Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:6]1[C:9](=[O:10])[NH:8][C@@H:7]1[CH2:11][C:12](=[O:27])[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])([CH3:5])[CH3:4].C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>C(#N)C>[N+:37](=[C:13]([C:12](=[O:27])[CH2:11][C@@H:7]1[C@@H:6]([C:3]([O:2][CH3:1])([CH3:5])[CH3:4])[C:9](=[O:10])[NH:8]1)[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)=[O:15])=[N-:38]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
To a solution of 4-nitrobenzyl 4-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidine-2-yl]-3-oxobutanoate (61.2 mg) in acetonitrile (1.22 ml) was added a solution of p-toluenesulfonyl azide (38.3 mg) in acetonitrile (0.345 ml) at 0° C. After stirring for 10 minutes at 0° C., a solution of triethylamine (81.3 μl) in acetonitrile (0.732 ml) was added dropwise at 0° C. After the resultant solution was stirred for 30 minutes at 0° C., the solvent was distilled off, and the residue was flash-chromatographed on silica gel (0.9 g) eluting with a mixture of methylene chloride and ethyl acetate (40:1 to 3:1) to give 4-nitrobenzyl 2-diazo-4-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]-3-oxobutanoate (56.5 mg) as an amorphous solid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[O:10][C:9](=[O:19])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([CH2:6][N:3]([CH3:4])[CH3:2])=[CH:8][C:9](=[O:19])[O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(CBr)cc(=O)oc2c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2c(CN(C)C)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.8 %

Procedure:
A mixture of dimethylamine hydrochloride (0.18 g), 4-bromomethyl-7-methoxycoumarin (0.30 g), potassium carbonate (0.5 g) and dichloromethane (10 ml) was stirred at room temperature for 2 days. The solid was filtered off and the filtrate concentrated. The residue was purified by chromatography on silica gel (eluent 5% methanol in dichloromethane), then crystallised from methanol to give the title compound as a white solid (0.145 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH2:20]([N:27]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[NH:30][CH:29]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:28]1=[O:44])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:20]([N:27]1[C:31]2([CH2:32][CH2:33][N:34]([S:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=3)(=[O:18])=[O:17])[CH2:35][CH2:36]2)[NH:30][CH:29]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:28]1=[O:44])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCC3(CC2)NC(Cc2ccccc2)C(=O)N3Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Triethylamine (0.12 ml, 0.89 mmol) and subsequently 4-methoxybenzenesulfonyl chloride (308 mg, 1.49 mmol) were added to a solution of 1,3-dibenzyl-1,4,8-triaza-spiro[4,5]decan-2-one (249 mg, 0.75 mmol) in CH2Cl2 (6.7 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred overnight. The organic phase was rendered alkaline using saturated aqueous sodium carbonate solution (20 ml), and the aqueous phase was extracted with CH2Cl2 (15 ml). The combined organic phases were dried over Na2SO4. After filtration, removal of the solvent, and column chromatography, the desired product 1,3-dibenzyl-8-(4-methoxy-benzenesulfonyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 301 mg (79% of theory).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)=[CH:9][CH:10]=1)=[O:5])C.O.[NH2:21][NH2:22]>C(O)C>[NH:21]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:11]([C:8]2[NH:7][C:6]([C:4]([OH:3])=[O:5])=[CH:10][CH:9]=2)=[N:22]1
Reactant: NN
Reactant: CCOC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 19.5 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.5 g) and hydrazine hydrate (0.7 g) in ethanol was heated at 80° C. for 24 hours. The resulted precipitate was collected by vacuum filtration, washed with water and dried to give 80 mg of the titled compound.
Reaction SMILES: C[N:2]1[CH:9]=[CH:8][C:6](=[O:7])[N:5](C)[C:3]1=O.[O-]CC.[Na+].[NH:15]1[C:19](N)=[CH:18]C=N1>C(O)C>[N:15]1[N:2]2[CH:9]=[CH:8][C:6](=[O:7])[NH:5][C:3]2=[CH:18][CH:19]=1
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: Nc1ccn[nH]1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1ccn2nccc2[nH]1
Temperature: 60 °C
Yield: 58 %

Procedure:
1,3-Dimethyl uracil (3.15 g, 22.5 mmol) and sodium ethoxide (23 mL of a 21% solution in ethanol) were added to a solution of 1H-pyrazol-5-amine (1.7 g, 20.4 mmol) in ethanol (50 mL). The resulting mixture was heated to 60° C. for 2 h and was then cooled to room temperature. The pale brown solid was isolated by filtration to give pyrazolo[1,5-a]pyrimidin-5(4H)-one (1.6 g, 58%). Retention time (min)=0.820, method [3], MS (ESI) 136.1 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[CH3:20][C:21]1([CH3:26])[CH2:25][O:24][CH2:23][NH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([N:22]3[C:21]([CH3:26])([CH3:20])[CH2:25][O:24][CH2:23]3)=[O:19])=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Reactant: CC1(C)COCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CS(=O)(=O)c1nc(C(=O)N2COCC2(C)C)ccc1C1CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 6 d)) was reacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=367.4 [MH+].
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C@@H:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:22]=2)=[CH:12][CH:11]=1)(C)(C)C.[ClH:45].C(O)C>ClCCl>[ClH:45].[ClH:45].[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C@@H:28]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:29][CH2:30][N:31]([CH:32]([CH3:33])[CH3:34])[CH:35]([CH3:37])[CH3:36])[CH:22]=2)=[CH:14][CH:15]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1O)C(C)C
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCN)cc2)ccc1O)C(C)C
Reaction time: 72 h

Procedure:
tert-butyl{2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}carbamate (Preparation 12, 450 mg, 0.75 mmol) was dissolved in dichloromethane (10 ml), hydrogen chloride (2M in diethyl ether, 6 ml, 12 mmol) was added followed by ethanol (1 ml). After 3 days, solvents removed in vacuo to furnish the title compound as a yellow foam, 420 mg.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][N:14]=[CH:15][C:8]=2[N:7]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[CH3:26])[N:19]([CH3:27])[CH:18]=2)[C:6]1=[O:28].[OH-].[Li+].Cl.O>O1CCOCC1>[CH3:27][N:19]1[C:20]2[C:25](=[C:24]([CH3:26])[CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][N:7]2[C:8]3[CH:15]=[N:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:5]([CH2:4][C:3]([OH:29])=[O:2])[C:6]2=[O:28])=[CH:18]1
Reactant: COC(=O)Cn1c(=O)c2ccncc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2c1c(Cn1c(=O)n(CC(=O)O)c(=O)c3ccncc31)cn2C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
To a solution of 70 mg of [1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl]-acetic acid methyl ester in 1,4-dioxane (2.0 mL) is added lithium hydroxide solution (11 mg of lithium hydroxide monohydrate in 0.5 mL of water) at room temperature. The solution is stirred at the same temperature for 5 h. Then 1.0 mL of 1.0 M hydrochloric acid is added along with 50 mL of water. The mixture is extracted with ethyl acetate (3×50 mL) and the organic layers are combined, dried over magnesium sulfate and concentrated to give crude product. The crude product is rinsed with methanol (3.0 mL) and dichloromethane (5.0 mL) and the remaining light yellow solid is dried to give 45 mg (67%) of [1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl]-acetic acid; LCMS (ESMS): m/z 379.16 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][C:4]2([CH2:11][CH2:10][C@H:9]3[C@H:12]4[C@H:21]([CH2:22][CH2:23][C@:7]23[CH3:8])[C:20]2[CH2:19][CH2:18][C:17](=[O:24])[CH2:16][C:15]=2[CH2:14][CH2:13]4)[CH2:3]1.CO.Cl>O>[OH:1][CH:2]1[CH2:6][O:5][C:4]2([CH2:11][CH2:10][C@H:9]3[C@H:12]4[C@H:21]([CH2:22][CH2:23][C@:7]23[CH3:8])[C@@H:20]2[C:15](=[CH:16][C:17](=[O:24])[CH2:18][CH2:19]2)[CH2:14][CH2:13]4)[CH2:3]1
Reactant: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC21CC(O)CO1)CC(=O)CC4
Agent: Cl
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC21CC(O)CO1
Reaction time: 2 h

Procedure:
A mixture of 15 parts of 4',5'-dihydro-4'-hydroxyspiro[estr-5(10)-ene-17,2'(3'H)-furan]-3-one, 79 parts of methanol, 8 parts of concentrated hydrochloric acid, and 5 parts of water is allowed to stand at room temperatures for 2 hours. To the resultant solution is added 600 parts of cold water. The precipitate which forms is filtered off, washed with water, dried in air, and recrystallized from ethyl acetate to give 4',5'-dihydro-4'-hydroxyspiro[estr-4-ene-17,2'(3'H)-furan]-3-one melting at 149°-154°.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Mg].I[CH3:15].[Cl-].[NH4+]>C(OCC)C.O>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(C)Oc1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of 4-isopropyloxy benzaldehyde of formula 5 (5 g, 30 mmol) in dry diethyl ether is slowly added to an ethereal solution of Grignard reagent prepared from magnesium metal (0.84 g, 35 mmol) and iodomethane (2.6 ml, 40 mmol) and the contents stirred for 1 hour at room temperature. After the completion of the reaction, the mixture is worked up by adding saturated aqueous solution of ammonium chloride (10 ml), followed by dilution with water (100 ml), separating the organic layer and extracting the aqueous layer with solvent ether (2×100 ml). The combined organic layer is washed with water (2×20 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to yield 1-(4-isopropyloxy phenyl) ethanol, in a semisolid of general formula 4 in 92.5% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:5]([Cl:24])=[CH:4][N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1>C(Cl)Cl.CO>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])=[N:7][C:2]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([CH2:32][N:29]3[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]3)=[CH:39][CH:38]=2)=[N:3][CH:4]=1
Reactant: O=S(=O)(c1cc(O)ccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccc(O)cc4S(=O)(=O)N4CCCC4)n3)cc2)CC1
Yield: 27 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 4-((2,5-dichloropyrimidin-4-yl)amino)-3-(pyrrolidin-1-ylsulfonyl)phenol and 4-((4-methylpiperazin-1-yl)methyl)aniline in 27% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.87 (d, 1H, J=8.4 Hz), 7.67 (s, 1H), 7.44 (d, 2H, J=8.1 Hz), 7.26 (1H), 7.23 (d, 2H, J=8.4 Hz), 7.10 (d, 1H, J=8.8 Hz), 3.53 (s, 2H), 3.33 (m, 4H), 2.63 (bs, 8H), 2.43 (s, 3H), 1.83 (m, 4H); MS (ESI): 558.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([OH:31])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:31][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OC1CCC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OC3CCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and cyclobutanol (53.6 mg; 0.736 mmol), example 64 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH3:14][NH:15][N:16]([NH:20][CH3:21])[C:17](Cl)=[S:18]>O>[CH3:14][NH:15][N:16]([NH:20][CH3:21])[C:17]([O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[S:18]
Reactant: CNN(NC)C(=S)Cl
Reactant: COC(=O)c1ncccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CNN(NC)C(=S)Oc1cccnc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of 3.06 g (20 mmol) of methyl 3-hydroxypyridine-2-carboxylate in 15 mL of water was made basic with 1.12 g KOH. To this solution was added 3.2 g (26 mmol) of N,N-dimethylaminothiocarbamoyl chloride and the solution was stirred at room temperature for 2 hours. The solution was partitioned between benzene and water and the aqueous layer was washed with two portions of water. The combined extracts were dried and concentrated to afford 4.1 g of a white solid, m.p. 74°-75° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:20][C:18]1[CH:19]=[C:14]([NH2:13])[CH:15]=[C:16]([Cl:22])[C:17]=1[O:21][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2nc(Oc3c(Cl)cc(N)cc3Cl)sc2c1
Yield: 56 %

Procedure:
To a solution of 2-chloro-6-methoxybenzothiazole (prepared as described by Weinstock et.al., J.Med.Chem.30: p1166 (1987)) and 4-Amino-2,6-dichlorophenol 1.3 g(available from Tokyo Chemical Industry Co., Ltd.) in DMSO(9 ml), was added K2CO3 3.12 g. The mixture was heated at 150 degree for 3 hr. The reaction mixture was purified by column chromatography(silica gel, AcOEt:Hexane=1:2) to provide the aniline 367 (1.43 g, 56%). mp 158–160° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]4OCC[O:21]4)[S:18][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.Cl.CO>C1COCC1>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[O:21])[S:18][CH:19]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Cc3csc(C4OCCO4)c3)ccc21
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(Cc3csc(C=O)c3)ccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A round bottom flask was mixed with 2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-thienyl}-1,3-dioxolane (5.1 g, 14.3 mmol), 3.0 N HCl (50 mL), methanol (20 mL) and THF (30 mL). The reaction mixture stirred for 6 hours at room temperature and was concentrated to one half volume. The resulting mixture was partitioned between water and ether. The ether layer was dried over MgSO4 and concentrated to dryness. The resulting oil showed an inseparable impurity by TLC from the starting material. The product was used without further purification (2.7 g).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([SiH2:9][O:10][C:11]([CH3:27])([CH3:26])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20]OS(C)(=O)=O)[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6]>CCO>[C:5]([SiH2:9][O:10][C:11]([CH3:26])([CH3:27])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCOS(C)(=O)=O)ccc1Cl
Reactant: NC1CC1
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCNC2CC2)ccc1Cl
Temperature: 25 °C
Yield: 54.7 %

Procedure:
Cyclopropylamine (1.14 mL, 16.3 mmol) was added to a sol. of methanesulfonic acid 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl ester (1.76 g, 4.65 mmol) in EtOH (46 mL). The mixture was heated to reflux for 2 h, and cyclopropylamine (0.57 mL, 8.2 mmol) was added again. The mixture was heated to reflux overnight, and was allowed to cool to rt. The solvents were removed under reduced pressure, and the residue was purified by FC (EtOAc/heptane 50:50→7M NH3/MeOH) to yield the title compound (865 mg, 68%). LC-MS: tR=0.92 min; ES+: 340.39.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH3:3].C([O-])(=O)C([O-])=[O:20]>>[CH2:15]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:20])[CH:13]=2)[CH2:8][CH2:7]1)[CH2:16][CH3:17]
Reactant: CCCN(CCC)CC1CCc2ccccc21
Reactant: O=C([O-])C(=O)[O-]
Product: CCCN(CCC)CC1CCc2ccc(O)cc21

Procedure:
N,N-Dipropyl-1-indanmethylamine, oxalate. M.P 99°-102° C. (Lu 21-091)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:10]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][N:3]=1
Reactant: Nc1cnc(Cl)cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: S=C=Nc1cnc(Cl)cn1
Yield: 83 %

Procedure:
A solution of 5-chloropyrazin-2-amine (12.95 g, 100 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (27.9 g, 120 mmol) was stirred in DCM (200 mL) at room temperature for 1 h. The reaction was concentrated to ca. 100 mL volume and filtered through a pad of silica gel (1 L), washing with 10% EtOAc in hexanes. The filtrate was concentrated and dried to afford 2-chloro-5-isothiocyanatopyrazine (14.32 g, 83 mmol, 83% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.38 (d, J=1.26 Hz, 1H) 8.18 (d, J=1.26 Hz, 1H). MS (LC/MS) R.T.=1.84; [M+H]+=172.09.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([OH:23])[CH:7]([N:18]1[CH2:21][CH2:20][C:19]1=[O:22])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[N+]=[N-]>[Pd].C(O)C.O>[NH2:1][CH2:4][CH2:5][CH:6]([OH:23])[CH:7]([N:18]1[CH2:21][CH2:20][C:19]1=[O:22])[C:8]([OH:10])=[O:9]
Reactant: [N-]=[N+]=NCCC(O)C(C(=O)OCc1ccccc1)N1CCC1=O
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: NCCC(O)C(C(=O)O)N1CCC1=O
Yield: 6 %

Procedure:
The fast moving diastereoisomer of benzyl 5-azido-3-hydroxy-2-(2-oxoazetidin-1-yl)valerate (0.76 g, 23.9 mmol) was hydrogenated over 5% palladium on carbon catalyst in ethanol (20 ml) and water (5 ml) for one hour. The catalyst was filtered off and the filtrate evaporated. The residual gum was triturated with ether to yield, after filtration the title compound as a pale yellow solid (456 mg, 97%). The yellow coloured impurity was removed by trituration with ethyl acetate. The title compound (400 mg) was further purified by column chromatography on silica gel (Merck Art. 9385) using water/ethanol (15:85) as eluant to yield the title compound (290 mg) as a white solid containing 1/7 molar equivalent of ethanol. δH (D2O, 400 MHz) 1.16 (t, CH3CH2OH), 1.84 (2H, m), 3.00 (2H, t, J 3.9 Hz), 3.15 (2H, m), 3.50 (1H, m), 3.58 (1H, m), 3.63 (q, CH3CH2OH), 4.07 (1H, d, J 5.4 Hz), 4.19 (1H, m), δC (D2O, 100 HMz), 31.66, 36.12, 37.61, 40.99, 63.19, 69.54, 174.79, and 174.97. Recrystallisation of a sample from aqueous methanol gave white prisms m.p. 130°-135°. νmax (KBr) 3349, 1723, 1653, 1611, 1390, 918 and 769. (Found: C, 43.93; H, 7.40; N, 12.49%. C8H14N2O4.H2O requires C, 43.63; H, 7.32; N, 12.72)
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.C[C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:10]1
Reactant: Clc1cccnc1Cl
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
Dissolve 2,3-dichloropyridine (8.5 g, 0.057 moles) and (R)-(−)-2-methylpiperazine (5.75 g, 0.057 moles) in DMA(125.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (23.75 g, 0.172 moles) to this mixture and stir at 135-140° C. for 48 hours. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3×200 mL) and wash the combined organic extract with brine (2×150 mL). Dry over MgSO4, concentrate under vacuum to afford crude product as orange yellow liquid. Distil the crude under high vacuum to afford pyridylpiperazine derivative as yellow viscous oil.
Reaction SMILES: [N:1]1([C:5]([C@@H:7]2[CH2:12][C@H:11]([N:13]([C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCCl>[N:1]1([C:5]([C@H:7]2[CH2:8][NH:9][CH2:10][C@@H:11]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]4[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:22]=4[N:21]=3)=[O:19])[CH2:12]2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCC3)CN(C(=O)OC(C)(C)C)C2)nc2cc(F)c(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCC3)C2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To tert-butyl (3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[{[5,6-difluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (270 mg) in 1,2-dichloroethane (3 ml) was added TFA (5 ml) and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate-water, and neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, fumaric acid (23 mg) was added, and the solvent was evaporated under reduced pressure to give the object product (210 mg).