Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)C)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH2:23]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:13][NH:11][CH3:9])=[CH:15]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNCc1cn(Cc2ccccc2)c2ccccc12
Reaction time: 5 h
Yield: 86.8 %

Procedure:
3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole (0.9 g, 2.3 mmole) was added to a suspension of Pearlman's catalyst (about 0.30 g) in MeOH at RT in a Parr flask. The reaction was placed under 50 p.s.i. of H2 and shaken for 5 hr. The mixture was filtered through celite® and the filter pad was washed with MeOH. The filtrate was concentrated to afford the title compound (0.5 g, 86%) as a light yellow solid: MS (ES) m/e 251 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](O)=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][C:28]=2[NH2:38])=[CH:22][CH:21]=1)(=O)C>>[Cl:33][C:31]1[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:28]2[N:38]=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[N:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][OH:17])=[CH:21][CH:22]=3)[C:27]=2[CH:32]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)OCCc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2N)cc1
Product: CC(NC(=O)OC(C)(C)C)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5 from N-(tert-butoxycarbonyl)-alanine and 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino phenyl)ethyl acetate (Example 339, step 2).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]1=O.Cl>C1COCC1.CO>[CH3:3][C:4]1[CH2:12][C:11]2[C:6]([CH:5]=1)=[C:7]([C:13]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=1)[CH:8]=[CH:9][CH:10]=2
Reactant: CC1Cc2cccc(-c3cccc4ccccc34)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2c(cccc2-c2cccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.3 g (33 mmol) of sodium borohydride were added at 0° C. to a solution of 12 g (44 mmol) of (16) in 100 ml of THF/methanol 2:1 and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured onto 100 g of ice, concentrated hydrochloric acid was added until the pH was 1 and the mixture as extracted a number of times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The crude product was taken up in 200 ml of toluene, admixed with 0.5 g of p-toluenesulfonic acid and refluxed for 2 hours on a water separator. The reaction mixture was washed 3 times with 509 ml each time of saturated sodium hydrogen carbonate solution and the solvent was removed under reduced pressure. The solid residue was washed with a little pentane and dried under reduced pressure. This gave 10.3 g of (37) in the form of colorless crystals. m.p. 143° C.; 1H-NMR (300 MHz, CDCl3): 7.92-7.18 (10H), 6.11 (m, 1H), 3.42 (s, 2H), 2.07 (3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([CH3:18])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:18][C:7]1[C:6](=[O:19])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c(CBr)cn(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 115 °C

Procedure:
In a 50 mL round-bottomed flask, 7-chloro-3-methyl-1-phenyl-1H-quinolin-4-one (0.142 g, 0.526 mmol), NBS (103 mg, 0.579 mol) and AIBN (13.0 mg, 0.079 mmol) were combined with carbon tetrachloride (3.5 mL) to give a colorless solution. The reaction mixture was heated at 115° C. for 1 h. The reaction mixture was cooled to room temp and then cooled to 0° C. The mixture was filtered to remove succinimide and the filtrate was concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)=[CH:37][CH:36]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[F:52][C:49]([F:50])([F:51])[C:46]1[CH:45]=[CH:44][C:43]([CH2:42][CH2:41][C:38]2[CH:39]=[CH:40][C:35]([CH2:34][O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][NH:9][CH:10]3[CH2:19][CH2:18][CH2:17][C:16]4[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]3=4)=[CH:36][CH:37]=2)=[CH:48][CH:47]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 ml of a 4 N solution of hydrogen chloride in dioxane were added to 1100 mg (1.57 mmol) of ethyl 5-[(tert-butoxycarbonyl)(2-{2-[(4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzyl)oxy]phenyl}-ethyl)amino]-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 153A), and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness. This gave 1045 mg of the target product which was reacted further without further analytical characterization.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2.[CH2:12]([O:14][C:15](=[O:21])[CH:16](Br)[CH:17]([CH3:19])[CH3:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2)[CH:17]([CH3:19])[CH3:18])[CH3:13]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: Cc1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1cccc2[nH]c(C)cc12)C(C)C

Procedure:
A mixture of 4-hydroxy-2-methylindole (1) (1.5 g, 0.010 mole), 2-bromo-3-methyl-butyric acid ethyl ester (2.2 g, 0.010 mole) and potassium carbonate (excess) in acetone (50 mL) was refluxed for 3 days. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (20:1 Hex:EtOAc) to afford intermediate 2. Yield: 1.88 g, 71%
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]2=O)[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]2[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][NH:23][N:22]=2)[C:10]([OH:9])=[CH:11][C:12]=1[OH:13])[CH3:2]
Reactant: CCc1cc2c(=O)c(-c3ccccc3)coc2cc1O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1cc(-c2n[nH]cc2-c2ccccc2)c(O)cc1O

Procedure:
This compounds was synthesised in the same manner as described above. 6-Ethyl-7-hydroxy-3-phenyl-chromen-4-one (0.29 g, 1.1 mmol), hydrazine hydrate (4 ml), ethanol (20 ml). The crude product was columned to give 4-Ethyl-6-(4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as a off white solid (0.23 g, 74.73%); Rf 0.7 Cf SM 0.9 ethyl acetate/hexane (70/30).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([N:12]([CH3:26])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[CH:17][N:16]=1)=[O:14])[CH2:6][CH2:5]2.[CH2:27](C([Sn])=C(CCCC)CCCC)[CH2:28]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:26][N:12]([C@H:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:27]=[CH2:28])[CH:3]=2)[CH2:8]1)[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[CH:17][N:16]=1)=[O:14]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CN(C(=O)c1ccc(OCC2CC2)cn1)[C@H]1CCc2cc(Br)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(c1)CC[C@H](N(C)C(=O)c1ccc(OCC3CC3)cn1)C2
Temperature: 100 °C

Procedure:
A mixture of N—((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-5-cyclopropylmethoxypyridine-2-carboxamide (1.50 g), tributylvinyltin (1.37 g), palladium(II) acetate (16 mg), triphenylphosphine (76 mg), diisopropylethylamine (8.5 ml) and DMF (20 ml) was heated to 100° C. for 12 hours. The cooled reaction mixture was partitioned between ethyl acetate and sodium carbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel. The product was thus obtained with the molecular weight of 362.48 (C23H26N2O2); MS (ESI): 363 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]=[C:11]=[S:12])[CH3:2].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:4]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:11]1=[S:12])[CH3:14]
Reactant: CCc1cccc(C)c1N=C=S
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C)c1N1C(=O)CN(CC)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 10 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. The residue was further purified by flash chromatography on silica gel (20% ethyl acetate in hexane). The title compound was obtained (8.6 g) as a light peach solid, m.p. 82°-84° C. Anal. Calcd. for. C14H18N2OS: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.27; H, 7.04; N, 10.60. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH2:22][CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1>CO.O1CCCC1>[CH3:1][O:20][C:19](=[O:21])[CH:18]([CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])[NH:17][S:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=1)(=[O:15])=[O:16]
Reactant: COc1ccc(S(=O)(=O)NC(CCN2C(=O)c3ccccc3C2=O)C(=O)O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(CCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(OC)cc1
Yield: 96 %

Procedure:
After addition of trimethylsilyl chloride (0.65 g, 5.1 mmol) to a solution of (±)-N-(4-methoxybenzensulfonyl)-2-(2-phthalimidoethyl)glycine (1.08 g, 2.6 mmol), the product of Example 21, in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml), the mixture was heated under reflux for 2 hours. The solvent of the reaction mixture was evaporated under reduced pressure. To the residue, a saturated aqueous solution of sodium hydrogencarbonate was added and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue for caking to afford the desired compound (yield 96%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CCc2ccccc2)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: [6-methoxy-2′-(phenethylamino-methyl)-4-'-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: Cl[C:2](Cl)=[N:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>C(#N)C>[CH:10]1([C:7]2[CH:8]=[CH:9][C:4]([N:3]=[C:2]3[NH:21][CH2:20][CH2:19][CH2:18][NH:17]3)=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCCCN
Reactant: ClC(Cl)=Nc1ccc(C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1cc(C2CCCCC2)ccc1N=C1NCCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.6 g of N-dichloromethylene 4-cyclohexylaniline in 40 ml of acetonitrile is added dropwise to a solution of 1 ml of 1,3-diaminopropane in 20 ml of acetonitrile in 15 minutes at room temperature. After the addition of 1 ml of triethylamine, the solution is stirred for 1 hour at room temperature, after which the reaction mixture is filtered while warm. After distilling off the solvent the residue is taken up in ether and successively washed with 2 N sodium hydroxide solution and water. The ether layer is dried and evaporated, after which the residue is recrystallised from acetonitrile. The resulting 2-(4-cyclohexylphenyl)imino-hexahydropyrimidine has a melting point of 180°-182° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[C:15]([Cl:18])[CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([Mg]Br)=[CH2:22]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[C:15]([Cl:18])[CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:19]([OH:20])[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-2-carbaldehyde (Example 22 E, 287 mg, 1 mmol) in THF (4 mL) at −50° C. was added a vinylmagnesium bromide solution (1.5 mL of 1 M solution) under Ar. The mixture was stirred for 2 h, slowly warmed to rt over 2 h and stirred at rt for 30 min. The reaction mixture was quenched by the addition of 0.2 mL of HOAc followed by water (15 mL) and EtOAc (40 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to obtain the crude title compound as a brown solid (315 mg, 100%) which was used in the next step without any further purification: 1H NMR (CDCl3) δ 7.10–7.50 (m, 6H), 6.47 (s, 1H), 6.01 (m, 1H), 5.05–5.25 (m, 4H), 5.05 (s, 1H); 13C NMR (CDCl3): δ 153.9, 149.8, 135.9, 135.4, 128.8, 127.7, 126.3, 119.8, 118.5, 113.6, 111.6, 70.4, 44.1.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(P([N:37]=[N+:38]=[N-:39])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:37]([CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[N+:38]=[N-:39]
Reactant: O=C(OCc1ccccc1)N1Cc2ccccc2C[C@H]1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
This compound is obtained using a protocol from the literature (D. Pagé et al J. Med. Chem, 44, 2387, 2001) starting from 23 g of the compound obtained in Step A (77.3 mmol) in the presence of diphenylphosphoryl azide and triphenylphosphine in solution in THF. After purification by chromatography over silica gel using petroleum ether and ethyl acetate as eluants, the title product is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:22]=[N:23][N:24]([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH:25]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:28]1[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N:24]1[CH:25]=[C:21]([CH3:20])[CH:22]=[N:23]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: Cc1cnn(-c2ccccc2C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cnn(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Yield: 35.4 %

Procedure:
A solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (180 mg, 0.70 mmol) and 2-(4-methyl-pyrazol-1-yl)-benzaldehyde (130 mg, 0.70 mmol) in acetic acid (5 mL) is warmed to 100° C. for 16 hours then cooled to room temperature and neutralized with NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) affords the title compound (105 mg, 35%). LCMS (ESMS): m/z 424.20 (M++1)
Reaction SMILES: Br[C:2]1[C:3]([CH3:26])=[N:4][C:5]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:6][CH:7]=1.[Cu](C#N)[C:28]#[N:29].CN1CCCC1=O>C(OCC)(=O)C>[CH3:26][C:3]1[N:4]=[C:5]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:15])([F:14])[F:16])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[C:28]#[N:29]
Reactant: N#C[Cu]C#N
Reactant: Cc1nc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1Br
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1nc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C#N
Temperature: 200 °C
Yield: 45 %

Procedure:
3-Bromo-2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-pyridine (3.3 g) and copper cyanide (I) (0.65 g) were added to N-methyl-2-pyrrolidinone (10 ml). The mixture was heated for 4 hours at 200° C. using a microwave reactor (trade name: INITIATOR™, manufactured by Biotage). Upon the completion of the reaction, the reaction mixture was diluted with ethyl acetate and the precipitate was filtered off through a short silica gel layer. The filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]nicotinonitrile (1.1 g).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16]C)=[O:15])[CH2:3]1.[OH-].[Na+]>CO>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@@H:2]([F:1])[CH2:3][C@H:4]1[C:14]([OH:16])=[O:15])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O

Procedure:
The crude product of 1-tert-butyl 2-methyl (2S,4S)-4-fluoro-1,2-pyrrolidinedicarboxylate obtained in Example 7-6 (127.5 g) was dissolved in methanol (400 mL) and then 1N NaOH (800 mL) was added at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[S:9](=[O:13])(=[O:12])([OH:11])[OH:10].C(O)(=O)[CH:15]([CH2:17][C:18](O)=O)[OH:16]>[Cl-].[Na+].O>[S:9](=[O:11])(=[O:10])([OH:13])[OH:12].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:15]([OH:16])=[CH:17][CH:18]=2)[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc2ccc(O)nc2n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2,6-Diaminopyridine (167 g, 1.53 mol) was added in portions to sulfuric acid (1.14 kg, 11.7 mol) at 40° C. The temperature of the solution was maintained at 40-50° C. during the addition with a water bath. When all of the 2,6-diaminopyridine was dissolved, the solution was cooled to 20° C. Malic acid (206 g, 1.53 mol) was added to the solution and the reaction mixture was gradually heated to 110° C. over 90 minutes. The mixture was stirred at 110-120° C. for one hour, cooled to room temperature, and poured slowly into a cold brine solution (167 g NaCl, 1.6 kg ice water). The quenched mixture was stirred at room temperature for one hour and filtered. The material was washed with hexanes (335 mL) and dried at 60° C. under vacuum to yield 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt as a yellow solid: 354 g, 89% yield; MS (DCI) M+1 at 162, 100%; 1H NMR (200 MHz, DMSO-d6) δ 4.32 (br. s, 5H, —OH, —NH2, H2SO4), 6.41 (d, J=9.0 Hz, 1H, C6), 6.56 (d J=9.0 Hz, 1H, C5), 7.85 (d J=6.6 Hz, 1H, C3), 7.91 (d J=6.6 Hz, 1H, C4).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:10]2[C:6](=[N+:7]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][CH:4]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:6][S:5]/[CH:4]=[C:3](\[N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[C:25]1=[O:26])/[CH3:2]
Reactant: C[O-]
Reactant: Cc1csc2n1c1ccccc1[n+]2Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CS/C=C(/C)n1c(=O)n(Cc2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Yield: 87.5 %

Procedure:
163 mg of 3-methyl-9-(4-nitrobenzyl)[1,3]thiazolo[3,2-a]benzimidazol-9-ium chloride (0.450 mmol) were solubilised in methanol (30 mL), then 122 mg (5 eq) of NaOMe were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure to afford 1-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-3-(4-nitrobenzyl)-1,3-dihydro-2H-benzimidazol-2-one as a pale yellow oil (140 mg, 91%). Rf=0.59 (CH2Cl2/AcOEt 8:2); 1H NMR (300 MHz, CDCl3) δ=2.18 (3H, d, J=1.1, CH3), 2.27 (3H, s, SCH3), 5.19 (2H, brs, CH2), 6.29 (1H, q, J=1.1, H5), 6.77-6.85 (1H, m, Ar), 6.88-6.96 (1H, m, Ar), 6.98-7.14 (2H, m, Ar), 7.42-7.52 (2H, m, Ar), 8.12-8.23 (4H, m, Ar); 13C NMR (75 MHz, CDCl3) δ=16.88, 20.40, 44.09, 108.04, 109.35, 121.75, 121.82, 124.02 (2C), 126.23, 127.74, 128.03 (2C), 128.15, 128.90, 143.60, 147.48, 152.12; HRMS m/z C18H18N3O3S [M+H]+ calcd: 356.1063, found: 356.1067.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:11]=[C:12]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)[CH:13]=1)=[O:7]>O.C1COCC1>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[CH:11]=[C:12]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)[CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2cnnn2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3cnnn3)c2)cc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A solution of LiOH.H2O (1.86 g, 44.2 mmol) in H2O (40 mL) was added dropwise to a suspension of 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid methyl ester (10 g, 34 mmol) in THF (25 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned clear. Solvent was removed under vacuum and the aqueous solution was acidified by addition of 10% HCl to pH=3. The resulting precipitate was collected and dried to afford 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid as white solid (8.85 g, 93%). MS (M+H)=281.