium carbonate (30 g) was added and the mixture was stirred for 48 hours. The mixture was poured into water, extracted with CH2Cl2 and separated. The organic layer was dried, filtered and evaporated, yielding 38 g (98%) of 1-(6-methoxy-3-pyridinyl)piperazine (interm. 29).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:27]([O:29]C)=[O:28])[CH:21]=4)[NH:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:27]([OH:29])=[O:28])[CH:21]=4)[NH:16]3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccc(F)cc3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)c2ccc(F)cc2)cc1
Yield: 95 %

Procedure:
To a mixture of methyl 2-(4-(4-fluorobenzamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (43 mg, 0.01 mmol) in methanol (3 mL) and water (1.5 mL) was add a solution of sodium hydroxide (68 mg, 0.17 mmol.) in water (1.5 mL). The resultant mixture was heated to reflux until the completion of the reaction (monitored by thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 2-(4-(4-fluorobenzamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 40 mg, Yield 95% MS (ESI+APCI) M+1=419.6.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][C:3]=1[CH3:17].I[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].CCCCCCCCCCCCC>[CH3:16][C:11]1[CH:10]=[C:9]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH3:17])[CH:4]=2)[C:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][CH:26]=2)[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: Ic1cccc2ccccc12
Reactant: Cc1ccc(Nc2ccc(C)c(C)c2)cc1C
Agent: [Cu+2]
Agent: CCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1ccc(N(c2ccc(C)c(C)c2)c2cccc3ccccc23)cc1C
Temperature: 25 °C
Yield: 37.4 %

Procedure:
In 100-ml three-neck flask were placed 7.2 g of 3,3',4,4'-tetramethyldiphenylamine synthesized in Example 3 (1), 12.2 g of 1-iodonaphthalene, 5 g of anhydrous potassium carbonate, 0.5 g of copper sulfate pentahydrate and 10 ml of n-tridecane, and after carrying out the reaction for 25 hours at 200° C. under a nitrogen gas atmosphere, the reaction mixture was cooled to room temperature. The reaction mixture was subjected to a column purification (solvent: n-hexane) with activated alumina and the solvent was distilled under reduced pressure. The residue was recrystallized from ethanol to provide 4.2 g of N,N-bis(3,4-dimethylphenyl)naphthalene-1-amine. (Melting point 125° to 127° C., light yellow crystals, IR spectrum shown in FIG. 5.)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8].C(O)C.[NH2:20][NH2:21]>O>[F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([NH:20][NH2:21])=[O:8]
Reactant: NN
Reactant: COC(=O)c1ccccc1OCC(F)(F)F
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccccc1OCC(F)(F)F

Procedure:
Methyl 2-(2,2,2-trifluoroethoxy)benzoate (1.22 g. 5.2 mmole), ethanol (15 ml.) and 5 ml. of 95 per cent hydrazine (4.75 g., 158 mmole) are refluxed for two hours, cooled, diluted with water (100 ml.) and cooled. The white solid product, 2-(2,2,2-trifluoroethoxy)benzoic acid hydrazide is recrystallized from ethanol, m.p. 102°-104°.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([C:7]1[N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([S:33]([NH:36][C:37]([NH:39][CH2:40][CH2:41][CH3:42])=[O:38])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[C:9]([C:14](=[O:19])[CH2:15]S(C)=O)=[C:10]([S:12][CH3:13])[N:11]=1)[CH2:4][CH2:5][CH3:6]>C(O)C.[Zn]>[C:14]([C:9]1[N:8]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[C:28]([S:33]([NH:36][C:37]([NH:39][CH2:40][CH2:41][CH3:42])=[O:38])(=[O:34])=[O:35])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[N:11][C:10]=1[S:12][CH3:13])(=[O:19])[CH3:15]
Reactant: CCCCc1nc(SC)c(C(=O)CS(C)=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CCCCc1nc(SC)c(C(C)=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1
Yield: 79.2 %

Procedure:
20 cm3 of a 10% aqueous solution of ammonium chloride and 650 mg of electrocyclic zinc are added to a solution of 1 g of the product obtained in Stage A above in 35 cm3 of ethanol. The resultant mixture is agitated for 24 hours then filtered, followed by evaporation, redissolving in ethyl acetate, washing with water, drying and evaporation. The residue is purified by passage over silica, eluting with methylene chloride with 2% methanol. 711 mg of expected product is obtained, melting at 176-177° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CC(C)([O-])C.[Li+].Cl[C:34]([O:36][CH2:37][Cl:38])=[O:35]>C(Cl)Cl.CC#N.O>[Cl:38][CH2:37][O:36][C:34](=[O:35])[N:20]([C:21](=[O:23])[CH3:22])[CH2:19][C@@H:17]1[O:16][C:15](=[O:24])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:4][CH2:3][S:2](=[O:1])(=[O:26])[CH2:7][CH2:6]3)=[C:9]([F:25])[CH:10]=2)[CH2:18]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: O=C(Cl)OCCl
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 74 %

Procedure:
(S)-N-{3-[4-(1,1-Dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1) (2.0 g, 5.2 mmol) in 13 mL of CH2Cl2 and 13 mL of CH3CN is cooled to 0° C. Lithium t-butoxide (1.0 M in hexanes, 5.7 mL, 5.7 mmol) is added and the mixture is stirred at 0° C. for 25 min and then at RT for 10 min. The mixture is re-cooled to 0° C. and chloromethyl chloroformate (0.6 mL, 6.2 mmol) is added dropwise. The mixture is stirred for 10 min at 0° C. and then allowed to stir at RT overnight. The solution is diluted with CH2Cl2 and water and the layers are separated. The organic layer is washed with water, brine, dried over Na2SO4, and conc in vacuo. Purification by silica gel chromatography afforded the title compound in 74% yield (1.8 g). 1H NMR (400 MHz, CDCl3): δ 7.47 (dd, 1H), 7.22 (t, 1H), 7.13 (dd, 1H), 5.91 (d, 1H), 5.76 (d, 1H), 4.82 (m, 1H), 4.16 (m, 1H), 4.07 (m, 2H), 3.69 (dd, 1H), 3.10 (m, 5H), 2.58 (s, 3H), 2.38 (m, 2H), 2.17 (m, 2H). MS-APCI (m/z+): 341, 385, 477.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:42]=[CH:43][CH:44]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([CH2:27][C@H:28]([O:33][CH3:34])[C:29]([F:32])([F:31])[F:30])[C:24]([N:35]=CN(C)C)=[C:23]([F:40])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:41])([CH3:4])([CH3:3])[CH3:2]>[Cl-].[Cl-].[Zn+2].CCCCCC.CCOC(C)=O>[NH2:35][C:24]1[C:25]([CH2:27][C@H:28]([O:33][CH3:34])[C:29]([F:31])([F:32])[F:30])=[CH:26][C:21]([CH2:20][C@H:13]2[C@H:12]3[C@@H:17]([N:9]([CH2:8][C:7]4[CH:42]=[CH:43][CH:44]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=4)[C:10](=[O:41])[O:11]3)[CH2:16][S:15](=[O:19])(=[O:18])[CH2:14]2)=[CH:22][C:23]=1[F:40]
Reactant: CO[C@@H](Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N=CN(C)C)C(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CO[C@@H](Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N)C(F)(F)F

Procedure:
The title compound was prepared in analogous manner as described for example 1n) from N′-[4-[(3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-6-((S)-3,3,3-trifluoro-2-methoxy-propyl)-phenyl]-N,N-dimethyl-formamidine and ZnCl2 to yield a yellow oil: TLC (hexane-EtOAc 2:1) Rf=0.22; HPLC RtA=2.40 min; ESIMS [M+H]+=587.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][CH2:26][CH:27]3[CH2:29][O:28]3)[CH:22]=[CH:21][C:19]=2[N:20]=1>C(O)C>[OH:28][C@H:27]([CH2:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([CH3:15])[S:17][C:18]=2[CH:24]=1)[CH2:29][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]1[CH3:1]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1nc2ccc(OCC3CO3)cc2s1
Solvent: CCO
Product: Cc1nc2ccc(OC[C@@H](O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)cc2s1

Procedure:
The compound of formula (B) was reacted with 2-methyl-6-(oxiran-2-ylmethoxy)benzothiazole (3 g, 7.3 mmol), a compound of formula (C), in ethanol. The reaction was refluxed for about 24 hours. When the reaction was substantially complete, the solvent was removed under reduced pressure, followed by preparative thin layer chromatography to render tert-butyl (3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-6-yloxy)propyl]-3-methylpiperazinecarboxylate, a compound of formula (D).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=2.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25]>>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:18]([C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:9]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=4[CH3:8])[NH:10]3)=[CH:15][CH:14]=2)=[O:19])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1cccc(C)c1-c1cc2ccc(C(=O)O)cc2[nH]1
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(NC(=O)c2ccc3cc(-c4c(C)cccc4C)[nH]c3c2)cc1C

Procedure:
The title compound was prepared from 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylic acid and 3,4-dimethylaniline analogous to Example 3-4. 1H NMR (CDCl3, 400 MHz): δ 8.38 (s, broad, 1H), 8.08 (s, 1H), 7.84 (s, broad, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.56 (dd, J=8.3, 1.6 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.37 (dd, J=8.1, 2.3 Hz, 1H), 7.25 (m, 1H), 7.12 (m, 3H), 6.46 (m, 1H), 2.27 (s, 3H), 2.24 (s, 3H), 2.17 (s, 61-1). MS (m/z) 369.2 (M+1), Retention time=1.73 min (Method 10).