Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[NH:25][N:24]=[C:23]([CH:26]([OH:28])[CH3:27])[CH:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:29][N:30]([CH3:35])[CH2:31][C:32]([O:28][CH:26]([C:23]1[CH:22]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[NH:25][N:24]=1)[CH3:27])=[O:33]
Reactant: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(OC(=O)CN(C)C)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A solution of N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide of Example 56 (90 mg, 0.225 mmol) in 2 ml of DCM was added to a suspension of N,N-dimethylglycine (47 mg, 0.45 mmol), DIPEA (0.13 ml; 0.75 mmol), anhydrous HOBt (61 mg, 0.45 mmol) and EDCI (87 mg, 0.45 mmol) in 2 ml of DCM. The reaction mixture was stirred at RT over three nights. The mixture was diluted with DCM and washed with water. Organic phase was dried over Na2SO4, filtered and evaporated. Crude product was purified twice by CombiFlash (1st column: silica, eluent: 0-10% MeOH in DCM; 2nd column: alumina, eluent: 0-10% MeOH in DCM) to obtain 26 mg (36%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 1.66 (d, 3H), 2.35 (d, 6H), 3.20 (d, 2H), 4.25-4.33 (m, 1H), 4.37-4.45 (m, 1H), 4.52-4.64 (m, 1H), 6.00 (q, 1H), 6.60 (m, 1H), 6.80 (s, 1H), 7.50 (dd, 1H), 7.67 (m, 1H), 7.74-7.87 (m, 2H), 8.09 (d, 1H), 11.6 (bs, 1H).
Reaction SMILES: C([N:5]([S:10](=[O:19])(=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6](=[NH:9])[O:7][CH3:8])(OC)=O.[H-].[Na+].O.C1C[O:26][CH2:25]C1>>[CH:12]1([N:11]2[C:25](=[O:26])[NH:9][C:6]([O:7][CH3:8])=[N:5][S:10]2(=[O:18])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: C1CCOC1
Reactant: COC(=N)N(C(=O)OC)S(=O)(=O)NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC1=NS(=O)(=O)N(C2CCCCC2)C(=O)N1

Procedure:
A solution of the isourea from Step 1. above (208.9 g) in anhydrous THF (500 ml) is added dropwise to a stirred suspension of 60% sodium hydride dispersion (57.0 g) in anhydrous THF (750 ml) and the reaction mixture is refluxed for 2 hours. Distilled water (450 ml) is added dropwise to the stirred mixture which is washed with diethyl ether. 20% sulfuric acid (400 ml) is added slowly to the stirred reaction mixture, which is extracted with methylene chloride, dried, filtered, and the filtrate evaporated and dried under high vacuum yielding the desired product as a crude solid which is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[N:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: COc1ccccc1C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccccc1C=Nc1cccc2nc(C)ccc12
Yield: 118.4 %

Procedure:
To 1.74 g (11 mmol) 5-amino-2-methylquinolin and 1.33 ml (11 mmol) 2-methoxybenzaldehyde in 33 ml toluene are added 50 μl acetic acid and 2 g molecular sieve. The mixture is heated over 2 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeothrophed with small portions of toluene. 3.6 g of [1-(2-methoxyphenyl)methylidene]-(2-methylquinolin-5-yl)amine are obtained as a yellow oil. 2,25 ml (26 mmol) 1,1,1-Trifluoroepoxypropane in 38 ml THF and 11 ml hexane are cooled to −100° C. and 15 ml of a 1.6 M n-butyl lithium solution in hexane are added over one hours while the temperature does not exceed −95° C. 10 Minutes after complete addition 3.6 g (11 mmol) raw [1-(2-methoxyphenyl)methylidene]-(2-methylquinolin-5-yl)amine in 49 ml THF are added over one hour while the temperature does not exceed −95° C. After one hour at −100° C. 12 ml diethyl ether are added and the reaction mixture is warmed to −100° C. over one hour. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (acetone in hexane 0 to 30%) yields 4.27 g {(2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methyl}-2-methylquinolin-5-amine as mixture of diastereomeres.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32]>>[OH:27][CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:38][C:37]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:36][C:35]=1[CH3:40])(=[O:32])=[O:33]
Reactant: Cc1nc(N)sc1S(=O)(=O)NCCO
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NCCO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-amide (example B.10) according to general procedure II. Yellow solid, MS (ISP) 593.1 [(M−H)−]; mp 166° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][C:37]2[C:45]3[S:44][C:43](=[O:46])[NH:42][C:41]=3[C:40]([OH:47])=[CH:39][CH:38]=2)[C:8](=[O:31])[CH2:9][CH2:10][N:11]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)C(=O)OCC2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:48].COC(C)(C)C>C(O)(=O)C>[BrH:48].[BrH:48].[CH:1]1([N:7]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][C:37]2[C:45]3[S:44][C:43](=[O:46])[NH:42][C:41]=3[C:40]([OH:47])=[CH:39][CH:38]=2)[C:8](=[O:31])[CH2:9][CH2:10][NH:11][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N(CCC(=O)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCC1)CCc1cccc(F)c1
Agent: Br
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: O=C(CCNCCc1cccc(F)c1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCC1
Reaction time: 1.33 h

Procedure:
To a solution of the product from step ii) (1 g) in acetic acid (3 mL) stirred at room temperature was added hydrobromic acid in acetic acid (33%, 3 mL). The mixture was stirred for 80 min and then tert-butyl methyl ether (8 mL) was added. The mixture was stirred for 5 min and then filtered, washing with t-butyl methyl ether (8 mL). Purification by recrystallisation from hot ethanol (20 mL) gave the title compound (0.82 g) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])([O-])=O.CO.[NH4+].[Cl-]>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cccc(Nc2ccccc2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(Nc2ccccc2N)c1
Temperature: 25 °C
Yield: 10.5 %

Procedure:
To a mixture of 3-(2-nitrophenylamino)benzonitrile (2.0 g, 8.40 mmol) in a 3:1 mixture MeOH:water (120 mL) were added NH4Cl (2.70 g, 0.05 mol) and iron powder (1.88 g, 0.03 mol) and the reaction mixture heated at reflux temperature for 1 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between DCM and water. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% MeOH in DCM) to afford the title compound as a yellow solid (185 mg, 11%). LCMS (Method J): RT 2.99 min [M+H]+ 210.0.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=[CH:37][C:38](N2CCSC2=S)=[O:39])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=[CH:37][C:38]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:19][CH2:20]2)=[O:39])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: c1ccc(C(OCCCN2CCNCC2)c2ccccc2)cc1
Reactant: COc1ccc(C=CC=CC(=O)N2CCSC2=S)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C=CC=CC(=O)N2CCN(CCCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 89 %

Procedure:
To a solution of 310 mg (1 mmol) of N-(3-benzhydroxypropyl)piperazine in dry tetrahydrofuran (5 ml) was added a solution of 483 mg (1 mmol) of N-[5-(3,4-dimethoxyphenyl)-2,4-pentadienoyl]thiazolidine-2-thione in dry tetrahydrofuran (5 ml), and the mixture was allowed to react at room temperature for overnight under argon atmosphere. The reaction mixture was concentrated by evaporation under reduced pressure, diluted with chloroform and washed; in turn, with 2N aqueous solution of sodium hydroxide and water. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (50:1), to give 470 mg (0.89 mmol) of N-[5-(3,4-dimethoxyphenyl)-2,4-pentadienoyl]-N'-(3-benzhydroxypropyl)piperazine. Spectrophotometric data of the product support the structure shown below. ##STR107##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of 3.0 g (8.7 mmoles) of 5amino-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a, 8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole and 10 ml of triethylamine in 25 ml of chloroform, cooled to 0°, was added dropwise 2.5 g (31.8 mmoles) of acetyl chloride. The reaction mixture was stirred overnight at room temperature and then for 30 minutes with 2.5 N aqueous sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with water, dried over potassium carbonate, and concentrated under vacuum. The residue was chromatographed on silica gel CC No. 7 with 57% methanol in chloroform to give 1.3 g of 5-acetamido-2-cyclopentylmethyl- 2,3,8,12b-tetrahydro1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole as an oil; nmr spectrum: δ 1.0-4.0 (m, 19); 2.1 (s, 3); 6.8-7.8 (m, 7).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH:11]([C:13]([CH3:15])=O)=[CH2:12]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:6]2[C:5]=1[C:13]([CH3:15])=[CH:11][CH:12]=[N:7]2)([O-:3])=[O:2]
Reactant: C=CC(C)=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2cccc([N+](=O)[O-])c12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
To a stirred solution of 3-nitroaniline (1 g. 7.2 mmol.) in acetic acid (10 ml), activated silferc (1.15 g. ferric chloride 7.2 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.55 g, 7.9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.0 g. 7.2 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 64%.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[C:12]([C:20]1[C:21](Cl)=[C:22]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:23]2=[N:24][CH:25]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:12]([C:20]1[C:21]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:22]2[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:23]2=[N:24][CH:25]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)=NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccccc3)cnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1ncc2c(ON=C(C)C)c(C(=O)c3ccccc3)cnc21
Yield: 72.7 %

Procedure:
In 25 ml of dry tetrahydrofuran (THF hereafter) was dissolved 1.6 g of acetone oxime, followed by 2.46 of potassium t-butoxide. After stirring 0.5 hour 5.0 g of 5-benzoyl-4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine in 50 ml of THF was added to the solution. After an additional 0.5 hour the reaction was quenched with ammonium chloride solution and the product was extracted with ether. Evaporation of the organic phase and recrystallization of the residue from ethanol gave 4.1 g of product, mp 115°-116° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[N:8][C:7]=2[NH2:17])=[CH2:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[N:8][C:7]=2[NH2:17])[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1cnc2c(N)nc3ccccc3c2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cnc2c(N)nc3ccccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of 2-vinylbenzo[f][1,7]naphthyridin-5-amine (Example 29) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stiffed for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-ethylbenzo[f][1,7]naphthyridin-5-amine as a solid. 1H NMR (methanol-d4): δ 8.78-8.81 (m, 2H), 8.45 (d, 1H), 7.55-7.63 (m, 2H), 7.35-7.40 (m, 1H), 2.97 (q, 2H), 1.43 (t, 2H). LRMS [M+H]=224.1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=O)(C)(C)C.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: Oc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccccc1OC1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
1-tert-Butyloxycarbonyl-3-hydroxypyrrolidine (1 g), 2-bromophenol (710 mg) and triphenylphosphine (1.29 g) were dissolved in tetrahydrofuran (15 ml) and the mixture cooled in an ice bath before dropwise addition of diisopropyl azodicarboxylate (0.96 ml). The mixture was allowed to warm to room temperature over 3 h, concentrated in vacuo, partitioned between ether (50 ml) and water (50 ml) and the aqueous phase was extracted further with ether (50 ml). The combined organic phases were washed with water (2×25 ml), brine (2×25 ml), dried (MgSO4) and concentrated in vacuo. The product was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was added and the reaction stirred for 1 h. The mixture was concentrated in vacuo and the residue was purified by cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures. This gave the title compound as a pale orange oil (437 mg).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:13][CH:12]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
To a solution of 4-hydroxydiphenylmethane (0.77 g, 4.18 mmol) in anhydrous DMF (22.5 mL) at 0° C. was added a 60% dispersion of NaH in mineral oil (0.23 g, 5.75 mmol) portionwise over 5 min. The resulting slurry was stirred at 0° C. for 45 minutes before a solution of tosylate from step 1 (1.50 g, 4.22 mmol) in DMF (11 mL) was added dropwise over 5 min. The subsequent mixture was stirred at 60° C. overnight. The reaction mixture was poured over ice and then concentrated under reduced pressure. The crude residue was extracted into ethyl acetate and sequentially washed with water, saturated aq. NaHCO3, water and brine. The combined organic layer was dried anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound (1.8 g, >100%) as a tan oil;
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH2:8][C:9]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C(=O)(O)[O-].[Na+]>C(#N)C.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][C:9](=[O:10])[N:11]([CH:12]3[CH2:13][CH2:14]3)[C:17]2=[O:18])=[CH:15][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(CNCc1ccc(Br)cc1)NC1CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1C1CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 2-(4-bromobenzylamino)-N-cyclopropylacetamide (7H4) (28.3 mmol, 8.0 g) in acetonitrile (200 ml) was added carbonyldiimidazole (56.5 mmol, 9.16 g) and 4-dimethylaminopyridine (56.5 mmol, 6.90 g). The reaction mixture was heated to 60° C. and stirred overnight before cooling to room temperature. Saturated sodium bicarbonate solution was added and the mixture extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated and the residue purified on silica eluting with heptane/acetone 9:1 to 7:3 to give 1-(4-bromobenzyl)-3-cyclopropylimidazolidine-2,4-dione (7H5) 8.3 g (98%); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 2H) 7.13 (d, 2H) 4.50 (s, 2H) 3.66 (s, 2H) 2.62 (m, 1H) 0.97 (d, 4H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:18]([C:13]2[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:23]=1
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCCC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CCOc1ccc(Cl)cc1-c1ccccc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
5-Chloro-2-(3-methyl-butoxy)-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (45 mg, 0.106 mmol) and NaOH (excess) were heated at 60° C. in ethanol (3 ml) for 2 hrs. The mixture was then cooled to room temperature, diluted with water, acidified with HCl (1M solution) and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated to yield the title compound (41 mg, 98%) as a white solid.
Reaction SMILES: [Br:1][C:2]1N=[CH:6][C:5]([O:8][C@H:9]2[CH2:13][O:12][CH2:11][C@H:10]2[NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:4][CH:3]=1.[CH3:21]S(O[C@H]1[C@H](OC2C=CC(Br)=CC=2)COC1)(=O)=O>>[Br:1][C:2]1[CH:21]=[CH:6][C:5]([O:8][C@H:9]2[CH2:13][O:12][CH2:11][C@H:10]2[NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1COC[C@@H]1Oc1ccc(Br)nc1
Reactant: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Product: CC(C)S(=O)(=O)N[C@@H]1COC[C@@H]1Oc1ccc(Br)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of cis-N-{4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-yl}propane-2-sulfonamide in Preparation 1, except that trans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate was used in place of trans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-yl methanesulfonate, and the chromatographic purification was carried out with a gradient of 15% to 35% acetone in heptane. Yield: 238 mg, 0.65 mmol, 31%. 1H NMR (400 MHz, CDCl3) δ 1.30 (d, J=6.8 Hz, 3H), 1.33 (d, J=6.8 Hz, 3H), 3.11 (septet, J=6.8 Hz, 1H), 3.66 (dd, J=9.1, 8.4 Hz, 1H), 3.89 (dd, J=10.7, 1.7 Hz, 1H), 4.07-4.13 (m, 2H), 4.19 (m, 1H), 4.71 (m, 1H), 5.12 (d, J=9.6 Hz, 1H), 6.75 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H).
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(-c2cc3c(O)ncnc3o2)c1
Product: O=[N+]([O-])c1cccc(-c2cc3c(Cl)ncnc3o2)c1
Temperature: 0 °C

Procedure:
11 g of 4-hydroxy-6-(3-nitrophenyl)furo[2,3-d]pyrimidine are heated for 4 h to RF in ca. 340 ml of phosphorus oxychloride. Afterwards, the reaction mixture is left to stand over night and then added to 5 kg of drained ice. The resulting suspension is filtered by suction and washed with a lot of H2O. The residue is dried in a HV and sublimated at ca. 200° C.; m.p.: 196-205° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(N)cc2)CC1
Yield: 92.1 %

Procedure:
A solution of 1-methyl-4-(4-nitrophenyl)piperazine (1.03 g, 4.66 mmol) in MeOH (100 ml) was hydrogenated at 20° C. at atmospheric pressure using an H-Cube (flow rate at 1 ml/min and full hydrogen mode) using a Pd/C cartridge. The solvent was removed in vacuo to afford 4-(4-methylpiperazin-1-yl)benzenamine (0.82 g, 4.29 mmol, 92%) as an off-white solid. 1H NMR (CDCl3) 2.37 (3H, s), 2.62 (4H, t), 3.09 (4H, t), 3.40 (2H, br. s), 6.65 (2H, d), 6.82 (2H, d). LCMS (1) Rt: 0.98 min; m/z (ES+) 192.