Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33](O)=[O:34])=[CH:31][N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:44]([NH2:48])([CH3:47])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:44]([NH:48][C:33]([C:32]1[C:26]2[C:27](=[N:28][CH:29]=[C:24]([C:16]3[C:17]4[C:22](=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[N:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]4)[N:15]=3)[N:25]=2)[N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:31]=1)=[O:34])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In a 10 ml round-bottomed flask, 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (85 mg, 0.14 mmol) was dissolved in DMF (1.5 ml) and tert-butylamine (0.06 ml, 0.57 mmol) and HATU (59 mg, 0.155 mmol) were added. The light yellow suspension was stirred at room temperature overnight then water and petroleum ether were added. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum. The residue was chromatographed over 8 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 47 mg (51%) of 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white solid.
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:19]([NH:38][C:39]1[S:40][CH:41]=[C:42]([C:44](=[N:48][O:49][CH3:50])[C:45]([OH:47])=O)[N:43]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:51][C:52]([O:54][CH2:55][C:56]1[CH2:65][S:64][C@@H:59]2[C@H:60]([NH2:63])[C:61](=[O:62])[N:58]2[C:57]=1[C:66]([OH:68])=[O:67])=[O:53]>CC(N(C)C)=O.C(Cl)Cl>[C:52]([O:54][CH2:55][C:56]1[CH2:65][S:64][C@@H:59]2[CH:60]([NH:63][C:45](=[O:47])[C:44]([C:42]3[N:43]=[C:39]([NH:38][C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:40][CH:41]=3)=[N:48][O:49][CH3:50])[C:61](=[O:62])[N:58]2[C:57]=1[C:66]([OH:68])=[O:67])(=[O:53])[CH3:51]
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
Another preferred embodiment of the process of the invention comprises reacting at low temperatures in dimethylacetamide in the presence of triethylamine, tosyl chloride and the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetic acid and reacting the resulting product with a solution of 7-amino-cephalosporanic acid in methylene chloride in the presence of triethylamine to obtain the syn isomer of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:31])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[C:14]([O:29][CH3:30])[CH:13]=2)[CH2:4][CH2:3]1.[OH-].[K+]>CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:31])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:14]([O:29][CH3:30])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCCCCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCC(=O)O

Procedure:
Using 2.5 g of N-(trans-4-methylcyclohexyl)-4-[5-(ethyoxycarbonyl) pentyloxy]-3-methoxycinnamamide (Example 177), 20 ml of 2 M aqueous potassium hydroxide solution, and 80 ml of methanol, a reaction similar to that conducted in Example 169 was carried out. As a result, 2.18 g of N-(trans-4-methylcyclohexyl)-4-(5-carboxypentyloxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([OH:23])=O)=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.[CH3:31][N:32](C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.CN>C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:24]([CH3:25])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[C:7]([C:21]([NH:32][CH3:31])=[O:23])[CH:8]=1)[CH3:20]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Agent: CN
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(=O)NC)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.9 %

Procedure:
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU) (0.14 g, 0.44 mmol) were added to methylene chloride (10 ml) and the reaction mixture was stirred at room temperature for 15 min. Methylamine (0.1 g, 3.2 mmol) was added and the reaction mixture was stirred at ambient temperature for 1.5 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethylacetate:methylene chloride (1:1) as eluent. The yield was treated with diethyl ether to give 40 mg (26%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N[C:10]1N=CC(C2N=NN(C3C=C(C=CC=3C)C(NC3C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=3OC)=O)C=2)=C[CH:11]=1>>[C:10]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])#[CH:11]
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(N)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccncc1Br
Product: C#Cc1cnccc1C

Procedure:
3-Ethynyl-4-methyl-pyridine was prepared from 3-bromo-4-methyl-pyridine in the same manner as 2-amino-3-ethynyl pyridine (Example 15).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[Br:15][C:16]([CH3:21])([CH3:20])[C:17](Br)=[O:18]>O1CCCC1>[Br:15][C:16]([CH3:21])([CH3:20])[C:17]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])=[O:18]
Reactant: C=CCCCCO
Reactant: CC(C)(Br)C(=O)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCCCOC(=O)C(C)(C)Br
Temperature: 4 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
5-Hexen-1-ol (42.6 g), triethylamine (45.8 g), and tetrahydrofuran (0.8 L) were mixed. After ice cooling, 2-bromoisobutyryl bromide (100 g) was dropped. The reaction liquid was stirred at 4° C. for 3 hours, and then at room temperature for 15 hours. The reaction liquid was then filtered, concentrated with an evaporator, and dissolved in diethyl ether (300 mL). The solution was washed with a 1N hydrochloric acid solution (2×300 mL), a saturated sodium bicarbonate solution (2×300 mL), and distilled water (2×300 mL), in this order. After that, the organic layer was dried over sodium sulfate, filtered, and concentrated with an evaporator. The product was then purified through a silica gel column (developing solvent: hexane/ethyl acetate=15/1), and concentrated to give 74.2 g of 5-hexenyl 2-bromo-2-methylpropanate of the following chemical formula (compound 1).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]#[C:6][C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12.[CH3:23]I>CN(C)C=O>[CH3:23][O:3][CH2:4][C:5]#[C:6][C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12
Reactant: CI
Reactant: CN1Cc2c(C#CCO)ncn2-c2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COCC#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2
Reaction time: 1 h

Procedure:
5.05 g (90 mmol) of freshly powdered potassium hydroxide was suspended in 50 ml of N,N-dimethylformamide and cooled to 3°. 6.0 g (22.5 mmol) of 4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 6.39 g (45 mmol) of methyl iodide was added thereto in succession, the ice-bath was removed and the mixture was stirred for a further 1 hour. The reaction mixture was poured into 200 ml of water, acidified to pH 7 with 4N hydrochloric acid and extracted five times with methylene chloride. The combined organic extracts were dried over magnesium sulphate, evaporated and after crystallization of the residue from ethyl acetate there was obtained 4,5-dihydro-3-(3-methoxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 114°-115°.
Reaction SMILES: OC1C=C(CCC[N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])C=CC=1.ClC1C=CC=C(Cl)C=1CBr>>[C:12]1(=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[NH:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Agent: Clc1cccc(Cl)c1CBr
Product: O=C1NC(=O)c2ccccc21

Procedure:
Alkylation reaction of phenol 58 with 2,6-dichlorobenzylbromide gave 2-(3-3-(2,6-dichlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.780 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.82-7.85 (m, 2H), 7.69-7.72 (m, 2H), 7.35-7.38 (m, 1H), 6.86-6.79 (m, 2H), 6.81 (s, 1H), 6.80 (dd, J=8.2, 2.4 Hz, 1H), 5.25 (s, 2H), 3.76 (t, J=6.2 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.00-2.09 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][C:7]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:16]1[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=1
Reactant: COCCOc1ccc(NC(C)=O)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOc1ccc(N)cc1-c1ccnn1C
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a suspension of N-(4-(2-methoxyethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (289 mg, 1.0 mmol) in MeOH (3 mL) was added a solution of sodium hydroxide (240 mg, 6.0 mmol) in water (0.4 mL) and the mixture was stirred at 160° C. in a microwave oven. After 30 minutes, the mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The residue was taken up in water, and extracted three times with dichloromethane. The extracts were combined, dried with sodium sulfate, filtered, and evaporated to dryness to afford the title compound (231 mg, 93% yield) as a brown oil which was used without further purification. LCMS m/z (%) 248.1 (M+H, 100%). 1H NMR (400 MHz, DMSO-d6) δ 3.19 (s, 3H) 3.48-3.53 (m, 2H) 3.63 (s, 3H) 3.89-3.96 (m, 2H) 4.81 (s, 2H) 6.16 (d, J=1.77 Hz, 1H) 6.48 (d, J=3.03 Hz, 1H) 6.62 (dd, J=8.72, 2.91 Hz, 1H) 6.86 (d, J=8.84 Hz, 1H) 7.39 (d, J=1.77 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]C(C)([O-])C.[K+].C(OP(C=[N+]=[N-])(=O)OCC)C>CCOCC>[C:6]([N:8]1[C@H:12]([C:13]#[CH:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Reactant: CC(C)(C)[O-]
Agent: CCOP(=O)(C=[N+]=[N-])OCC
Agent: [K+]
Solvent: CCOCC
Product: C#C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(R)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine was prepared according to Method X above by the treatment of tert-butyl-(S)-4-formyl-2,2-dimethyl-3-oxazolidine-carboxylate (1.00 g, 4.36 mmol) (Aldrich) with potassium tert-butoxide (730 mg, 6.54 mmol) and diazomethyl-phosphonic-acid-diethylester (1.20 g, 6.54 mmol) (see Method X, supra). The reaction was allowed to slowly warm up to room temperature and stirred for a total of 12 hrs. The product was obtained after silica gel column chromatography with 20% Et2O in hexanes. (Yield 600 mg, 61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[NH:10][CH:11]=[N:12]2>C(O)(C)C>[N:1]1([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[NH:10][CH:11]=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C1CNCCN1
Solvent: CC(C)O
Product: c1nc(N2CCNCC2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an isopropanol solution (50 mL) of piperazine (5.57 g, 64.7 mmol), 6-chloropurine (1.00 g, 6.47 mmol) was added, followed by stirring at room temperature for 1.5 hours and then heating under reflux for 2.5 hours. The reaction solution was concentrated, saturated brine was added thereto, the mixture was extracted with chloroform and THF in that order, the extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated to give the target compound. Thereafter, the water layer after extraction was allowed to stand, and then the precipitated crystals were recovered by filtration to give the target compound (1.07 g in total, 5.25 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][N:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: COC(=O)c1c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred brown solution of 2-(di-tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl ester (51.53 g, 126 mmol) in methylene chloride (600 mL), was added trifluoroacetic acid (18.2 mL, 245 mmol), and the mixture was stirred at room temp overnight. Sat. sodium bicarbonate (400 mL) was added to the solution, and the mixture was stirred for 10 minutes. The organic layer was separated, dried over magnesium sulfate and evaporated to give 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl ester as a brown oil (41.4 g, 106% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:27])([CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:31])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)NS(C)(=O)=O)ccc4N3)c2)cc1
Yield: 20 %

Procedure:
A mixture of 2-(4′-tert-butyl-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.24 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (70 mg, 0.36 mmol), 4-dimethylaminopyridine (44 mg, 0.36 mmol), methane sulfonamide (68.4 mg, 0.72 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(4′-tert-butyl-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (23.5 mg, 20%) as a light yellow solid: MS (ESI) M+1=491.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C=CC=NC=1.Cl[C:56]1[CH:61]=[C:60]([O:62][C@@H:63]([C@@H:65]2[CH2:69][O:68][C:67]([CH3:71])([CH3:70])[O:66]2)[CH3:64])[N:59]=[C:58]([S:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[C:76]([F:80])[C:75]=2[F:81])[N:57]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:81][C:75]1[C:76]([F:80])=[CH:77][CH:78]=[CH:79][C:74]=1[CH2:73][S:72][C:58]1[N:57]=[C:56]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:61]=[C:60]([O:62][C@@H:63]([C@@H:65]2[CH2:69][O:68][C:67]([CH3:70])([CH3:71])[O:66]2)[CH3:64])[N:59]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: c1cncnc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulphonamide (prepared according to patent WO 2004/011443, 0.16 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (17 mg), cesium carbonate (0.28 g) and 4 chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-pyrimidine (the product of step i) (0.25 g) in dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 20 min. Saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (3:7) as eluent to give the subtitle compound as a yellow oil. Yield: 0.13 g.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[ClH:45].CCOCC>ClCCl>[ClH:45].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2cnccn2)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cnccn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
A solution 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(2-pyrazinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see Intermediate 74) (204 mg, 0.403 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 30 min then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined to give a residue. Purification of this residue on SP4 using a 25 G silica cartridge (gradient:1 to 10% (2M NH3 in MeOH) in DCM) gave a second residue which was purified by MDAP (modifier: formic acid) to give a third residue which was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined to give a residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.2 mL, 0.2 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-2-pyrazinyl-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (77 mg, 0.159 mmol, 39.3% yield) as a cream solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.[C:10]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:17](=[O:18])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:11][CH:12]=1)[CH2:2]2
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: NC1CN2CCC1CC2
Product: O=C(Cc1ccc(-c2ccccc2)cc1)NC1CN2CCC1CC2
Yield: 44 %

Procedure:
Using general procedure I, 1-aza-bicyclo[2.2.2]oct-3-ylamine (200 mg, 1.00 mmol) and biphenyl-4-yl-acetic acid gave the title compound as a white solid (140 mg, 44%). 1H NMR (400 MHz, CD3OD) δ 7.56 (t, J=8.0 Hz, 4H), 7.29-7.41 (m, 5H), 4.19 (br s, 1H), 3.70 (t, J=7.2 Hz, 1H), 3.58 (s, 2H), 3.24-3.31 (m, 5H), 3.12-3.19 (m, 1H), 2.16-2.17 (m, 2H), 1.95-1.98 (m, 2H), 1.82 (br s, 1H) ppm. 13C NMR (400 MHz, CD3OD) δ 173.1, 140.8, 140.0, 134.7, 129.4, 128.7, 126.9, 52.3, 46.4, 45.9, 44.3, 41.9, 24.4, 21.5, 17.1 ppm. Purity: 93.9% HPLCMS (210 nm); retention time 2.87 min; (M+1) 321.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.C[C@H]1CNCCN1>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1
Reactant: C[C@@H]1CN(c2ccccc2F)CCN1
Agent: C[C@H]1CNCCN1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H]1CN(c2ccccc2F)CCN1

Procedure:
The title compound was prepared following the protocol used for the preparation of Intermediate 5, but starting from (S)-2-methylpiperazine (40%). TLC-Chloroform/Methanol (9/1); Rf: 0.25. HPLC purity: 97%.
Reaction SMILES: [C:1]([C:3](=[CH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([O:30][CH2:31][CH3:32])=[CH:19][C:18]=1[N+:33]([O-:35])=[O:34])[CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][CH2:6][C:7](O)=[O:8])#[N:2].[CH3:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39][NH2:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:36][C:37]([CH3:42])([CH3:41])[CH2:38][CH2:39][NH:40][C:7](=[O:8])[CH2:6][CH2:5][CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:3]([C:1]#[N:2])=[CH:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([O:30][CH2:31][CH3:32])=[CH:19][C:18]=1[N+:33]([O-:35])=[O:34]
Reactant: CCOc1cc([N+](=O)[O-])c(C=C(C#N)C(CCC(=O)O)C2CCOCC2)cc1Oc1ccccc1
Reactant: CC(C)(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc([N+](=O)[O-])c(C=C(C#N)C(CCC(=O)NCCC(C)(C)C)C2CCOCC2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-cyano-6-(4-ethoxy-2-nitro-5-phenoxy-phenyl)-4-(tetrahydro-pyran-4-yl)-hex-5-enoic acid (160 mg, 0.33 mmol), 3,3-dimethylbutylamine (40 mg, 0.4 mmol), HBTU (155 mg, 0.4 mmol) and DIEA (150 μL) in DMF (10 mL) was stirred at room temperature overnight. Water was then added, and the resulting mixture was extracted with methylene chloride (3×). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude mixture was purified by chromatography (silica gel, 20-50% ethyl acetate in heptane) to yield a yellow oil.