Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[C:20](N=C(N(C)C)N(C)C)([CH3:23])([CH3:22])[CH3:21].BrCC(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([N:8]([CH2:21][CH:20]([CH3:23])[CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:10])=[O:11])=[N:6][CH:7]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1cc(Cl)cnc1NS(=O)(=O)c1ccc(F)cc1
Solvent: CC(C)CBr
Solvent: CC#N
Product: Cc1cc(Cl)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
N-(5-chloro-3-methylpyridin-2-yl)-4-fluorobenzenesulfonamide (502 mg, 1.67 mmol) was dissolved in acetonitrile (3.5 mL) and to this solution was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (350 μL, 1.67 mmol). The solution was left to stir for 15 minutes then 1-bromo-2-methylpropane (363 μL, 3.34 mmol) was added. The reaction vessel was sealed and heated by microwaves to 150° C. for 1 hour. After cooling, additional 0.5 eq of 2-(tert-butyl)-1,1,3,3-tetramethylguanidine was added, along with 1 eq of 1-bromo-2-methylpropane. The reaction vessel was sealed and heated by microwaves to 150° C. for an additional 1 hour. The solution was concentrated in vacuo and the crude product extracted to the organic phase of an aqueous workup between ethyl acetate and water. The organic phase was passed through a hydrophobic frit, concentrated in vacuo and purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient). The relevant fractions were combined and evaporated to give the title compound (396 mg). LCMS (2 min, formic) Rt 1.38 min, m/z (ES+) 357 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[Cl:23])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[CH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[Cl:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[C:4]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C(O)CCC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CCC(=O)O)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Yield: 35.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(3-fluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.72 g, 1.53 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.3 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.3 g, 36%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:17])([O-:3])=[O:2].C[O:19]C(OC)N(C)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH:17]=[O:19])([O-:3])=[O:2]
Reactant: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-nitro-5-phenoxytoluene (57.3 g, 0.25 mol) prepared in Step A above and dimethylformamide dimethyl acetal (43.1 mL, 0.324 mol) in DMF (259 mL) was heated overnight at 140° C. The mixture was cooled to room temperature, and the solvent was evaporated in vacuo. The residue was dissolved in THF (500 mL) and transferred to a 3 L 3-neck flask equipped with an overhead stirrer. The mixture was diluted with 500 mL of water, and NalO4 (160 g, 0.75 mol) was added in portions (slight exotherm). The mixture was stirred overnight at room temperature. The solids were filtered and washed well with EtOAc. The filtrate was washed 3× with saturated aqueous NaHCO3 solution, and then dried (MgSO4). The solution was filtered and the solvent was evaporated in vacuo. The crude product was chromatographed (10-40% CH2Cl2:hexane) to yield 2-nitro-5-phenoxy-benzaldehyde as a yellow crystalline solid.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)([CH3:3])[CH3:2].C1CN([P+](ON2N=[N:49][C:44]3[CH:45]=[CH:46][CH:47]=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(CN)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:45]1([CH2:44][NH:49][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([S:13]([N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5]3)(=[O:14])=[O:15])=[CH:17][CH:18]=2)[CH2:47][CH2:46]1
Reactant: CC(C)c1cn(S(=O)(=O)c2ccc(C(=O)O)cc2)c2ccccc12
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cn(S(=O)(=O)c2ccc(C(=O)NCC3CC3)cc2)c2ccccc12
Yield: 87.1 %

Procedure:
Stir mixture of 4-(3-isopropyl-indole-1-sulfonyl)-benzoic acid (0.181 g, 0.53 mmol), PyBOP (0.243 g, 0.55 mmol) and cyclopropylmethyl amine (0.064 g, 0.59 mmol) in CH2Cl2 (20 mL) add Hunigs base (0.28 mL, 1.62 mmol) under N2. Stir the resulting mixture overnight at ambient temperature. Extract the reaction with H2O, wash with brine dry (MgSO4), filter, evaporate and chromatograph using hexane-EtOAc (0-100%) to give 0.183 g of the title compound as an off white solid: Mass spectrum (m/e) (M+H) 397.1593; found 397.1586.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>CO.[Pd].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1c(N)cccc1N
Reaction time: 2 h
Yield: 96 %

Procedure:
Methyl 2,6-dinitrobenzoate (15.0 gm.) is suspended in methanol (500 ml.) and 5% palladium on charcoal (1.5 gm.) added. Reduction is carried out on a Parr apparatus for two hours. The solution is filtered with suction and the catalyst washed with a few ml. of methanol. Removal of the methanol gives a brown crystalline product. Extraction with chloroform (50 ml.) and treatment with Darco® gives the product (10.9 gm. 96% yield, m.p. 78°-79.5°). The thin layer chromatogram (Silica gel, 3% methanol in chloroform) shows the material to be homogeneous.
Reaction SMILES: N.[SH2:2].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]#[N:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CO>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12](=[S:2])[NH2:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC#N
Reactant: S
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(N)=S
Yield: 75.7 %

Procedure:
25 g of ammonia gas and 50 g of hydrogen sulfide gas were successively dissolved in 230 ml of methanol with ice-cooling and stirring. To this was added 71.45 g of (tert-butoxycarbonylamino)acetonitrile, and the mixture was stirred overnight at room temperature. The reaction solution was cooled with ice. To this was slowly added 500 ml of water, and the mixture was stirred for an additional 2 hours with ice- cooling. The crystals precipitated were collected by filtration, washed with 300 ml of cold water, and then dried under reduced pressure to give 65.88 g of (tert-butoxycarbonyl-amino)acetothioamide as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:34][CH2:33][C:18]3([O:23][CH2:22][C:21](=[O:24])[N:20]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH2:19]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:34][CH2:33][C:18]3([O:23][CH2:22][C:21](=[O:24])[N:20]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH2:19]3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: COc1ccc(N2CC3(CCN(c4ccc(OCc5ccccc5)cc4)CC3)OCC2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CC3(CCN(c4ccc(O)cc4)CC3)OCC2=O)cc1
Yield: 82 %

Procedure:
The benzyloxy compound (529 mg, 1.15 mmol) obtained in (a) was dissolved in a mixed solvent of methanol/tetrahydrofuran (1/1), then 10% palladium-carbon (110 mg, 0.103 mmol) was added thereto and stirred overnight in a hydrogen atmosphere. The reaction solution was filtered through Celite, the Celite was washed with mixed solvent of chloroform/methanol, and the mother liquid was concentrated to obtain the entitled compound (350 mg, 82%) as a violet solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[N+](C1C=CC=C([N+]([O-])=O)C=1C(O)=O)([O-])=O.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])([O-:3])=[O:2]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]

Procedure:
As shown in scheme G, 2,6-dinitrobenzoyl chloride prepared from 2,6-dinitrobenzoic acid is treated with glycine in the presence of sodium carbonate to yield 2-(2,6-dinitrobenzamido)acetic acid (intermediate 10). Treatment of intermediate 10 either with K18F or K19F gave 2-(2-fluoro-6-nitrobenzamido)acetic acid, which on reduction with indium powder in the presence of either acetic acid or acetic anhydride-acetic acid gave the corresponding 2-(2-amino-6-fluorobenzamido)acetic acid (compound 8) or 2-(2-acetamido-6-fluorobenzamido)acetic acid (compound 9) respectively.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([NH:12][C:13]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)(=[O:18])=[O:17])=[O:14])[N:6]=1.[CH3:29][OH:30]>>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([O:30][CH3:29])[N:8]=[C:7]([NH:12][C:13]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)(=[O:18])=[O:17])=[O:14])[N:6]=1
Reactant: CO
Reactant: C[O-]
Reactant: O=C(Nc1nc(Cl)cc(Cl)n1)NS(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccc3cccnc23)n1
Temperature: 25 °C

Procedure:
To 0.86 g sodium methoxide in 15 ml methanol is added 1.6 g of N-[(4,6-dichloropyrimidin-2-yl)aminocarbonyl]-8-quinolinesulfonamide portionwise. This mixture is then heated to reflux temperature for 2 hours. The resultant white suspension is cooled to room temperature and filtered. The filtered white solid is dissolved up in a minimum amount of water and carefully acidified with 10% aqueous hydrochloric acid. The resultant white solid is filtered to give 0.65 g, m.p. 175°-177° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:10]1([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of commercially available 6-bromopicolinaldehyde (3.000 g; 16.12 mmol), phenylboronic acid (3.009 g; 24.19 mmol), and Pd(PPh3)4 (931 mg; 0.80 mmol) in toluene (40 ml) and aq. 2 M Na2CO3 (34 ml) was heated to reflux, under nitrogen, for 4 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded 6-phenylpicolinaldehyde as a pale yellow oil. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 184.17 g/mol.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:4]=2[CH2:3]1.[N:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2=[O:34])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[CH3:19][C:17]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][C:8]=3[CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4=[O:34])[CH2:21][CH2:22]3)[CH2:3][C:4]=2[CH:18]=1
Reactant: O=C1CCCCN1CCN1CCNCC1
Reactant: CSc1ccc2c(c1)C(Cl)Cc1cc(C)ccc1O2
Solvent: ClC(Cl)Cl
Product: CSc1ccc2c(c1)C(N1CCN(CCN3CCCCC3=O)CC1)Cc1cc(C)ccc1O2

Procedure:
A solution of 3 g. of 10-chloro-10,11-dihydro-2-methyl-8-methylthio-dibenz[ b,f]oxepin and 5.73 g. of 1-[2-(1-piperazinyl)-ethyl]-2-piperidone in 18 ml. of chloroform is heated at reflux for 20 hours. The solvent is removed in vacuo. The residue is partitioned between benzene and 10% aqueous sodium carbonate solution. The benzene solution is extracted with dilute hydrochloric acid. The acid-aqueous solution is made alkaline with sodium bicarbonate and extracted with benzene. The benzene extract is washed several times with water, dried, evaporated in vacuo, and there is obtained 1-[2-{4-[10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-piperidone. The dihydrochloride is prepared in ethanol by the addition of an excess of alcoholic hydrogen chloride. By the addition of ether, there are obtained crystals having a melting point of 183°-185° C. (with decomposition). By re-dissolving the dihydrochloride in water, there is obtained the monohydrochloride having a melting point of 117°-120° C.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[C:13]=2[CH3:37])[CH2:10][CH2:9]1.N1CCCCC1>C(O)C.O>[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[C:7]4[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]4)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[C:13]=2[CH3:37])[CH2:9][CH2:10]1
Reactant: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=O)cnn2c1NC1CC1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=C3NC(=O)NC3=O)cnn2c1NC1CC1
Temperature: 80 °C
Yield: 15.5 %

Procedure:
Hydantoin (7.5 mg, 0.08 mmol) and 2-(4-(7-(cyclopropylamino)-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (15 mg, 0.04 mmol) were dissolved in ethanol (0.5 mL) along with piperidine (8 uL, 0.08 mmol). The reaction was heated at 80° C. for 1 hour in the microwave. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give 2-(4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (3 mg, 17% yield). LCMS (M+1=485)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH3:26]>>[Br-:1].[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[CH3:26])=[CH:8][CH:9]=1
Reactant: BrCCCCCc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccnc(C)c1
Product: Cc1cc[n+](CCCCCc2ccc(-c3ccccc3)cc2)c(C)c1
Product: [Br-]
Temperature: 65 °C
Yield: 77 %

Procedure:
A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (331 mg, 1.09 mmol) and 2,4-lutidine (1 mL) was heated at 60-70° C. for 12 hrs. The resulted mixture was washed with diethyl ether and then dissolved in water (15 mL). The aqueous solution was extracted with diethyl ether (30 mL×3). Water was removed by lyophilization to afford 342 mg of the title compound. Yield: 77%. 1H NMR (300 MHz, CDCl3) δ 1.51 (m, 2H), 1.71 (m, 2H), 1.92 (m, 2H), 2.55 (s, 3H), 2.65 (t, J=7.8 Hz, 2H), 2.84 (s, 3H), 4.73 (t, J=7.8 Hz, 2H), 7.20-7.75 (m, 11H), 9.31 (d, J=6.3 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 20.1, 22.0, 25.8, 30.5, 30.8, 35.2, 57.4, 126.7, 126.9, 127.0, 128.2, 128.6, 128.8, 130.4, 138.5, 140.7, 140.9, 145.4, 152.8, 158.4 ppm.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1([O:24][C:25]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][N:15]([C:25]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])[CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: c1ccc2c(OCC3CCNC3)cccc2c1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)N1CCC(COc2cccc3ccccc23)C1
Temperature: 60 °C

Procedure:
A solution of 0.20 g (0.88 mmol) of 3-[(1-naphthalenyloxy)methyl]pyrrolidine, prepared in Step 12.2., and 0.35 g (1.5 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate, prepared in accordance with Example 1.1, in 6 ml of toluene is heated at 60° C. overnight. It is evaporated to dryness and the residue is taken up in a mixture of water, dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic phase is decanted, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with dichloromethane and then with a 99/1 mixture of dichloromethane and methanol. This gives 0.24 g of product in oil form, which is used as it is in the following step.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:25]1
Reactant: NCC1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2CCC(CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 35.4 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-aminomethylpyrrolidine (80 mg), DBU (110 mg) and anhydorous acetonitrile (3 ml) was refluxed for 2.5 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized from a solution of dichloromethane-methanol (1:1) to give the title compound (90 mg) as white powdery crystals, mp 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14].[NH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(OCC)C>C(Cl)Cl>[OH:21][CH2:20][CH2:19][CH2:18][NH:17][S:13]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])(=[O:15])=[O:14]
Reactant: NCCCO
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCCCO)c(OC)c1OC
Reaction time: 8 h

Procedure:
2,3,4-Trimethoxybenzene sulfonyl chloride (20.4 g, 0.765 m) in methylene chloride (100 ml) was added dropwise to 3-aminopropanol (17.2 g) in methylene chloride (300 ml). After stirring overnight the reaction was washed with dilute aqueous HCl, dried and stripped to provide a solid. Trituration with diethyl ether provided the product N-(3-hydroxypropyl)-2,3,4-trimethoxy-benzenesulfonamide, m.p. 95°-97° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:11])[C:9]=1[Cl:10])[C:5]#[N:6].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:11][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:9]=1[Cl:10])[C:5]#[N:6]
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Reactant: COCCOCCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOCCNc1cc(C#N)cc(N)c1Cl
Temperature: 100 °C
Yield: 28.2 %

Procedure:
To a solution of 3,5-diamino-4-chlorobenzonitrile (220 mg, 1.313 mmol) in DMF (3 mL) was added IIlunig's Base (2.75 mL, 15.75 mmol) followed by 1-bromo-2-(2-methoxyethoxy)ethane (1442 mg, 7.88 mmol). The resulting solution was heated at 100° C. for 16 h. LC-MS indicated ca. 30% conversion. It was diluted with EtOAc and water. After separating the layers, the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated. Purification via silica gel chromatography (0-70% EtOAc in Hexanes, 24 g) gave 3-amino-4-chloro-5-((2-(2-methoxyethoxy)ethyl)amino)benzonitrile (100 mg) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][O:11][CH3:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.Cl[C:14]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=1[C:16]#[N:17].[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:14]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])[O:11][CH3:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CONS(=O)(=O)c1ccc(Cl)s1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1C#N)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a solution of 5-chloro-N-methoxy-2-thiophenesulfonamide (0.46 g (2.02 mmol)) and 2-chloro-5-nitrobenzonitrile (0.45 g (2.46 mol)) in DMF (3.0 ml), sodium hydride (60%, 0.09 g (2.25 mmol)) was added bit by bit under cooling with ice and with stirring and the mixture was stirred under cooling with ice for one hour and at room temperature for one hour. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:3) as eluent to give 0.41 g (54%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]=[C:24]1[NH:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][O:25]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([N:28]3[C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:26][O:25][C:24]3=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2)CC1
Yield: 90.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 4-(4-iodobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (3.75 g) described in Preparation Example 161 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.99 g), the title compound (4.14 g) was obtained.