Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]=O>C(O)C.O>[CH:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[Cl:22])[CH2:23]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNC2CCCCC2)c(Cl)c1
Reactant: C=O
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CN(C3CCCCC3)CC2=O)c(Cl)c1

Procedure:
2-Cyclohexylamino-N-(2-chloro-4-sulphamoylphenyl)-acetamide (17.2g) was dissolved in ethanol (150 ml) and paraformaldehyde (3g) in water (300 ml) added. The mixture was refluxed 2 hrs, cooled and filtered. The residue was crystallised from ethanol/petroleum ether. Yield 13.5 g, m.p. 188°-190° .
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[NH:36][NH2:37]>>[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:37]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1Cl
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1Cl

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and 2,3-dichloro-phenylhydrazine according to the method described for example 1. MS: M=515.0 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Br[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:18]1([O:1][C:2]2[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (1.14 g, 5.0 mmol), bromocyclopentane (0.7 mL, 6.5 mmol), potassium carbonate (2.0 g, 14 mmol), and anhydrous acetonitrile (15 mL) was refluxed under N2. After 19 h, the reaction was allowed to cool to rt, concentrated, and purified by silica gel chromatography (4:1→3:2; hexanes:ethyl acetate) to give methyl 3-(cyclopentyloxy)-4-methoxy-2-nitrobenzoate: MS (ESI): 296.5.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][Si](C(C)(C)C)(C)C)=[C:6](Br)[C:5]([CH3:17])=[CH:4][C:3]=1O.[CH:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][O:32][CH3:33])[CH:25]=O)([CH3:21])[CH3:20].C(O)(C(F)(F)F)=O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][O:32][CH3:33])=[C:22]([CH:19]([CH3:21])[CH3:20])[CH:23]=2)[C:5]([CH3:17])=[CH:6][C:7]=1[OH:8]
Reactant: COCOc1ccc(C=O)cc1C(C)C
Reactant: Cc1cc(O)c(C)c(O[Si](C)(C)C(C)(C)C)c1Br
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCOc1ccc(Cc2cc(C)c(O)cc2C)cc1C(C)C

Procedure:
Intermediate 2,5-dimethyl-4-(3′-iso-propyl-4′-methoxymethoxybenzyl)phenol was prepared from 2,5-dimethyl-4-bromo-t-butyldimethylsilyloxyphenol, and 3-iso-propyl-4-methoxymethoxybenzaldehyde according to the procedure described in (G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607) and transformed into the title compound by the procedure used for the synthesis of compound 7-13, step b followed by example 7, step b, (0.14 g, 90%); 1H NMR (300 MHz, CD3OD): δ 6.88 (d, J=8.7 Hz, 2H), 6.79 (s, 1 H), 6.64-6.72 (m, 2 H), 4.20 (d, J=10.2 Hz, 2 H), 3.80 (s, 2 H), 3.10-3.15 (m, 1 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 1.17 (d, J=6.9 Hz, 6 H); LC-MS m/z 365 [C20H25O6P+H]+; HPLC conditions: ODSAQ AQ-303-5 column; mobile phase=CH3OH: 0.05% TFA (7:3) flow rate=1.0 mL/min; detection=UV@254 nm retention time in min: 10.96; Anal Calcd for (C20H25O6P+0.3H2O): C, 61.84; H, 6.92. Found: C, 61.60; H, 6.72.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([N:20]2[CH:24]=[N:23][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.C(OCC)C.[NH3:37]>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([O:10][C:9]1[CH:8]=[C:7]([N:20]2[CH:24]=[N:23][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:21]2)[S:6][C:5]=1[C:3]([NH2:37])=[O:2])[CH3:12]
Reactant: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1OC(C)c1ccccc1Cl
Reactant: N
Solvent: CCOCC
Solvent: CO
Product: CC(Oc1cc(-n2cnc(Nc3ccccc3)n2)sc1C(N)=O)c1ccccc1Cl
Temperature: 100 °C
Yield: 27 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(3-phenylamino-[1,2,4]triazol-1-yl)-thiophene-2-carboxylic acid methyl ester (66 mg, 0.15 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 100° C. in a pressure tube for 3 days. The solvent was removed in vacuo and the product isolated by column chromatography (10% MeOH/DCM) followed by tritruation from diethyl ether to give the title compound as an off-white solid (17 mg, 0.04 mmol, 27%); 1H NMR (400 MHz, d-6 DMSO) δ. 1.72 (3H, d), 5.88 (1H, q), 6.88 (1H, t), 7.03 (1H, br s), 7.26 (1H, s), 7.30 (2H, t), 7.36-7.43 (2H, m), 7.52 (1H, dd), 7.57 (2H, d), 7.66 (1H, dd), 7.75 (1H, br s), 9.02 (1H, br s), 9.65 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:11][C:4]1[CH:5]=[N:6][C:7]([CH:8]2[CH2:9][CH2:10]2)=[C:2]([Cl:1])[CH:3]=1)[C:16]#[N:17]
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cnc(C3CC3)c(Cl)c2)c(Br)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
5-chloro-6-cyclopropylpyridin-3-ol (250 mg, 1.47 mmol), 3-bromo-4-fluorobenzonitrile (Preparation 37, 295 mg, 1.47 mmol) and potassium carbonate (611 mg, 4.42 mmol) were suspended in dimethylsulfoxide (6 mL). The reaction mixture was stirred at 5 hours at 50° C. then water (60 mL) was added and the suspension was extracted by ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to afford the title compound as a clear oil which solidified on standing (485 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[O:24]([CH2:31][CH:32]1[CH2:34][O:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][CH:32]([OH:33])[CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Br)cc3c2C1
Reactant: c1ccc(OCC2CO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(c3cc(Br)ccc3n2CC(O)COc2ccccc2)C1
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of tert-butyl 8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (449.7 mg, 1.28 mmol) and powdered potassium hydroxide (86.9 mg, 1.54 mmol) in acetone (4.0 ml) was stirred for 15 minutes before the addition of 2-(phenoxymethyl)oxirane (254 mg, 1.69 mmol). After 1 h the reaction was condensed, diluted with EtOAc and washed twice with water and then brine. The organic layer was then dried over Na2SO4, filtered and condensed. The crude mixture was purified by silica gel chromatography (1% MeOH/CH2Cl2+0.1% Et3N). Yield=21%. ESI (m/z): 546.6 (M+CHCOO−).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([C:72]2[CH:79]=[CH:78][C:75]([CH:76]=O)=[CH:74][CH:73]=2)[CH:71]=[CH:70][CH:69]=[N:68]1>C(O)C.CN(C=O)C>[N:67]1([C:72]2[CH:79]=[CH:78][C:75]([C:76]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Br:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:74][CH:73]=2)[CH:71]=[CH:70][CH:69]=[N:68]1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(-n2cccn2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(-n4cccn4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 38 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(1H-pyrazol-1-yl)benzaldehyde (1.1 eq, 0.056 mmol, 10 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 38%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.63 (s, br, 4H, piperazine N(CH2)2), 3.63 (s, 2H, CH2), 3.70 (s, br, 4H, piperazine N(CH2)2), 6.61 (t, br, J=2.0 Hz, 1H, pyrazole H-4), 7.41 (s, br, 1H, pyridine H-5), 7.80 (s, br, 1H, pyridine H-4), 7.81 (d, J=1.9 Hz, 1H, pyrazole H-3 or H-5), 8.03 (d, J=8.4 Hz, 2H, phenyl H-2 & H-6), 8.26 (s, br, 1H, imidazo[4,5-b]pyridine H-5), 8.30 (d, J=8.5 Hz, 2H, phenyl H-3 & H-5), 8.50 (s, br, 1H, pyridine H-6), 8.58 (s, br, 1H, pyridine H-2), 8.61 (d, J=2.4 Hz, 1H, pyrazole H-3 or H-5), 13.56 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]12([CH2:15][C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.Cl.O([NH2:20])C.N1C=CC=CC=1>CO.Cl>[C:1]12([CH2:15][CH:14]([NH2:20])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: CON
Reactant: O=C1CC2(CCCCC2)Oc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: NC1CC2(CCCCC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 1A (3.022 g, 13.99 mmol) in methanol (50 mL) was added methoxylamine hydrochloride (1.17 g, 14.0 mmol) and pyridine (5.7 mL, 70.5 mmol). The mixture was stirred overnight at room temperature and was then evaporated in vacuo. The residue was partitioned between ethyl acetate and H2O, and the organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue thus obtained was dissolved in methanol (50 mL) and was hydrogenated (balloon) over 10% Pd-on-carbon in the presence of 4 drops of conc. HCl overnight at room temperature. After this time, the catalyst was filtered off (Celite), and the filtrate was evaporated in vacuo. The residue was taken up in ether (50 mL) and was extracted with 1N HCl (3×20 mL). These acidic extracts were then basified to pH 10 with 2N NaOH and were extracted with ethyl acetate (3×20 mL). The organic extracts were dried over Na2SO4, filtered and evaporated in vacuo to yield the title compound as a yellow oil, 880 mg (29%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.52 (m, 1H), 7.06 (m, 1H), 6.82 (td; J=7.4, 1.3 Hz; 1H), 6.69 (dd; J=8.1, 1.3 Hz; 1H), 3.83 (dd; J=11.1, 6.3 Hz; 1H), 2.08 (dd; J=13.5, 6.3 Hz; 1H), 1.90 (m, 1H), 1.74 (m, 2H), 1.31-1.57 (m, 8H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:29]5[CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=[CH:31][CH:30]=5)[N:10]4[N:9]=3)=[CH:17][CH:16]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: OCc1cccc(B(O)O)c1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(CO)c5)n4n3)cc2)CC1
Yield: 81.4 %

Procedure:
Analogous to Example 1497, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.125 g, 0.323 mmol) and (3-Hydroxymethylphenyl)-boronic acid (98.1 mg, 0.646 mmol) were reacted to afford (3-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanol (109 mg; Yield=81.5%). LCMS (HPLC): 0.74 min, m/z=415 (M+H); 1H-NMR (DMSO-d6): 9.22 (s, 1H), 8.93 (s, 1H), 8.19 (s, 1H), 7.99 (d, 1H, J=7.8 Hz), 7.64 (d, 2H, J=9.0 Hz), 7.49 (m, 1H), 7.37 (d, 1H, J=7.6 Hz), 7.13 (d, 1H, J=4.7 Hz), 6.92 (m, 3H), 5.25 (t, 1H, J=5.8 Hz), 4.60 (d, 2H, J=5.8 Hz), 3.08 (m, 4H), 2.46 (m, 4H), 2.23 (s, 3H).
Reaction SMILES: Br[CH:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][C:10]([CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])([C:13]#[N:14])[C:11]#[N:12])=[CH:7][CH:6]=1)[CH2:3][Br:4].CC(C)([O-])C.[K+].O>CN(C)C=O>[Br:4][CH:3]=[CH:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]([CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20])([C:13]#[N:14])[C:11]#[N:12])=[CH:21][CH:22]=1
Reactant: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(Br)CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C=CBr)cc1
Yield: 41 %

Procedure:
First, 0.2 g of (2-(4-(1,2-dibromoethyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (43)) was dissolved in 5 ml of N,N-dimethylformamide, to which 0.1 g of potassium t-butoxide was added, while stirring under ice cooling. After stirring for 5 hours at room temperature, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was successively washed with water, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.05 g of 2-(4-(2-bromovinyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (58)).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH3:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.Br[CH2:29][C:30]([O:32][C:33](C)(C)[CH3:34])=[O:31]>C1COCC1>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)[CH3:34]
Reactant: Cc1cnccn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCc1cnccn1
Temperature: 2.5 °C
Yield: 49.9 %

Procedure:
Butyl lithium (2.5M in hexane-2560 mL) was added within 2 hours into a 10 L flask charged with THF (3350 mL) and diisopropylamine (658 g) while the temperature was maintained at 0-5° C. with an ice bath. The LDA solution was then precooled to −50° C. and a mixture of methylpyrazine (606 g) and THF (590 mL) was added within 2 hours under vigorous stirring at −40 to −30° C. The deep red anion solution is then pumped to a cooled (−60° C.) mixture of tert-butyl bromoacetate (1255 g) and THF (3360 mL) in a 20 L reactor. During the addition of the anion solution, the temperature in the reaction vessel did not exceed −55° C. After the addition, the mixture is stirred for further 30 min at −55° C. and then transferred to a 30 L reactor (the transesterification and removal of solvents can be done for two runs at once). A solution of sodium ethylate (142 g) dissolved in EtOH (2200 mL) was then added to the orange mixture and about 12 L of solvents were distilled off until a temperature of 80° C. was reached in the distillation head and 100° C. in the boiling liquid. The mixture was cooled to approximately 30° C. and then toluene (840 mL), AcOEt (840 mL), and water (1180 mL) were added. After separation of the phases, the organic layer was extracted three times with AcOEt (420 mL) and toluene (170 mL) each. The combined organic phases were then concentrated in vacuo and the residue was distilled over a Vigreux column (bp 115 to 130° C. @ 0.07 mbar) giving the title compound (579 g).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25]OS(C)(=O)=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:13]([O:20][C:21](=[O:22])[NH:23][CH2:24][CH2:25][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]2[N:3]=[CH:2][O:1][CH:5]=2)=[CH:11][CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OCCNC(=O)OCc1ccccc1
Reactant: Oc1ccc(-c2cocn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NCCOc1ccc(-c2cocn2)cc1)OCc1ccccc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A stirred mixture of 290.0 g (1.80 mol) of 4-oxazol-4-yl-phenol (H. Jones, et al., J. Med. Chem., 21, 1110 (1978)), 737.7 g (2.70 mol) of methanesulfonic acid 2-benzyloxycarbonylamino-ethyl ester, and 746.0 g (5.40 mol) of potassium carbonate in 4.6 l of dry dimethylsulfoxide was heated to about 85° C. An additional 500 ml of dimethylsulfoxide was added and the viscous slurry was stirred at about 80° C. for about an additional two hours. The resulting mixture was cooled to about 50° C., poured into about 1 l of stirred ice water, slurried for about one hour, and then filtered. The wet filter cake was washed with water (2×1 l), and then partially dried by aspiration under vacuum for about two hours. The moist solid was charged into a round-bottomed flask, 6 l of methanol was added, and the mixture was then warmed to about 60° C. where 3 l of water was added. The heating source was removed, the mixture was stirred for about eighteen hours, and then filtered. The filter cake was washed with 2:1 methanol/water (v/v; 2×500 ml), and then dried under vacuum at about 40° C. for about eighteen hours. The title compound (389.5 g, 64% yield) was obtained as a beige powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:18]([C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH:22]=O)[CH3:19].CO>[Cl-].[Cl-].[Zn+2].C(N(CC)CC)C>[C:13]([C:9]1[N:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:1][CH2:22][C:21]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=3[CH2:18][CH3:19])[C:3]2=[N:11][C:10]=1[CH3:12])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCc1cccc(C)c1C=O
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(C)cn12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C)cn12
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A mixture of 8-amino-3-carboethoxy-2,6-dimethylimidazo[1,2-a]pyridine (1.4 g, 6 mmol), 2-ethyl-6-methylbenzaldehyde (0.9 g, 6.5 mmol), ZnCl2 (1.0 g, 7.4 mmol), NaB(CN)H3 (0.41 g, 6.5 mmol) and MeOH (30 ml) was refluxed for 5 h. More ZnCl2 (0.2 g) and NaB(CN)H3 (0.1 g) were added. The reaction mixture was refluxed for additional 2 h. Triethylamin (2 ml) was added and the mixture was stirred at R.T for 10 min. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride as eluent. 1.1 g (50%) of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.[C:23]([NH:27][CH2:28][C:29](O)=O)(=[O:26])[CH2:24][CH3:25].ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([S:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]3[NH:8][C:29]([CH2:28][NH:27][C:23](=[O:26])[CH2:24][CH3:25])=[N:1][C:2]=3[CH:3]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc(N)c(N)c2)cc1
Reactant: CCC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NCc1nc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a solution of N-(3,4-diamino-phenyl)-4-isopropyl-benzenesulfonamide×HCl (500 mg, 1.32 mmol) in DMF (20 ml) at 0° C. was added propionylamino-acetic acid (170 mg, 1.32 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (220 mg, 1.59 mmol). After stirring the mixture at 0° C. for 15 min EDC (N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide) (300 mg, 1.45 mmol) was added. DIPEA (diisopropylethylamine) (0.92 ml, 5.29 mmol) was added after stirring another 15 min at 0° C. The mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 and the organic layer was dried over MgSO4, filtered, and the solvent evaporated under reduced pressure. A solution of the obtained oil in acetic acid was heated to 70° C. for 6 h. After evaporation of the solvent in vacuo the residue was purified by column chromatography to give the product as a yellow oil (320 mg, 61%).
Reaction SMILES: [CH2:1]([C:3]1([S:6]([O:9]CCCC)(=[O:8])=[O:7])[CH2:5][CH2:4]1)[CH3:2].[S-]C#N.[K+:17]>O1CCOCC1.O>[CH2:1]([C:3]1([S:6]([O-:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1)[CH3:2].[K+:17]
Reactant: CCCCOS(=O)(=O)C1(CC)CC1
Agent: N#C[S-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCC1(S(=O)(=O)[O-])CC1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a solution of butyl 1-ethylcyclopropane-1-sulfonate (0.46 g, 2.23 mmol prepared from Preparation #6 Step A and ethyl iodide using KKK) in 1,4-dioxane (2.79 mL) and water (2.79 mL) was added potassium thiocyanate (0.12 mL, 2.23 mmol). The reaction is heated to about 100° C. for about 16 h. The reaction mixture was cooled to ambient temperature and was concd under reduced pressure to afford potassium 1-ethylcyclopropane-1-sulfonate (0.42 g, 100%) as a white crystalline solid: 1H NMR (400 MHz, DMSO) d 1.70-1.58 (m, 2H), 0.89 (t, J=7.5, 3H), 0.80 (q, J=3.8, 2H), 0.32 (q, J=3.8, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]#[N:36])=[CH:30][CH:29]=2)O1>>[C:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:29][CH:30]=1)#[N:36]
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CC#N)cc2)cc1
Yield: 68.1 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (356 mg, 0.91 mmol, prepared in example 2) and [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile (275 mg, 1.13 mmol) were treated as described in example 6. The product was chromatographed on Chromatotron® eluting with 99.5:0.5 methylene chloride:ethyl acetate to afford 237 mg (68%) of the title compound as a white solid. The NMR was consistent with the assigned structure.