Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])[N:6]=1.C1(N)C(F)=C(F)C(F)=[C:14]([NH2:21])C=1F.Cl.Cl.CO[C:28]1[C:32](OC)=[N:31][S:30](=[O:36])(=[O:35])[N:29]=1>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:28]2[C:32]([NH:21][CH3:14])=[N:31][S:30](=[O:36])(=[O:35])[N:29]=2)[N:6]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: NCCSCc1csc(N)n1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(N)n1
Reaction time: 1.5 h

Procedure:
A solution of 2-[(2-aminothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 3.0 g; 11.4 mmoles) [prepared in Step A] in 25 ml of methanol was added dropwise over 1.5 hours to a cold (5°), stirred, partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.03 g; 11.4 mmoles) in 55 ml of methanol. After 1.5 hours, anhydrous methylamine was bubbled into the solution for 30 minutes and stirred at 5° for 19 hours. The reaction mixture was evaporated under reduced pressure and the residue placed on 400 g of silica gel and chromatographed using acetone-methylene chloride (7:3). The appropriate fractions were combined and evaporated to give product. Recrystallization from 95% ethanol yielded the title compound, mp 200°-201°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19](O)=[O:20])[C:13]=3[N:12]=[C:11]2[C:22](=[O:33])[NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH:36]1[CH2:39][NH:38][CH2:37]1>>[CH:30]([N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:22]([C:11]2[N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([N:38]4[CH2:39][CH:36]([O:35][CH3:34])[CH2:37]4)=[O:20])[C:13]=3[N:12]=2)=[O:33])[CH2:29][CH2:28]1)([CH3:31])[CH3:32]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CCc2ccc(Cl)cc2)CC1
Reactant: COC1CNC1
Product: COC1CN(C(=O)c2cccc3c2nc(C(=O)NC2CCN(C(C)C)CC2)n3CCc2ccc(Cl)cc2)C1

Procedure:
1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-methoxy-azetidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 50 mg (0.097 mmol) 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 13.5 mg (0.015 mmol) 3-methoxy-azetidine. The title compound was obtained as its formiate in form a white amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: Fc1cccc(Oc2cncc(Cl)n2)c1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1cc(Nc2cncc(Oc3cccc(F)c3)n2)cc(OC)c1OC
Yield: 61 %

Procedure:
Using Method EE with 2-chloro-6-(3-fluorophenyloxy)-pyrazine (200 mg, 0.89 mmol) and 3,4,5-trimethoxyaniline (196 mg, 1.07 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (200 mg). Yield: 61%. 1H NMR (250 MHz, DMSO-d6) δ 3.44 (s, 6H, [CH3O]3+5), 3.55 (s, 3H, [CH3O]4), 6.77 (s, 2H, Harom 2′+6′), 7.02-7.09 (m, 2H, Harom 4+6), 7.16 (d, 1H, Harom 2, JF=8.8 Hz), 7.43 (q, 1H, Harom 5, J=8.5 Hz), 7.78 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.61 (s, 1H, NH). m/z: 372.1 [(M+H)+, calcd for C19H18FN3O4 371.1].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Reactant: C#CCCCCC
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCCCCC#Cc1nn(Cc2ccccc2)c2ccccc12

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (84 mg, 54%); 1H NMR δ (CDCl3): 7.9 (d, J=8.02 Hz, 1H), 7.4-7.19 (m, 8H), 5.5 (s, 2H), 2.48 (t, J=7.22 Hz, 2H), 1.65 (p, J=7.18 Hz, 2H), 1.5-1.32 (m, 4H), 0.94 (t, J=7.21 Hz, 3H); LCMS m/z: 302.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[C:5]2([CH3:16])[CH3:15].Br[C:18]#[N:19]>O.C1COCC1>[NH2:19][C:18]1[NH:1][C:2]2=[CH:3][C:4]3[C:5]([CH3:15])([CH3:16])[C:6](=[O:14])[N:7]([CH2:12][CH3:13])[C:8]=3[CH:9]=[C:10]2[N:11]=1
Reactant: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Reactant: N#CBr
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21

Procedure:
Analogously to general procedure (III) 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (1.32 g) is cyclized using BrCN (3 M; 2.2 ml; 6.6 mmol) at RT in water (5 ml) and THF (13 ml). After aqueous work-up and re-crystallization from EtOAc the desired compound (1.03 g) is obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:15])[CH:7]=1
Reactant: Cc1c(Br)cnc(O)c1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Br)cn(C)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of 5-bromo-4-methyl-3-nitropyridin-2-ol (15.00 g, 64.37 mmol) [Combi-Blocks, AN-1086] in N,N-dimethylformamide (250 mL) was treated with sodium hydride (3.09 g, 77.3 mmol) (60% dispersion on mineral oil) slowly and portionwise, and stirred at RT for 30 min. The reaction mixture was treated with methyl iodide (4.81 mL, 77.2 mmol) dropwise and stirred at RT for 3 h. LCMS indicated a clean peak for methylated product. The reaction mixture was poured over water/ice (˜400 mL) and allowed to stir while the ice melted. The aqueous mixture was extracted with EA. The organic layer was washed with water (3×) and brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (14.9 g, 93%) that was used without further purification. LCMS calculated for C7H8BrN2O3 (M+H)+: m/z=247.0, 249.0. found: 247.0, 248.9.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.[CH2:17](O)[CH3:18]>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(Br)cc1
Yield: 99 %

Procedure:
Concentrated sulfuric acid (10 ml) was added to an ethanol (300 ml) solution of 4-bromophenylacetic acid (25 g, 120 mmols), and heated under reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water with ice, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an oil of ethyl 4-bromophenylacetate (28 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([CH2:21][CH:22]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28](COCC[Si](C)(C)C)[CH:27]=3)[C:23]([OH:25])=[O:24])=[N:10]2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH:22]([CH2:21][C:11]2[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)[C:23]([OH:25])=[O:24])=[CH:27]1
Reactant: COc1ccc(-n2nc(CC(C(=O)O)c3cn(COCC[Si](C)(C)C)c4ccccc34)cc2-c2ccc(C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CC(C(=O)O)c3c[nH]c4ccccc34)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A solution of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionic acid (Example 70, 0.17 g, 0.29 mmol) and 1.0 M TBAF (2.88 mL) in THF was heated to 60° C. for 24 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), and washed with water (3×30 mL) and brine (1×30 mL). The organic layer was dried with Na2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by reversed-phase HPLC giving 111 mg (85%) of 2-(1H-indol-3-yl)-3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionic acid. HPLC: Rt=3.0 (Method B). MS (ES+): mass calculated for C28H25N3O3, 451.19; m/z found 452.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 10.97 (s, 1H), 7.64 (d, J=6.3 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.13-7.07 (m, 5H), 7.04 (d, J=8.1 Hz, 2H), 6.98 (t, J=8.0 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.36 (s, 1H), 4.22 (dd, J=6.1, 9.0 Hz, 1H), 3.77 (s, 3H), 3.45 (dd, J=9.0, 14.7 Hz, 1H), 3.06 (dd, J=6.2, 14.7 Hz, 1H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH2:22][CH:23]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:4]=1.[CH:38]([N:41]([CH:52]([CH3:54])[CH3:53])[CH2:42][CH2:43][NH:44][C:45](N1C=CN=C1)=[O:46])([CH3:40])[CH3:39]>C(O)(C)C>[NH3:1].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:23]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:22][NH:21][C:5]2[N:4]=[C:3]([CH2:2][NH:1][C:45]([NH:44][CH2:43][CH2:42][N:41]([CH:52]([CH3:54])[CH3:53])[CH:38]([CH3:39])[CH3:40])=[O:46])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[CH:29][CH:28]=1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Reactant: NCc1nc(NCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: CC(C)O
Product: CC(C)N(CCNC(=O)NCc1nc(NCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)C(C)C
Product: N
Yield: 139.7 %

Procedure:
(2R,3R,4S,5R)-2-(2-(Aminomethyl)-6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (0.1 g, 0.18 mmol) (Preparation 63) was dissolved in a mixture of isopropanol (0.5 ml) and Genklene (Trade Mark) (5 ml). N-[2-(Diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (48 mg, 0.20 mmol) (Preparation 27) was added and the reaction mixture was heated under reflux for 2 hours. More N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (35 mg, 0.15 mmol) (Preparation 27) was then added and the reaction mixture was heated under reflux for a further 2 hours. The reaction mixture was then allowed to cool and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:2 by volume) to give the title compound (0.09 g) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:5]=[CH:6][C:7]=1[C:8](=[O:13])N(OC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.CCCCCCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:13]
Reactant: CON(C)C(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a cooled (0° C.) solution of (S)-tert-butyl 1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate (1.175 g, 3.6 mmol) in THF (36 mL) was added a solution of LAH in THF (1.0 M, 18 mL, 18 mmol) and the resulting mixture was stirred at 0° C. for 20 min. The reaction mixture was quenched by addition of a saturated Na2SO4 solution until gas evolution ceased. The reaction mixture was extracted with EtOAc (2×100 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate as a white solid (760 mg, 79% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[Cl-].[NH4+].C1COCC1.O>CO.[Fe]>[NH2:19][C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Yield: 100 %

Procedure:
A solution of the product of Example 38a (2.7 g, 8.97 mmol), iron powder (2.0 g, 35.9 mmol) and ammonium chloride (0.58 g, 10.76 mmol) in a methanol (6 mL), THF (6 mL), and water (2 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (2.46 g, 77%).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.B.CSC.CO>O1CCCC1>[CH:9]1[C:8]2[CH2:2][NH:3][C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[S:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2c(c1)CNc1ccccc1S2
Reaction time: 18 h

Procedure:
To a mixture of 3.3 g of 10,11-dihydro-11-oxodibenz[b,f][1,4]thiazepine in 25 ml of tetrahydrofuran is added 4.0 ml of 10 molar borane-dimethylsulfide in tetrahydrofuran. The mixture is stirred[at room temperature for 18 hours, 50 ml of anhydrous methanol added and the solvent removed. An additional 30 ml of methanol is added and the solvent removed to give white crystals. A sample is purified by chromatography on silica gel with hexane-chloroform-ethyl acetate (2:1:1) as solvent to give white crystals, m.p. 145°-148° C.
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8](=O)[CH:9]([CH:16]=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C.[NH2:19][C:20]([NH2:22])=[S:21].C(O)(=O)C>C(O)C>[O:7]=[C:8]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][NH:22][C:20](=[S:21])[NH:19]1
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c[nH]c(=S)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
Sodium ethoxide (6.105 g, 89.71 mmol) was added to absolute ethanol (150 mL) under an atmosphere of nitrogen followed by diethyl-2-formylsuccinate (I105) (crude, 16.5 g) in absolute ethanol (30 mL) and thiourea (6.829 g, 89.71 mmol). The reaction mixture was heated at reflux for 1 hour then cooled to room temperature at which stirring was continued for 16 hours. The volatiles were evaporated under reduced pressure to give a brown oily solid. Cold aqueous acetic acid solution (15%; 120 mL) was added and the resulting mixture was sonicated and then stirred at 0° C. until all the residue was in suspension. The resulting precipitate was collected by filtration. The filter cake was washed with water (100 mL) and dried to give the title compound (I106) (6.31 g, 19% yield over 2 steps) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 7.44 (s, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.28 (s, 2H), 1.17 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][NH2:14])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[N:15]#[C:16]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:11]([O:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]2[N:7]([C:16]([NH2:15])=[N:14][N:13]=2)[N:8]=1)[CH3:12]
Reactant: N#CBr
Reactant: CCOc1cc(NN)nnc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOc1cc2nnc(N)n2nc1OCC
Reaction time: 8 h
Yield: 63.9 %

Procedure:
(5,6-Diethoxy-pyridazin-3-yl)hydrazine (W3.120; 50 mg) was initially charged in a mixture of ethanol (3.5 ml) and water (0.75 ml) at RT while stirring. Thereafter, cyanogen bromide (55 mg, dissolved in 0.75 ml of ethanol and 0.15 ml of water) was cautiously added dropwise. After stirring for 7 h, the mixture was left to stand overnight. Thereafter, a further 2 equivalents of cyanogen bromide, dissolved in 0.75 ml of ethanol and 0.15 ml of water, were added and the mixture was stirred further at RT for 2 h and then at 55° C. for 8 h. After cooling, the solvent was drawn off and the residue was admixed with water. After it had been alkalized with saturated potassium carbonate solution, it was extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A). The clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 36 mg of the title compound were obtained. LC-MS rt: 0.54 min [M+H]+: 224.2 (met. b)
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14]=2[CH:12]([N:13]=1)[CH2:11][CH2:10][CH2:9]3.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>C(O)C>[ClH:1].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14]=3[CH:12]([N:13]=2)[CH2:11][CH2:10][CH2:9]4)=[CH:18][CH:17]=1
Reactant: ClC1=NC2CCCc3cccc(c32)N1
Reactant: NCc1ccc(Cl)cc1
Solvent: CCO
Product: Cl
Product: Clc1ccc(CNC2=NC3CCCc4cccc(c43)N2)cc1

Procedure:
10.3 g (0.05 mol) of 2-chloro-3a,4,5,6-tetrahydroperimidine and 7.1 g (0.05 mol) of 4-chloro-benzylamine in 100 ml of ethanol are heated to 80° C. for 1 hour. After cooling, the crystals which have precipitated are filtered off and purified by dissolving in hot ethanol and precipitating with water. 2-(4-Chlorobenzylamino)-3a,4,5,6-tetrahydro-perimidine hydrochloride is obtained. Yield: 10 g (57.5% of theory) of melting point 257°-258° C.
Reaction SMILES: [CH3:1][N:2]([C:4]1(O)[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH:6]([CH3:28])[CH2:5]1)[CH3:3].CCN(S(F)(F)[F:36])CC>ClCCl>[F:36][C:4]1([N:2]([CH3:3])[CH3:1])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH:6]([CH3:28])[CH2:5]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(N(C)C)CC3C)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: CC(=O)NCC1CN(c2ccc(N3CCC(F)(N(C)C)CC3C)c(F)c2)C(=O)O1
Yield: 62 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-(N,N-dimethylamino)-methyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.22 mmol) with DAST (1.53 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 62% yield.
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>CCCCCC>[CH:18]1([N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:34]([NH:33][C:27]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=3[F:25])=[O:35])[CH:11]=2)[C:34]([NH:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])=[O:35])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)cc1F)N(Cc1cccc(CN(C(=O)Nc2ccc(F)cc2F)C2CCCCCC2)c1)C1CCCCCC1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 1 g N,N'-dicycloheptyl-m-xylylene-diamine in 50 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexane solution containing 1 g 2,4-difluorophenyl isocyanate under ice cooling. Stirring was continued at room temperature for two hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and then recrystallized from isopropanol, giving 1.6 g of 1,3-bis[[1-cycloheptyl-3-(2,4-difluorophenyl)ureido]methyl]benzene.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]([C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:17]=1)[NH2:14])([CH3:10])([CH3:9])[CH3:8].C([N:24]([CH2:27][CH3:28])CC)C>C1COCC1>[C:18]([C:16]1[CH:15]=[C:13]([NH:14][C:2]([C:1]([NH:24][C:27]2[CH:28]=[C:16]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:17]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=2)=[O:5])=[O:3])[CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:17]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)C(=O)Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
Oxalyl chloride (2.16 mL, 25 mmol) was added dropwise to a stirred solution of 3,5-di-t-butylaniline (10.28 g, 50 mmol) and triethylamine (7.0 mL, 50 mmol) in THF (200 mL) at 0° C. Upon addition, the reaction was allowed to warm up to r.t. and stirred for 1 h. The reaction mixture was then concentrated in vacuo and diluted with water (100 mL). The white precipitate was collected by filtration, washed with dilute HCl (100 mL), water (2×100 mL), and dried in vacuo. Obtained 9.07 g (78%) of N,N′-Bis(3,5-di-t-butylphenyl)oxamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Mg]C.C([Li])CCC.[CH3:20][S:21]SC>C1COCC1>[F:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([S:21][CH3:20])[CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: CSSC
Agent: C[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(F)ccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
A solution of 2-bromo-4-fluorobenzoic acid (15 g, 68.5 mmol, Marshallton Research Laboratories) in THF (150 mL) under argon at 0° C. was treated with chloro(methyl)magnesium (5.64 g, 75.34 mmol, 2.94 M in THF) over 5 minutes. The temperature during addition was maintained below 10° C. The resulting solution was cooled to −78° C. and n-butyllithium (9.65 g, 150.7 mmol, 2.5M in hexanes) was added over 10 minutes. The reaction was kept below −65° C. during the addition. The reaction was stirred at −78° C. for 50 minutes. A solution of (methyldithio)methane (38.71 g, 410.9 mmol) in THF (20 mL), precooled to −78° C., was added by cannula. The reaction was stirred for 10 minutes, warmed to zero ° C. and stirred at zero ° C. for 2 hours until a solid began to precipitate. The reaction was allowed to warm to 25° C. and stirred overnight. The reaction was poured into 1N HCl and extracted with EtOAc. The water layer was extracted with EtOAc twice more, the organic layers were combined, dried over Na2SO4, filtered and evaporated. The crude solid was suspended in 5% EtOAc/Hexanes and stirred for an hour, then filtered and dried to give the product as a white solid.