Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N+:11]([O-])([OH:13])=[O:12]>O>[N+:11]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2ccccc2c1
Solvent: O
Product: O=[N+]([O-])c1cccc2ccccc12

Procedure:
To a 2-liter resin flask equipped with a stirrer, thermometer, a dropping funnel, a N2 sparge tube and a condenser vented to a caustic scrubber was added 1025 g (8.0 moles) naphthalene. The reactor contents were heated until the naphthalene became molten, at which time agitation was started, and the heating was stopped. 680 ml nitric acid (72.5% concentration, 10.0 moles) was introduced over a period of 3 hours. During the first 40 minutes of addition time the temperature was gradually reduced to about 62° C. and for the remaining addition period the reaction temperature was maintained between 50° and 60° C. By using reduced pressure (ca. 25 mm Hg) water and excess nitric acid were distilled off at 60°-75° C. for about 1.25 hours, and residual water and HNO3 was driven off by sparging the molten reaction product with nitrogen gas while maintaining reduced pressure. During the 30 minutes sparging period the temperature was kept at 75°-80° C. The molten product (1408.5 g, 100% of theory) was removed from the reactor.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][S-:27].[Na+]>>[CH3:26][S:27][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: C[S-]
Reactant: Clc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [Na+]
Product: CSc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 92.2 %

Procedure:
The title compound was prepared by a similar method to preparation 7 from 2-chloro-N-phenethyl-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine (17.5 g, 49 mmol) (preparation 41) and sodium thiomethoxide (7.2 g, 75 mmol). This gave the title compound (16.7 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[N:36]1([S:33]([C:30]2[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:28][CH:29]=2)(=[O:34])=[O:35])[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-(4-bromo-benzenesulfonyl)-morpholine (example B.26) (276 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (450 mg, 77%). MS (ISP) 581.2 [(M+H)+]; mp 229–231° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].ClC1C=C(C(OO)=[O:40])C=CC=1.CCOC(C)=O>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29]([CH3:30])=[O:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)O)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 64.6 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (30.0 mg, 0.068 mmol) in CH2Cl2 (5.0 ml) was added 3-chlorobenzenecarboperoxoic acid (23 mg. 0.103 mmol). The resultant mixture was stirred at room temperature 10 mins. Flash chromatography (EtOAc/Hex=1:1) then provided the title compound (20 mg, 64%). LC-MS (ES) m/z 456 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].B(Br)(Br)Br>ClCCl>[C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COc1cccc(C2(C#N)CCOCC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CC1(c2cccc(O)c2)CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 68 %

Procedure:
To a dichloromethane (80 ml) solution of 4-cyano-4-(3-methoxyphenyl)-3,4,5,6-tetrahydro-2H-pyran (2.32 g, 10.35 mmol) cooled to 0° C. was added boron tribromide (3.15 ml, 33.3 mmol) dropwise over 10 min. The ice-bath was removed and the reaction mixture stirred at ambient temperature for 19 h, and then at reflux for 4 h. The reaction mixture was cooled and poured into water (150 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml×3). The combined organic extracts were washed with brine (50 ml), dried (MgSO4) and concentrated in vacuo. The crude product was crystallized from isopropyl ether to afford titled compound as off-white solids (1.43 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[O:21])=[O:10])=[N:6][CH:7]=1.Cl.[OH:31][NH2:32].CCN(CC)CC>CCO>[NH2:29][C:28](=[N:32][OH:31])[C:25]1[CH:24]=[CH:23][C:22]([C:20]([NH:19][C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[O:21])=[CH:27][CH:26]=1
Reactant: NO
Reactant: COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NC(=O)c2ccc(C(N)=NO)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of compound N-(5-chloro(2-pyridyl)) {2-[(4-cyanophenyl)carbonylamino]-5-methoxyphenyl}carboxamide (150 mg) in EtOH (10 mL) was added hydroxyamine hydrochloride (80 mg) and Et3N (200 μL). The mixture was stirred at 60° C. overnight and the reaction was complete. The solvent was evaporated and the crude material was purified by RP-HPLC to give the title compound. MS found for C21H18ClN5O4 (M+H)+: 440.1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]1.O1C=CC(C(O)=O)=[CH:10]1.S1CCC(C(O)=O)C1.BrCC(C(OC)=O)CCBr.[S-2].[Na+].[Na+]>[Ni]>[O:1]1[CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH2:10][CH2:4][CH2:5]1
Reactant: O=C(O)C1CCOC1
Reactant: O=C(O)c1ccoc1
Agent: [Ni]
Agent: COC(=O)C(CBr)CCBr
Agent: O=C(O)C1CCSC1
Product: O=C(O)C1=COCCC1

Procedure:
Tetrahydrofuran-3-carboxylic acid (formula I: n=1, X=S) can be prepared by hydrogenation of furan-3-carboxylic acid with Raney Nickel (Boekelheide and Morrison, J. Am. Chem. Soc. 80 (1958) 3905), tetrahydrothiophene-3-carboxylic acid (formula I: n=1, X=S) is accessible by reaction of methyl 1,4-dibromobutane-2-carboxylate with sodium sulfide and subsequent alkaline hydrolysis of the ester group (Kapovits and Kucsman, Acta Chim. Acad. Sci. Hung. 34 (1962) 79), (2H)-tetrahydropyran-3-carboxylic acid (formula I: n=2, X=S) can be obtained by hydrogenation of 2,3-dihydro-(4H)-pyran-5-carboxylic acid with Raney Nickel (Silberman, J. Org. Chem. 25 (1960) 151), (2H)-tetrahydrothiopyran-3-carboxylic acid (formula I: n=2, X=S) can be prepared, for example, from ethyl 1,5-dibromopentane-2-carboxylate by ring closure with sodium sulfide and subsequent alkaline hydrolysis (Kapovits and Kucsman, Acta Chim. Acad. Sci. Hung. 34 (1962) 79).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH2:8][S:9][CH2:10][C:11]=2[C:12]#[N:13])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[C:11]([C:12]#[N:13])=[CH:10][S:9][CH:8]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: N#CC1=C(Nc2ccc(Cl)cc2[N+](=O)[O-])CSC1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1C
Product: N#Cc1cscc1Nc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
3-(4-Chloro-2-nitroanilino)-2,5-dihydrothiophene-4-nitrile (14.09 g, 0.05 mol) dissolved in xylene (150 ml) was added to a solution of chloranil (12.3 g, 0.05 mol) in hot xylene (100 ml). The mixture was allowed to reflux for 2 hours. After cooling, the xylene was evaporated off under vacuum to leave a red-brown solid which was triturated with methanol to give a brick-red solid. The solid was recrystallised from hot methanol to give red crystals which were filtered off, washed with methanol and dried at 50° C. under vacuum. The dried product so obtained was the title compound, m.p. 214° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:46][CH2:47][N:48]4[CH2:52][CH2:51][CH2:50][CH2:49]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a suspension of 4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (124 mg, 0.32 mmol) in methylene chloride (2.5 ml) was added triphenylphosphine (179 mg, 0.628 mmol), 1-(2-hydroxyethyl)pyrrolidine (75 mg, 0.65 mmol) followed by diisopropyl azodicarboxylate (134 μl, 0.68 mmol) in portions. After stirring overnight at ambient temperature the mixture was poured onto a column of silica and eluted with ethyl acetate/methyl ene chloride (1/1) followed by ethyl acetate/methylene chloride/methanol (4/5/1) followed by methylene chloride/methanol (9/1). After removal of the solvent, the solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (51 mg, 37%).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[CH:6][CH:7]=1.N([O-])=[O:11].[Na+]>O.S(=O)(=O)(O)O>[C:8]([C:5]1[N:4]=[CH:3][C:2]([OH:11])=[CH:7][CH:6]=1)#[N:9]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(O)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
A solution of 1 g (8.06 mmol) of 3-amino-6-cyanopyridine in 12 ml of water and 1.2 ml of sulfuric acid is cooled to 0° C. and 1 g (14.5 mmol) of sodium nitrite is added slowly. The reaction mixture is left to return to room temperature and then stirred at 100° C. for 3 hours. It is left to stand overnight in a refrigerator. The precipitate formed is filtered off and washed with iced water. The expected product also present in the filtrate is extracted with ethyl acetate and combined with the previous precipitate. This crude product is purified by chromatography on silica gel using a dichloromethane/methanol mixture (98/2; v/v) as the eluent to give 613 mg of the expected compound in the form of a brown powder (yield=63%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[S:16][C:17]([C:20]2([OH:47])[CH2:25][CH2:24][CH:23]([N:26]3[CH2:29][CH:28]([NH:30][C:31](=[O:46])[CH2:32][NH:33][C:34](=[O:45])[C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=4)[CH2:27]3)[CH2:22][CH2:21]2)=[CH:18][N:19]=1)(C)(C)C>>[NH2:14][C:15]1[S:16][C:17]([C:20]2([OH:47])[CH2:25][CH2:24][CH:23]([N:26]3[CH2:29][CH:28]([NH:30][C:31]([CH2:32][NH:33][C:34](=[O:45])[C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:44])[F:42])[CH:36]=4)=[O:46])[CH2:27]3)[CH2:22][CH2:21]2)=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compound was prepared as colorless oil from TFA de-protection of [5-(1-hydroxy-4-{3-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-azetidin-1-yl}-cyclohexyl)-thiazol-2-yl]-carbamic acid tert-butyl ester, as prepared in the previous step, using the procedure described in Step B of Example 16.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2N)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Methanesulfonyl chloride (364 mg) was added to a solution of 1-t-butoxycarbonyl-4-(2-aminophenyl)piperidine (880 mg) and pyridine (252 mg) in dichloromethane. The mixture was heated under reflux for 30 min., cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between aqueous citric acid (10%) and ethyl acetate (100 mL). The organic layer was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (1.15 g), δH (CDCl3) 1.48 (9H, s), 1.60 (2H, m), 1.73 (2H, m), 2.83 (2H, m), 3.04 (3H, s), 3.09 (1H, m), 4.26 (2H, m), 6.21 (1H, br s), 7.21-7.37 (2H, m). m/e (ES+) 355 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(C(F)(F)F)n1

Procedure:
The title compound, MS: m/e=362.2 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-fluoro-6-trifluoromethyl-pyridine.
Reaction SMILES: [C:1](N1C2C(=NC=CC=2)N=N1)(=[O:3])[CH3:2].[OH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=1.[OH-].[Na+]>C1COCC1.Cl>[C:1]([O:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][OH:13])=[CH:18][C:19]=1[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)n1nnc2ncccc21
Reactant: COc1cc(OCCO)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(OCCO)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-acetyl-1H-1,2,3-triazolo[4,5-b]pyridine (0.248 g, 1.532 mmol) in dry THF (6.13 mL) was added to a solution of 4-(2-hydroxyethoxy)-2-methoxyphenol (0,2821 g, 1.532 mmol) in 1N aq. NaOH (1.532 mL, 1.532 mmol) at 25° C. The reaction was stirred at 25° C. for 3 h. The reaction was diluted with 1IN HCl (20 mL) and extracted with Et2O (3×20 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 50% EtOAc in hexanes over 360 mL, gradient to 100% EtOAc over 2034 mL) to afford 4-(2-hydroxyethoxy)-2-methoxyphenyl acetate. Rf=0.28 (50% EtOAc/hexanes). LCMS calc.=249.1; found=249.0 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 6.87 (d, J=8.7 Hz, 1 H); 6.52 (d, J=2.7 Hz, 1 H); 6.38 (dd, J=8.7, 2.7 Hz, 1 H); 3.96 (t, J=4.7 Hz, 2 H); 3.84 (t, J=4.7 Hz, 2 H); 3.71 (s, 3 H); 2.97 (s, 1 H); 2.24 (s, 3 H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15].CS(CCO)(=O)=[O:19].[H-].[Na+]>CN(C=O)C>[OH:19][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15]
Reactant: CS(=O)(=O)CCO
Reactant: CN1CCc2c(F)ccc([N+](=O)[O-])c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(O)ccc([N+](=O)[O-])c2C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 5-fluoro-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (2.24 g, 10 mmol) in DMF (15 mL) is added 2-(methylsulfonyl)ethanol (1.86 g, 15 mmol) and the solution cooled to 0° C. Sodium hydride (1.2 g, 30 mmol) is added and the reaction mixture allowed to warm to room temperature and then stirred for 1 hour. The mixture is quenched with a 1N HCl solution and partitioned between ethyl acetate and brine. The organic layer is concentrated to dryness and the crude organics purified by flash column chromatography to give 5-hydroxy-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one in 70% yields. 1H-NMR (400 MHz, δ, ppm) Acetone-d6: 2.85-3.0 (m, 2H), 3.06 (s, 3H), 3.6-3.7 (m, 2H), 7.05-7.1 (m, 1H), 7.35-7.41 (m, 1H), 9.62 (brs, 1H).
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][CH:7]([C:14]#[N:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[OH-:19].[Na+]>OS(O)(=O)=O>[CH:16]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH:7]([C:14](=[O:19])[NH2:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:18])[CH3:17]
Reactant: [OH-]
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)N(CCC(C(N)=O)c1ccccc1)C(C)C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
N,N-Diisopropyl-3-cyano-3-phenylpropanamine (11.6 g, 47.5 mmol) was mixed with H2SO4 (90%, 100 mL) and the mixture was stirred at 100° C. for 30 min. The reaction mixture was poured on ice, made alkaline (11 M NaOH) and extracted twice with diethyl ether. The combined organic phases were dried (Na2SO4) and the solvent evaporated, affording the title compound as a colourless oil, 12.4 g (100%); 1H NMR (CDCl3) δ1.26 (m, 12H), 2.14 (m, 1H), 2.60 (m, 1H), 2.73 (t, 2H), 3.31 (m, 2H), 3.86 (t, 1H), 6.06 (br, 2H), 7.51-7.61 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([N+:33]([O-])=O)[CH:27]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36].[CH:37](O)=O>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[NH:32][CH:37]=[N:33][C:28]=3[CH:27]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36]
Reactant: O=CO
Reactant: CCCC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Agent: [Pd]
Product: CCCC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1

Procedure:
Prepared from 4-amino-N-[1-((4-amino-3-nitro-phenyl)methyl)-2-(4-propyl-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)([CH2:5][CH3:6])[C:3]#[N:4].[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].CC(N1CCCC1)(C)C(N)C1C=CC=CC=1>C(OCCCC)CCC.C1COCC1.CO>[CH3:1][C:2]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)([CH2:5][CH3:6])[CH:3]([NH2:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Li]c1ccccc1
Reactant: CCC(C)(C#N)N1CCCC1
Agent: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)(C(N)c1ccccc1)N1CCCC1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
The title compound (13.4 g, 94%) was prepared from 2-methyl-2-(1-pyrrolidinyl)butanenitrile D21 (9.6 g, 0.063 mol) and phenyllithium in dibutylether (63 ml of a 2M solution; 0.126 mol) in THF (200 ml), followed by reaction with sodium borohydride (3.5 g, 0.092 mol) in methanol (200 ml) in a similar manner to that described in D5, except that after addition of the sodium borohydride stirring was continued with ice cooling for 0.5 hours then at room temperature for 66 hours. Mass spectrum (Electrospray LC/MS), ES+: Found 233 (MH+). C15H24N2 requires 232. Ret. times 0.78 and 1.06 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH2:21](O)[CH3:22]>>[N+:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:21][CH3:22])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 5-nitrosalicylic acid (10.8 g) in ethanol (100 ml) was added concentrated sulfuric acid (92.0 g) with stirring at room temperature, and the resulting mixture was refluxed for 7.5 hours. After cooling to room temperature, the reaction mixture was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, 0.5N hydrochloric acid and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford the title compound (10.7 g, yield: 85%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].CC(C)([O-])C.[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCCCCC>CS(C)=O.C(OCC)(=O)C>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: N#Cc1ccc(O)c(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reaction time: 24 h
Yield: 105.7 %

Procedure:
To a solution of 3,4-dihydroxy-benzonitrile (1.36 g, 10 mmol) and potassium tert-butoxide (1.5 g, 13 mmol) in dimethylsulfoxide (15 mL) was added benzyl chloride (1.5 mL, 13 mmol) under nitrogen atmosphere at room temperature, and the solution was stirred for 24 hours. Silica gel (100 mL) was added portionwise to the reaction solution for adsorption, a pale yellow oil of 4benzyloxy-3-hydroxy-benzonitrile (2.38 g) was obtained by silica gel column chromatography (hexane:ethyl acetate=7:3), in addition, this was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate, then ethyl acetate:methanol=90:10, then 85:15), and 4-benzyloxy-3-hydroxy-benzonitrile (0.588 g, 2.61 mmol, 24.8%) was obtained as a pale yellow solid.
Reaction SMILES: [OH2:1].[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1>O>[CH:8]1[CH:9]=[CH:10][C:5]2[N:4]([OH:1])[N:3]=[N:2][C:6]=2[CH:7]=1
Reactant: O
Reactant: c1ccc2[nH]nnc2c1
Product: On1nnc2ccccc21

Procedure:
H2O: 1H-benzotriazole monohydrate