Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1Cl.[H-].[Na+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:15]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: N#Cc1ccc2sc(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)nc2c1
Yield: 99.4 %

Procedure:
The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-5-carbonitrile (243) (960 mg, 5.0 mmol), 1,2,3-trichloro-5-nitrobenzene (Acros, 1.13 g, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 262 (1.9 g, 99%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])[CH:7]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:22](=[O:23])[C:21]2[CH:20]=[C:19]([C:18]([F:33])([F:32])[F:17])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=2)[CH:7]=1
Reactant: CNc1cnccc1-c1cc(Cl)ccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(5-chloro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 70:30) for the chromatographic purification. Colorless solid (35%). MS (ESI): m/z=473.084 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[O:1]=[C:2]1[C:7]([C:8]([NH:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[O:9])=[CH:6][NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
A mixture of 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-2-carboxylic acid (2.57 g, 0.01 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.012 mole) in dimethylformamide is heated at 100 for 60 minutes under nitrogen. The reaction mixture is cooled and stirred at room temperature for 15 minutes. 5-Aminotetrazole monohydrate (1.24 g, 0.012 mole) is added and the resulting mixture is heated at 100 for 60 minutes, cooled, and filtered. The product is recrystallized from dimethylformamide to give white crystals (1.1 g, 34%), m.p. above 300.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:12])[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O>C(Cl)Cl.O>[OH:11][C:10]1[CH:9]=[C:8]2[C:7](=[CH:6][C:5]=1[CH3:12])[C:10](=[O:11])[CH2:9][CH2:8]2
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(cc1O)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a stirred suspension of aluminum chloride (3.0 g, 22.2 mmol) and o-cresol (2.0 g, 18.5 mmol) in methylene chloride (10 mL) was added 4-chloropropionyl chloride (2.0 mL, 20.4 mmol). After stirring overnight at rt, the reaction was quenched by the addition of methanol followed by 2N hydrochloric acid. The product was extracted in methylene chloride (3×30 mL), dried over magnesium sulfate and concentrated in vacuo to give a colorless oil. This oil was treated with concentrated sulfuric acid (10 mL) at 90° C. for 1 h, diluted with water (50 mL) and the product extracted into methylene chloride (3×30 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 33% ethyl acetate/hexanes gave 0.47 g of the title compound: 1H NMR (500 MHz, CDCl3): δ 7.56 (s, 1H), 6.81 (s, 1H), 5.36 (s, 1H, OH), 3.04 (t, J=5.9 Hz, 2H), 2.65 (t, J=5.8 Hz, 2H), 2.28 (s, 3H)
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=1)=[O:27]>C1(C)C=CC=CC=1>[C:13]([C:12]1[C:7]([N:1]2[CH2:2][CH2:3][N:4]([CH2:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=3)=[O:27])[CH2:5][CH2:6]2)=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:14]
Reactant: O=C(CCl)Nc1cccc([N+](=O)[O-])c1
Reactant: N#Cc1cccnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: N#Cc1cccnc1N1CCN(CC(=O)Nc2cccc([N+](=O)[O-])c2)CC1
Temperature: 90 °C
Yield: 24.6 %

Procedure:
2-(1-Piperazinyl)-3-pyridinecarbonitrile (640 mg, 3.40 mmol) and N,N-diisopropylethylamine (1.0 mL) in toluene (15 mL) at room temperature were treated with N-chloroacetyl-3-nitroaniline (Lancaster, 610 mg, 2.84 mmol) and the reaction was heated at 90° C. for 18 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with 85% hexanes:ethyl acetate) to provide 256 mg (25% yield) of the title compound as a light tan solid. mp 143-145° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.69 (m, 4H), 3.27 (s, 2H), 3.70 (m, 4H), 6.93 (dd, 1H, J=7.4, 5.0 Hz), 7.61 (dd, 1H, J=8.1, 8.1 Hz), 7.93 (br d, 1H, J=8.2 Hz), 8.06 (dd, 2H, J=7.8, 7.8 Hz), 8.42 (m, 1H), 8.70 (br s, 1H), 10.28 (br s, 1H); MS (DCI/NH3) m/e 367 (M+H)+; Anal. calcd for C18H18N6O3: C, 59.01; H, 4.95; N, 22.94. Found: C, 59.31; H, 5.25; N, 22.66.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[CH:8]([O:17][C:18]([O:20]C2C=CC=CC=2)=O)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:32].C(O)(=O)C>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:32][C:18](=[O:20])[O:17][C:8]=2[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(Cl)s1
Yield: 58 %

Procedure:
A mixture of ethyl 6-(5-chloro-2-thienyl)-6-oxo-5-phenoxycarbonyloxyhexanoate (30.5 g), ammonium acetate (28.6 g) and acetic acid (100 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into 500 ml of water, and the resulting solid precipitate was collected, washed with water and isopropyl ether and air-dried to give crystals of ethyl 4-[4-(5-chloro-2-thienyl)-2-oxo-4-oxazolin-5-yl]butanoate (13.6 g, 58%). Recrystallization from acetone-isopropyl ether gave pale yellow prisms. Melting point 95-96° C.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH3:29])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCCOc1ccnc(N(CCCCCCC(=O)OCC)c2ccccn2)c1
Solvent: CO
Solvent: CN(C)C=O
Product: CCCOc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 22.5 h
Yield: 50 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (16 mg, 0.045 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22.5 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:5 to 100:8) to furnish IV as a colourless oil (14 mg, 50%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:7]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)CNc1cc(Cl)nc(Cl)n1
Product: CC(C)(C)CNc1cc(Cl)nc(N2CCCC2)n1
Yield: 75 %

Procedure:
The reaction of 2,4-dichloro-6-(2,2-dimethylpropylamino)pyrimidine with pyrrolidine as described in Example 12 affords the title compound in a yield of 75.0%, m.p.: 130°-135° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)=[CH:25][CH:24]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Reactant: COc1ccc(NCc2ncc[nH]2)cc1
Product: COc1ccc(N(Cc2ncc[nH]2)[C@@H]2c3cc([N+](=O)[O-])ccc3O[C@](C)(C(OC)OC)[C@H]2O)cc1
Yield: 27.5 %

Procedure:
The title compound (280 mg, 28%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (591 mg, 2.10 mmol) and 4-methoxyphenyl-1H-imidazol-2-ylmethylamine (427 mg, 2.10 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH:9](=O)[CH:10]([CH3:12])[CH3:11].O>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH:10]([CH:12]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([CH3:11])[CH3:9]
Reactant: Oc1ccccc1O
Reactant: CC(C)C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C1Oc2ccccc2O1
Yield: 33.5 %

Procedure:
Catechol (22 g, 0.2 mole) and isobutyraldehyde (16 g, 0.24 mole) were dissolved in benzene (600 ml). A catalytic amount (5 drops) of sulfuric acid was added to the mixture. The mixture was heated under reflux and the water formed in the reaction was removed by use of a Dean-Stark trap. The reaction mixture was washed twice with aqueous sodium carbonate solution and dried. 2-Isopropyl-1,3-benzodioxole (11 g, 0.067 mole) was obtained by vacuum distillation. The 2-isopropyl-1,3-benzodioxole thus obtained boiled at 29-31° C. at 0.25 mm Hg. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@H:5]([CH:7]([CH2:17][O:18][CH3:19])[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])[CH3:2].[CH2:21]=O.O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[CH:21][C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]=1[CH2:17][O:18][CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:20])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)C(COC)c1c[nH]c2ccccc12
Reactant: C=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1COC
Yield: 30.6 %

Procedure:
20.3 g of beta-methoxymethyl-tryptophane-ethylester is dissolved in 350 ml of benzene, mixed with 2.48 g of paraformaldehyde and heated for 3.5 h in the water separator. After cooling, the benzene is distilled off, the residue is absorbed in 350 ml of toluene, and after adding 4.5 g of 10% palladium carbon, the mixture is heated with reflux for 20 h. The cooled solution is filtered and concentrated. The residue is chromatographed on silica gel with hexane/ethyl-acetate. The crystallization of the main fraction out of ethylacetate/diisopropylether yields 6.4 g of 4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester with a m.p. 118°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (311 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide (86 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][Mg]Cl>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C[Mg]Cl
Solvent: ClCCl
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2,4,6-trichloro-1,3,5-triazine (1.0 g, 5.4 mmol) in CH2Cl2 (17 mL) was added MeMgCl (1.8 mL) drop wise and the reaction mixture was stirred at RT for 0.5 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2,4-dichloro-6-methyl-1,3,5-triazine (0.800 g, 90%) as a solid. The crude material was taken to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([NH:27][C:26]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(F)cc1F
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Nc3ccc(F)cc3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis-(4-methoxyphenyl)-6-chloropyridazine (264.2 mg, 0.809 mmol) and 2,4-difluoroaniline were reacted as starting materials at 100° C. for 12 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (328.8 mg, 97.0%). Melting point: 177.4-178.0° C. (chloroform-diethyl ether-hexane).
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:14][S:15][CH:16]=2)[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH2:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH3:18]>C(O)(=O)C>[CH2:17]([N:19]1[CH2:24][CH2:23][N:22]([C:3]2[C:4]3[C:5](=[CH:14][S:15][CH:16]=3)[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:21][CH2:20]1)[CH3:18]
Reactant: CSC1=Nc2ccccc2Nc2cscc21
Reactant: CCN1CCNCC1
Solvent: CC(=O)O
Product: CCN1CCN(C2=Nc3ccccc3Nc3cscc32)CC1

Procedure:
A mixture comprising 2.5 g. of 10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine (U.S. Pat. No. 3,951,981 -- Ex. 2), 11.4 g. of N-ethylpiperazine and 3 drops of acetic acid is stirred and refluxed overnight. The mixture is evaporated. The residue is slurried in water and then the residue is dissolved in 50 ml. of 2N acetic acid, filtered and the filtrate is made alkaline with ammonium hydroxide. The mixture is cooled and filtered. The solid is recrystallized twice from ethanol giving 10-(4-ethyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:34]([CH3:35])=[N:33][N:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:21]=2)=O)[C@H:10]([CH2:42][C:43]([F:46])([F:45])[F:44])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[N:19]=[C:18]3[N:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:33]=[C:34]([CH3:35])[C:17]=23)[C@H:10]([CH2:42][C:43]([F:44])([F:45])[F:46])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(-c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)C[C@H]3CC(F)(F)F)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COCOc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CC(F)(F)F)c3c(C)nn(C4CCCCO4)c3n2)cc1
Yield: 84.4 %

Procedure:
To a solution of 557 mg of (R)-4-[6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-3-(2,2,2-trifluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester in 8 ml of dry THF 6.9 ml of borane-dimethylsulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 3.5 h. The reaction was quenched by the addition of methanol, and the solvents were evaporated. The residue was purified by flash chromatography (silica, heptanes/ethyl acetate) yielding 460 mg (84%) of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1
Reactant: NCc1ccccc1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1nc(NCc2ccccc2)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Temperature: 75 °C
Yield: 46.3 %

Procedure:
In a similar manner, to 2-methylthio-4-chloro-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine (3.19 g, 8.65 mmol), a compound of formula (M), in 90 mL acetonitrile at 0° C. was added cesium carbonate (3.66 g, 11.2 mmol), followed by the addition of benzylamine (0.95 mL, 8.65 mmol). The reaction mixture was heated at 75° C. for 4 hours. The reaction mixture was filtered, the filtrate evaporated and the residue chromatographed on silica gel (ethyl acetate:methanol, 10:1) to afford 1.76 g (48%) of 2-methylthio-4-(benzyl)amino-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (N).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([C:34]([F:37])([F:36])[F:35])[C:5]=1[OH:38])(=[O:3])[CH3:2].[N-:39]=[N+:40]=[N-:41].[Na+].Cl.C(N(CC)CC)C>>[OH:38][C:5]1[C:6]([C:34]([F:36])([F:35])[F:37])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:24]=[CH:23][CH:22]=[C:19]([C:20]4[N:39]=[N:40][NH:41][N:21]=4)[CH:18]=3)=[CH:12][CH:11]=2)[CH:32]=[CH:33][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4nn[nH]n4)c3)cc2)c(C(F)(F)F)c1O
Yield: 96.2 %

Procedure:
Employing the procedure of Example 1 using 3-[[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (384 mg, 0.731 mmol), sodium azide (475 mg, 7.31 mmol), and triethylamine hydrochloride (1.01 g, 7.31 mmol) to yield the title compound as a tan solid (400 mg, 96%): 1H NMR (CD3CN) δ 1.44-1.91 (m, 6H), 2.56 (s, 3H), 3.44 (m, 1H), 3.78 (m, 1H), 4.66 (q, 1H), 5.23 (d, 2H), 5.91 (d, 1H), 6.73 (dd, 1H), 7.39-7.62 (m, 5H), 7.89-8.08 (m, 3H), 13.75 (s, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[C:30]1([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O.C(OCC)(=O)C>[C:30]1([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][CH2:12][CH:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:28])([F:29])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: FC(F)(F)c1nc2c3c(ccc2[nH]1)OCC(CNCCCCc1ccccc1)O3
Temperature: 85 °C
Yield: 49.3 %

Procedure:
A mixture of 0.50 g (1.2 mmole) of [(8R)-2-trifluoromethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 0.75 g (5.0 mmole) of 4-phenylbutylamine in 25.0 mL of DMSO was heated at 80-90° C. under nitrogen for 4 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 500 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform as eluant and the product fractions evaporated to give 0.24 g of the desired product. This was recrystallized from ethanol with the addition of oxalic acid to give 0.092 g of the (S)-enantiomer of the title compound as a white solid oxalate, hydrate, m.p. 124-127° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:32])[CH2:16][N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([CH3:24])[CH2:19][C:20]([O:22]C)=[O:21])[CH:11]=[CH:10][C:9]=2[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:5])C.CO.[OH-].[Na+].[ClH:45]>O1CCCC1>[ClH:45].[CH2:25]([N:17]([CH2:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)=[O:32])[CH:18]([CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)CC(=O)OC)ccc(OCc3ccccc3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(CC(=O)O)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)O)cc12)Cc1ccccc1

Procedure:
38 g of 4-[N-benzyl-N-(2-methoxycarbonyl-1-methylethyl)aminoacetyl]-7-benzyloxyindole-2-carboxylic acid ethyl ester is stirred at room temperature for 4 hours in a mixture of 1 liter of tetrahydrofuran, 1 liter of methanol, and 350 ml of 2N sodium hydroxide solution. The reaction mixture is then acidified with 2N hydrochloric acid, concentrated until the onset of crystallization, cooled in an ice bath, and the resultant crystals are vacuum-filtered, thus producing 25.8 g of 4-[N-benzyl-N-(2-carboxy-1-methylethyl)aminoacetyl]-7-benzyloxyindole-2-carboxylic acid hydrochloride, decomposing from 150° C. on.
Reaction SMILES: [O:1]([CH:8]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(Cl)=[O:18]>C(OC(=O)C)C>[O:1]([CH:8]([C:11]1[S:15][C:14]([N:16]=[C:17]=[O:18])=[N:13][N:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Oc1ccccc1)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC(Oc1ccccc1)c1nnc(N=C=O)s1

Procedure:
The procedure of Example Ib was followed using 8 g. of the 5-(1-phenoxypropyl)-2-amino-1,3,4-thiadiazole (prepared above) and 100 ml. of ethylacetate saturated with phosgene. Topping and removing of the phosgene resulted in a glassy, orange residue of 5-(1-phenoxypropyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (10.9 grams).