Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:22])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:30]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:22][C:34]([CH:30]2[CH2:33][CH2:32][CH2:31]2)=[O:35])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1)C1CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 0.2 g (0.66 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(pyrimidin-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.18 mL (1.32 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.082 g (0.69 mmol) of cyclobutanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for two hours at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.18 g (62%) as a white solid; mp=112-114° C.; MS (+) ESI m/z=386 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([F:18])[CH:7]=1)[C:3]([OH:5])=[O:4].[S]>C1(OC2C=CC=CC=2)C=CC=CC=1.CC(C)=O>[CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C(=O)O)c1ccc(C2CCCCC2)c(F)c1
Agent: [S]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC(C)=O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 250 °C
Reaction time: 6 h
Yield: 45.1 %

Procedure:
A mixture of 5.00 g of α-methyl-4-cyclohexyl-3-fluorophenylacetic acid (m.p. 83° to 84° C.) and 2.3 g of sulphur in 10 ml of diphenyl ether was subjected to heating with stirring at 250° C. for 6 hours. The resulting reaction liquid was dissolved in acetone, and the insoluble substances were removed by filtration. The filtrate was poured into an aqueous sodium hydroxide solution. The resulting mixture was repeatedly washed with benzene, and hydrochloric acid was added to the aqueous layer. The crystals thus precipitated were collected by filtration, and recrystallized from a mixed benzene-n-hexane solvent to obtain 2.2 g of α-methyl-2-fluoro-4-biphenylylacetic acid (m.p. 112° to 114° C.).
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(O[C:19]([CH3:21])=[CH2:20])(=O)C.C(N(CC)CC)C>ClCCl>[CH3:12][O:11][C:9]([C@H:6]1[CH2:7][CH2:8][C@H:3]([C:2]2[CH:20]=[C:19]([CH3:21])[O:14][N:13]=2)[CH2:4][CH2:5]1)=[O:10]
Reactant: COC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Reactant: C=C(C)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](c2cc(C)on2)CC1
Reaction time: 20 h

Procedure:
To a solution of trans-methyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (5.90 g, 26.9 mmol) and isopropenyl acetate (53.8 g, 537 mmol) in dichloromethane (134 ml) was added triethylamine (5.44 g, 53.7 mmol) at 0-5° C. The cooling bath was removed 15 minutes after completed addition, and the mixture was stirred for 20 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (250 ml) and 0.1 M aqueous hydrochloric acid solution (200 ml). The organic layer was washed with one 100 ml-portion of 0.1 M aqueous hydrochloric acid solution. The combined aqueous layers were extracted with one 150 ml-portion of ethyl acetate. The combined organic layers were washed with one 200 ml-portion of 2 M sodium carbonate and one 100-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave the title compound (3.00 g, 50%) as off-white solid. MS m/e: 224 ([M+H]+)
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:11](OP(C1C=CC=CC=1)(=O)O)([OH:14])(=[O:13])=[O:12].[Cl-].[Ba+2].[Cl-]>O>[S:11]([C:3]1[CH:2]=[C:1]([P:7](=[O:9])([OH:8])[OH:10])[CH:6]=[CH:5][CH:4]=1)([OH:14])(=[O:13])=[O:12]
Reactant: O=P(O)(OS(=O)(=O)O)c1ccccc1
Reactant: O=P(O)(O)c1ccccc1
Agent: [Ba+2]
Agent: [Cl-]
Solvent: O
Product: O=P(O)(O)c1cccc(S(=O)(=O)O)c1

Procedure:
20.2 g of phenylphosphonic acid and 8.56 g of sulfotrioxide were mechanically mixed at 180° C. for 24 hr to prepare nz-sulfophenylphosphonic acid. After diluting with excess water, the mixture was added with 15% barium chloride. The precipitate was removed by filtering and excess dimethylether was added to extract unreacted phenyl phosphonic acid and obtain a m-sulfophenylphosphonic acid solution.
Reaction SMILES: CN(CCN(C)C)C.C([Li])CCC.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN([CH:24]=[O:25])C>C1COCC1>[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH:24]=[O:25]
Reactant: Fc1cccnc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccncc1F
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a solution of TMEDA (389 uL, 2.58 mmol) in THF (10 mL) at −78° C. was added a solution of n-butyl lithium in THF (2.5M, 1.03 mL, 2.58 mmol). After 30 minutes at −78° C., 3-fluoropyridine (221 uL, 2.57 mmol) was added. After another 2 hours at −78° C., DMF (219 uL, 2.83 mmol) was added. After a further 2 hours at −78° C., the reaction was quenched with saturated aqueous NaHCO3 (20 mL), extracted with ether (4×15 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the crude oil. Purification by column chromatography on silica gel (Hexanes: EtOAc 4:1) afforded the title compound as a pale yellow oil (120 mg, 37%). 1H NMR (CDCl3) 7.68 (t, 1H, J=5.2 Hz), 8.62 (d, 1H, J=4.7 Hz), 8.70 (s, 1H), 10.42 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)OCCO2
Solvent: CC(=O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a solution of 1 (20.0 g, 133.3 mmol) in acetic acid (135 mL) was added a solution of fuming HNO3 (10 mL) in acetic acid (50 mL) dropwise over 30 minutes. The mixture was stirred at ambient temperature for 10 minutes, then poured into a beaker containing ice to give a crystalline precipitate, which was collected by vacuum filtration and washed with water to afford the product (25.8 g, 99.2 %) as an off-white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[CH:10][S:11](=[O:12])[C:7]=2[CH:6]=1)=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][CH2:2][CH2:3][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[CH:10][S:11](=[O:12])[C:7]=2[CH:6]=1
Reactant: O=C(CBr)c1ccc2c(c1)S(=O)C=N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=S1C=Nc2ccc(CCBr)cc21

Procedure:
In a 500-cm3 ground-necked flask surmounted by a condenser, and placed in an oil bath, 40.8 g (0.15 mol) of 6-(bromoacetyl)benzothiazolinone are dissolved in 90 cm3 of trifluoroacetic acid with magnetic stirring and while the temperature is stabilized at 60° C. 52.7 cm3 (0.33 mol) of triethylsilane are introduced dropwise via a dropping funnel. After the addition, the heating is stopped and the mixture is then left stirring vigorously for 30 hours. The reaction medium is hydrolyzed by pouring it into ice-cold water, and the precipitate obtained is drained and washed with water until the filtrate is neutral and then with hexane. The product is dried and recrystallized in absolute ethanol.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:35])[C:10](=[O:36])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>N1C=CC=CC=1>[CH2:41]([O:40][C:38](=[O:39])[N:15]([CH2:14][CH2:13][CH2:12][N:11]1[C:10](=[O:36])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][CH2:23][N:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:35])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:42]
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCNCCCCNCCCn1c(=O)[nH]c2ccccc2c1=O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)N(CCCCN(CCCn1c(=O)[nH]c2ccccc2c1=O)C(=O)OCC)CCCn1c(=O)[nH]c2ccccc2c1=O
Reaction time: 2 h

Procedure:
3-(3-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl)-1H-quinazoline-2,4-dione(2 g, 4.1 mmol) was dissolved in 40 mL pyridine and ethyl chloroformate (0.46 mL, 4.9 mmol) was added thereto. After 2 hours, pyridine was removed under reduced pressure and dichloromethane and water was added to the remaining residue. After each layer was separated, dichloromethane was removed and silica gel column-chromatography of the remaining residue was performed to give the title compound of yellow solid (0.61 g, 24%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:21])(=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:14]1([NH:13][S:12]([C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:22])=[O:2])[CH:11]=[CH:10][CH:9]=2)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a) (0.220 g, 0.69 mmol) was dissolved in methanol (3 ml), 1N NaOH (2.08 ml, 2.08 mmol) was added and the resultant solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 10% HCl and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5 to give the title compound as a white solid (0.173 g, 82%).
Reaction SMILES: Cl.Br[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]1(/[C:12](=[N:14]/[S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])/[CH3:13])[CH2:11][CH2:10]1>C1COCC1.[Zn].[Cu]Cl>[C:17]([S:15]([NH:14][C:12]([CH:9]1[CH2:11][CH2:10]1)([CH3:13])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:16])([CH3:18])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: C/C(=N\S(=O)C(C)(C)C)C1CC1
Agent: Cl[Cu]
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(NS(=O)C(C)(C)C)C1CC1
Temperature: 0 °C
Yield: 78.9 %

Procedure:
To a flask containing zinc (Note: the zinc powder was activated by stirring 10 gr in 20 mL of 2.0M aqueous solution HCl (caution: strong exotherm occurs)) (3.49 g, 53.4 mmol) and copper (I) chloride (529 mg, 5.34 mmol) under a stream of argon was added dry THF (10.0 ml), the suspension was stirred at reflux for 30 minutes then the heating bath was removed. Slow addition of a solution of ethyl 2-bromoacetate (1.78 g, 10.7 mmol, Eq: 2.0) in dry THF (5.00 ml) (caution: reaction exothermic), when addition completed the suspension was stirred for 30 min at rt then 30 min at 50° C. The reaction was then cooled down to 0° C. and a solution of (E)-N-(1-cyclopropylethylidene)-2-methylpropane-2-sulfinamide (1 g, 5.34 mmol) in dry THF (5.00 ml) was added to the reaction. The reaction was then stirred at 0° C. and let to warm up to room temperature overnight. The reaction mixture was filtered through a pad of Celite and the filter pad was washed twice with ethyl acetate. The filtrate was washed with a 0.25M aqueous solution of citric acid, a 1M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane/ethyl acetate to yield the title compound (1.16 g, 79%) as a yellow oil; MS (ESI, m/z): 276.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[O-:15][C:16]#N.[K+]>O>[OH:13][CH2:12][CH2:11][CH2:10][N:9]1[C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:16]1=[O:15]
Reactant: N#C[O-]
Reactant: Cc1ccc(NCCCO)c(N)c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
To a stirred and cooled solution of 54 parts of 3-[(2-amino-4-methylphenyl)amino]-1-propanol in 30 parts of hydrochloric acid solution 10% and 200 parts of water is added dropwise a solution of 28 parts of potassium cyanate in 50 parts of water at a temperature below 10° C. Upon completion, stirring is continued first for 1 hour at room temperature and further for 24 hours at reflux temperature. After cooling to room temperature, the product is extracted with trichloromethane. The extract is washed with a hydrochloric acid solution 5%, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 19.5 parts (31%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol2-one; mp. 114.1° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)(=O)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:1][C:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NC1=NN(c2ccc(Cl)cc2)CC1
Solvent: CC(=O)O
Product: Clc1ccc(C=NC2=NN(c3ccc(Cl)cc3)CC2)cc1
Yield: 93 %

Procedure:
3-Amino-1-(4-chlorophenyl)-2-pyrazoline (prepared in Reference Example 6 of our European patent specification No. 22-578) (1.95 g) in S.V.M. (5 ml) was mixed with excess 4-chlorobenzaldehyde (1.50 g) and the mixture was heated to reflux after the addition of 1 drop of glacial acetic acid. A virtually clear solution formed which rapidly crystallised to form a bright orange product which was collected, washed with S.V.M. and dried in vacuo to produce 2.95 g 3-(4-chlorobenzylideneamino)-1-(4-chlorophenyl)-2-pyrazoline, m.p. 193°-195° (decomp).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)N>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccncc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccncc1
Yield: 11 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 4-hydrazinopyridine according to the method described for Example 1 in 11% yield. MS: M=316.1 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C@H:4]1[OH:16].[NH2:17][C:18]1[C:23]2[CH2:24][CH2:25][O:26][C:22]=2[C:21]([C:27](N2C=CN=C2)=[O:28])=[CH:20][C:19]=1[Cl:34]>C(#N)C>[NH2:17][C:18]1[C:23]2[CH2:24][CH2:25][O:26][C:22]=2[C:21]([C:27]([NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][C@H:4]2[OH:16])=[O:28])=[CH:20][C:19]=1[Cl:34]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)[C@H](O)C1
Reactant: Nc1c(Cl)cc(C(=O)n2ccnc2)c2c1CCO2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc(Cl)c(N)c3c2OCC3)[C@H](O)C1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
A mixture of intermediate (1-f) (0.09 mol) and intermediate (3-c) (0.087 mol) in ACN (600 ml) was stirred and refluxed for 1 hour. The reaction mixture was cooled to 0° C., and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried), yielding 28.7 g (78%) of (±)-1,1-dimethylethyl cis-4-[[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]amino]methyl]-3-hydroxy-1-piperidinecarboxylate (interm. 4. mp. 218° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:12][C:3]1[C:2]([NH:1][C:21]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Br:13])=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1cc2ccccc2cc1O
Product: O=C(Nc1cc2ccccc2cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 3-amino 2-hydroxy napthalene (0.320 g, 2 mmol) and 2-bromo phenyl isocyanate (0.40 g) by general Method B. It was purified by dilution of the with methylene chloride and precipitation with hexane (0.339, 47%). EI-MS m/z 357 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][C:24]1([OH:28])[CH2:27][CH2:26][CH2:25]1>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][C:24]1([OH:28])[CH2:27][CH2:26][CH2:25]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCC1(O)CCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
A solution of 4-chloro-3-nitroquinoline (30.0 g, 144 mmol) in dichloromethane (350 mL) was cooled to 0° C. under a nitrogen atmosphere, and triethylamine (22.1 mL, 158 mmol) was added. A solution of 1-(aminomethyl)cyclobutanol (16.0 g, 158 mmol) in dichloromethane (130 mL) was then added over a period of one hour, followed by a rinse of dichloromethane (100 mL). The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was triturated in water (500 mL) and saturated aqueous sodium bicarbonate (200 mL) for two hours. A solid was present and was isolated by filtration, washed with a large amount of water, and dried in a vacuum oven at 55° C. to provide 38.7 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanol as a yellow solid.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[N:11]=[N:10][C:9]([CH:12]([OH:14])[CH3:13])=[N:8]2)[CH:2]=1.[H-].[Na+].CS([C:22]1[N:23]([CH3:33])[C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:25][N:26]=1)(=O)=O>>[CH3:33][N:23]1[C:22]([O:14][CH:12]([C:9]2[N:10]=[N:11][N:7]([C:3]3[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=3)[N:8]=2)[CH3:13])=[N:26][N:25]=[C:24]1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1
Reactant: Cc1cccc(-n2nnc(C(C)O)n2)c1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(-n2nnc(C(C)Oc3nnc(-c4ccncc4)n3C)n2)c1
Yield: 80.5 %

Procedure:
The title compound (70 mg, 79%, off-white solid) was prepared from 1-(2-m-tolyl-2H-tetrazol-5-yl)-ethanol (50.3 mg, 0.24 mmol), sodium hydride (16 mg, 0.4 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (70.2 mg, 0.30 mmol). The product was purified by chromatography using a silica SPE tube (2.5-4% methanol in dichloromethane). 1H NMR (CDCl3) δ (ppm): 8.76 (br.d, 2H), 7.95 (s, 1H), 7.94 (d, 1H), 7.62 (d, 2H), 7.44 (t, 1H), 7.32 (d, 1H), 6.61 (q, 1H), 3.63 (s, 3H), 2.28 (s, 3H), 2.04 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]#[CH:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:24][C:23]#[CH:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: C#CCn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
1110 mg (3.61 mmol) of the compound from Example 5A were dissolved in 30 ml of acetonitrile, and 451 mg (3.79 mmol) of 3-bromo-1-propyne and 2.35 g (7.22 mmol) of cesium carbonate were added. The mixture was heated under reflux for 1 h. For work-up, the reaction mixture was allowed to cool to RT, and about 30 ml of water were added. The mixture was extracted twice with in each case 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 3:1). This gave 203 mg (16% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].Cl>>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23])([O-:15])=[O:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-nitrobenzenesulfonyl chloride as described in the synthetic METHOD B. The reaction mixture was applied on a Hydromatrix column pre-treated with aqueous HCl (0.5 mL, 2 M) and the eluted with DCM. After concentration the material was purified by preparative LCMS and lyophilized to give a white solid (26.6 mg) with purity >90%: 1H-NMR (DMSO-d6) δ 11.40 (s, NH), 8.24 (m, 1H), 7.65 (m, 3H), 6.39 (s, 1H), 4.21 (dd, J=7.2 Hz, J=14.4 Hz, 2H), 3.73 (s, 2H), 1.28 (t, J=7.2 Hz, 3H); HRMS Calcd (found) for C13H13N3O6S2 m/z 371.0246 (371.0248).
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=1.Cl([O-])(=O)(=O)=O.[Li+].CCOCC>C(Cl)(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][CH2:4][C:2]([CH3:3])([OH:5])[CH3:1])[CH3:14])=[CH:9][CH:8]=1
Reactant: CC1(C)CO1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C[C@H](NCC(C)(C)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Isobutylene oxide (1.0 g) and (S)-1-(4-fluorophenyl)ethylamine (2.25 mL) were added to a solution of lithium perchlorate (14.8 g) in an ether (27.8 mL) at room temperature, and the reaction solution was stirred at room temperature for 1.5 hours. Isobutylene oxide (0.5 mL) was added to the reaction solution, which was then stirred overnight. Ice water and chloroform were added to the reaction solution, and the organic layer was separated. Thereafter, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (chloroform:2-propanol=100:1 to 1:1) to obtain 2.13 g of the title compound.