Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:37]=[CH:36][C:18]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.[Si:38]([O:45][CH2:46][CH2:47][CH2:48][O:49][C:50]1[CH:64]=[CH:63][C:53]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)=[CH:52][CH:51]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].CC(C)([O-])C.[Na+]>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].C(OCC)(=O)C>[Si:38]([O:45][CH2:46][CH2:47][CH2:48][O:49][C:50]1[CH:64]=[CH:63][C:53]([N:54]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)[C:15]2[CH:16]=[CH:17][C:18]([N:19]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[CH:36][CH:37]=2)=[CH:52][CH:51]=1)([C:41]([CH3:42])([CH3:44])[CH3:43])([CH3:40])[CH3:39]
Reactant: COc1ccc(Nc2ccc(OCCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Reactant: COc1ccc(N(c2ccc(Br)cc2)c2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCO[Si](C)(C)C(C)(C)C)cc3)cc2)cc1
Reaction time: 0.17 h

Procedure:
Anhydrous toluene (30.0 mL) was degassed by sparging with nitrogen for 10 minutes in a dry 200 mL schlenk flask. Tri(tert-butyl) phosphine (0.187 g; 0.924 mmol) and Pd2(dba)3 (0.283 g, 0.309 mmol) were added and the mixture was allowed to stir. After 10 minutes, 4-bromo-N,N-bis(4-methoxyphenyl)aniline (5.92 g; 15.4 mmol), 4-(3-(tert-butyldimethylsilyloxy)propoxy)-N-(4-methoxyphenyl)aniline (6.00 g; 15.4 mmol), and sodium tert-butoxide (2.08 g, 21.6 mmol) were added. The reaction was allowed to stir at 90° C. while being monitored by TLC (5:1 hexanes:ethyl acetate). Upon the disappearance of the starting materials the mixture was filtered through Celite eluting with ethyl acetate. The product was purified by flash chromatography (silica gel, 5:1 hexanes:ethyl acetate). The solvent was removed under reduced pressure. The residual solvent was removed in vacuo (9.06 g, 90.6%). 1H NMR (300 MHz, C3D6O) δ 6.98 (m, 8H), 6.86 (m, 8H), 6.82 (s, 4H), 4.06 (t, J=6.3 Hz, 2H), 3.83 (t, J=6.3 Hz, 2H), 3.76 (s, 9H), 1.95 (q, J=6.0 Hz, 2H), 0.890 (s, 9H), 0.058 (s, 6H). 13C{1H} NMR (300 MHz, C3D6O, δ): 156.40, 155.83, 143.65, 142.31, 126.24, 123.78, 116.04, 115.41, 65.28, 60.09, 55.63, 33.27, 26.23, −5.27. HRMS-EI (m/z): [M]+ calcd for C42H50N2O5Si, 690.35. found, 690.6). Anal. Calcd for C42H50N2O5Si: C, 73.01; H, 7.29; N, 4.05. Found: C, 73.25; H, 7.43; N, 4.01.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58]O)[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][CH:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:75])CC)C.CO.C(OCC)(=O)C>COCCOC>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][C@@H:28]2[O:57][C@H:56]([CH2:58][F:75])[C@@H:47]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:29]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:16]([CH2:60][O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:15][C@@H:10]1[O:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
The compound (6.43 g, 6.97 mmol) synthesized in Example 2 (2c) was dissolved in 1,2-dimethoxyethane (130 mL) and diethylaminosulfur trifluoride (2 mL, 20.50 mmol) was added thereto, followed by stirring of the mixture at 60° C. for 1 hour. Methanol (10 mL) was added to the reaction mixture under ice-cooling and the mixture was stirred for 30 minutes. After ethyl acetate (50 mL) was added thereto and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL) and dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 6:1, V/V) to obtain the desired title compound (5.06 g, yield 78%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[NH2:29][C@H:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C@@H:31]1[F:43]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([NH:29][C@H:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:32][C@@H:31]3[F:43])=[N:9]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@@H](F)C1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1

Procedure:
Prepared from 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.123 g, 0.25 mmol, prepared according to Example 7, Step B), and ±(3S*,4S*)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (0.164 g, 0.750 mmol, prepared according to the procedure described in WO 2006/087543) according to the procedure described for Example 143, Step A. LRMS (APCI+): m/z 581 (M+1) detected.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.COC1C=CC=CC=1C([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)C#N.Cl.C[CH2:37][O:38][CH2:39][CH3:40]>O1CCCC1.O>[CH3:37][O:38][C:39]1[CH:40]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:30][CH2:29][NH:26][N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: CCOCC
Reactant: COc1ccccc1C(C#N)N1CCN(c2ccccc2)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1CCNN1CCN(c2ccccc2)CC1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
2.3 g (60 mmol) of Lithium aluminium hydride are suspended in 100 ml of ether under a nitrogen atmosphere and cooled to about −10° C. 1.6 ml (30 mmol) of conc. sulphuric acid are carefully added dropwise thereto, with-further cooling, and the resulting mixture is stirred for 1.5 hours at about −5° C. Then a solution of 9.2 g (30 mmol) of (2-methoxyphenyl)-(4-phenylpiperazine-1-yl)-acetonitrile in 50 ml of tetrahydrofuran is slowly added dropwise. The mixture is allowed to come up to ambient temperature and is then refluxed for about 10 minutes. It is then allowed to cool and stirred overnight at ambient temperature. A mixture of 8 ml of tetrahydrofuran and 8 ml of water is then added, initially very carefully, to the grey suspension, whilst cooling with ice, and then 165 ml of 2N hydrochloric acid are added. The reaction mixture is then washed twice with 70 ml of ether and the ethereal phases are discarded. 18.2 g of Seignette salt and 45 ml of conc. sodium hydroxide solution are then added. The mixture is extracted four times with 70 ml of ether, the combined organic phases are dried over sodium sulfate and the solvent is eliminated in vacuo. 8.6 g of 2-(2-methoxyphenyl)-(4-phenylpiperazine-1-yl)-ethylamine are obtained (92% yield) as a yellowish oil. There is no additional purification before the further reactions.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F

Procedure:
First, the amino group of 2-fluoro-5-nitroaniline is sulfonylated by using methanesulfonyl chloride to give N-(2-fluoro-5-nitrophenyl)methanesulfonamide.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(OC([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:56]=[CH:57][CH:58]=1)[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47](=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[F:54])[C:28](=[O:41])[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:56]=[CH:57][CH:58]=1)[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47](=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[F:54])[C:28](=[O:41])[C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2ccccc2N(CCCCNC(=O)c2ccccc2F)C(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1cccc(Oc2ccccc2N(CCCCNC(=O)c2ccccc2F)C(=O)c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (5 ml) was added to an ethyl acetate (5 ml) solution of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]phenyl]-N-[4-[(2-fluorobenzoyl)amino]butyl]-4-phenylbenzamide (0.13 g, 0.18 mmols), and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The solid precipitated was taken out through filtration, and washed with ethyl ether to give an amorphous solid of N-[2-[3-(aminomethyl)phenoxy]phenyl]-N-[4-[(2-fluorobenzoyl)amino]butyl]-4-phenylbenzamide hydrochloride (0.07 g, 64%).
Reaction SMILES: C(O)(C)(C)C.CCN(C(C)C)C(C)C.Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:17]=1.C(O)(=O)C.[NH2:44][CH2:45][C:46]1[C:47]([N:52]([CH3:57])[S:53]([CH3:56])(=[O:55])=[O:54])=[N:48][CH:49]=[CH:50][CH:51]=1>ClCCCl>[CH3:57][N:52]([S:53]([CH3:56])(=[O:55])=[O:54])[C:47]1[C:46]([CH2:45][NH:44][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=3)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:17]=2)=[CH:51][CH:50]=[CH:49][N:48]=1
Reactant: CC(C)(C)OC(=O)c1cccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c1
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1CNc1nc(Nc2cccc(C(=O)OC(C)(C)C)c2)ncc1C(F)(F)F)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of tert-butanol (20.0 mL), DCE (20.0 mL) and DIEA (3.13 mL, 18.0 mmol) was treated with C8 (5.60 g, 15.0 mmol) and B5 (5.02 g, 15.0 mmol), and the resulting mixture was stirred at 80° C. under an atmosphere of nitrogen for 16 hours. The mixture was cooled to 25° C. and concentrated. The resultant residue was partitioned between EtOAc and 1 N sodium hydroxide, and the organic phase was collected. The aqueous layer was extracted with EtOAc, and the combined organic phases were dried over MgSO4 and filtered. The resultant filtrate was concentrated under reduced pressure, and the resultant residue was triturated with hot EtOAc to provide 9 as a white solid. Yield: 7.83 grams, 95%. LC/MS (standard) 25°=3.0 min., m/z 553.6 (MH+). HPLC (FAK1) 25°=8.14 min. 1H NMR (d6-DMSO) δ: 9.75 (bs, 1H), 8.44 (d, J=5.2 Hz., 1H), 8.29 (s, 1H), 8.05 (bs, 1H), 7.82 (d, J=7.8 Hz., 1H), 7.60 (t, J=5.7 Hz., 1H), 7.44-7.40 (m, 2H), 7.17 (t, J=5.7 Hz, 1H), 4.82 (d, J=5.7 Hz., 2 H), 3.16 (s, 3H), 3.13 (s, 3H), 1.51 (s, 9H) ppm. FAK IC50: 0.0006 μM
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][O-:4].[CH2:7]([Al+:9]CC)[CH3:8].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[Al]>>[F:1][C:2]([F:6])([F:5])[CH2:3][O-:4].[F:12][C:13]([F:17])([F:16])[CH2:14][O-:15].[CH2:7]([Al+2:9])[CH3:8]
Reactant: CC[Al+]CC
Reactant: OCC(F)(F)F
Agent: [Al]
Agent: [O-]CC(F)(F)F
Product: CC[Al+2]
Temperature: 55 °C
Reaction time: 1 h

Procedure:
In a flask were placed 10.27 g (55.75 mmoles) of the product of Example 1, under a nitrogen blanket. Then, 5.71 g (0.058 mole) of 2,2,2-trifluoroethanol was added dropwise. When the reaction mixture temperature reached 50° C., the flask was immersed in a chilled oil bath (0° C.) and the addition of fluoroalkanol was continued at a rate sufficient to maintain the temperature at 50°-55° C. After addition was completed, the reaction mixture was stirred for one hour at 55° C. The product was a viscous, colorless liquid. Analysis for aluminum showed 10.43% Al, which correlated well with the theoretical value of 10.58%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12](=[O:13])[CH2:11][C:10]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:9]=2[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Br:25])[CH2:7]1)[CH3:2].[C:27](N=P(N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)([CH3:30])([CH3:29])[CH3:28].CCCCCC.ICC(C)C.Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:7][CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Br:25])[C:9]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[CH:11]([CH2:28][CH:27]([CH3:30])[CH3:29])[C:12]1=[O:13])[CH3:2]
Reactant: CCOC(=O)CN1CC(c2ccccc2Br)c2cc(Cl)ccc2CC1=O
Reactant: CN(C)P(=NP(=NC(C)(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C
Agent: CC(C)CI
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)CN1CC(c2ccccc2Br)c2cc(Cl)ccc2C(CC(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
440 mg of the compound from Example 12A (1.01 mol) are dissolved in 5.2 ml of THF. At −78° C., 1.51 ml of a 1 M solution of 3-tert-butylimino-1,1,1,5,5,5-hexakis(dimethylamino)-3-[tris(dimethylamino)phosphoranylidene]amino-1λ5,3λ5,5λ5-1,4-triphosphazadiene in n-hexane (1.51 mol) are added drop wise, and the reaction mixture is stirred at −78° C. for 30 min. 278 mg of 1-iodo-2-methylpropane (1.51 mol) are added drop wise, and the mixture is stirred at −78° C. for a further 3 h. The reaction solution is mixed with 14 ml of 1 N hydrochloric acid and water and extracted three times with dichloromethane. The combined organic phases are washed twice with saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 200 mg (40% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[O:32][CH2:31][CH2:30][N:29]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCOC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 117.3 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-morpholin-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (247 mg, 0.521 mmol) in DMF (5 mL) was treated with 2-chloro-N,N-dimethylacetamide (115 mg, 0.94 mmol), potassium carbonate (658 mg, 4.8 mmol) and potassium iodide (19 mg, 0.12 mmol) and the mixture vigorously stirred at 60° C. for 18 h. Basic, aqueous workup and purification by column chromatography (CH2Cl2:MeOH:NH3) gave 312 mg (50%) of the desired compound. 1H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 1 H), 7.76 (dd, 1 H, J=9, 1 Hz), 7.53 (s, 1H), 7.25 to 7.36 (m, 3H), 7.18-7.23 (m, 2H), 7.09 (d, 1 H, J=9 Hz), 6.60 (s, 1H), 5.63 (s, 2H), 3.14 (s, 2H), 3.03 (s, 3H), 2.89-2.94 (m, 2H), 2.80 (s, 3H), 2.62 (s, 3H), 2.12-2.24 (m, 2H), 1.93-2.03 (m, 2H), 1.63-1.79 (m, 2H); ES-MS m/z 523.2 [M+H]+, HPLC RT (min) 2.21.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[C:7]1([C:13]2([CH2:19][C:20]#[N:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[C:7]1([C:13]2([CH2:19][C:20]([NH2:1])=[NH:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: N#CCC1(c2ccccc2)CCCCC1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)CC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a suspension of NH4Cl (2.34 g, 43.65 mmol) in toluene (20.0 mL) was added drop-wise a solution of trimethyl aluminium (3.15 g, 43.65 mmol, 2M in toluene) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h prior to the addition of a solution of (1-phenyl-cyclohexyl)-acetonitrile (253) (2.9 g, 14.55 mmol) in toluene (10.0 mL). The resulting solution was heated to 80° C. for 16 h. The cooled reaction mixture was poured into a slurry of silica-gel (10.0 g) in CHCl3 (20.0 mL) followed by vigorous stirring for 30 min. The silica gel was filtered off and the cake was rinsed in turn with methanol. The solvent was evaporated and the crude product was taken up in 10% methanol in dichloromethane (200.0 mL) and stirred for 30 min. The solid suspension was removed by filtration and the filtrate was evaporated. The crude product was triturated in diethyl ether and the solid was collected by filtration and dried under vacuum to afford HCl-salt of 2-(1-phenyl-cyclohexyl)-acetamidine (254) (2.5 g, 68.0%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.[C:22]([CH2:24][S:25][CH2:26][C:27]([O-])=[O:28])#[N:23]>>[C:22]([CH2:24][S:25][CH2:26][C:27]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:28])#[N:23]
Reactant: N#CCSCC(=O)[O-]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSCC#N)[C@H]2SC1

Procedure:
The title compound was prepared by the reaction of 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.28 g, 10 mmol) and N-hydroxysuccininimidyl cyanomethylmercaptoacetate (3.4 g, 15 mmol) by the procedure of Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[O:19]1[CH2:22][CH:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][N:26]3[CH2:27][CH2:28][CH:23]([CH:21]4[CH2:22][O:19][CH2:20]4)[CH2:24][CH2:25]3)[S:8][C:6]=2[N:7]=1
Reactant: C1CC(C2COC2)CCN1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)sc2n1
Reaction time: 6 h
Yield: 23.1 %

Procedure:
A solution of 5 -chloro-7-morpholin-4-ylthiazolo [5,4-d]pyrimidine-2-carbaldehyde (1.0 g, 3.52 mmol), 4-oxetan-3-ylpiperidine (536 mg, 4.23 mmol) and molecular sieves (4 Å, powdered, 6.56 g) in DCE (30 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (1.49 g, 7.05 mmol) was added and the mixture stirred for 6 h, then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 97:3) to afford the title compound as a cream solid (334 mg, 41%). LCMS (Method A): RT=2.48 min, M+H+=410
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.NO.[N:16]1C=CC=CC=1.CCO>CC(OC(C)=O)=O.O>[Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:16])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: c1ccncc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: N#Cc1c(Cl)[nH]c2ccccc12
Yield: 58 %

Procedure:
A mixture of 2-chloroindole-3-carboxaldehyde (7.0 g, 36 mmol) was reacted with a slight excess of hydroxylamine hydrochloride and pyridine in refluxing EtOH for 1 hour, to give the crude oxime (Latrell R, Bartmann W, Musif J, Granzer E, German Patent 2,707,268, 31 Aug 1978, Chem. Abstr. 1978;89:179858y). A solution of this in Ac2O (100 mL) was heated under reflux for 1 hour, cooled, and stirred with water (700 mL). The precipitated solid was collected, washed with water, and crystallized from aqueous MeOH to give 2-chloro-1H-indole-3-carbonitrile (3.7 g, 58%); mp 177°-180° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=2)[CH:12]=1)=[O:7])[CH3:4].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]OS(C)(=O)=O>C1COCC1>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:14]=2)[CH:12]=1)=[O:7])[CH3:4]
Reactant: CS(=O)(=O)OCc1ccccn1
Reactant: CCOC(=O)c1cn(-c2cccc(CO)c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2cccc(COCc3ccccn3)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
To a suspension of NaH (120 mg, 3 mmol, 60% in mineral oil) in dry THF (10 mL) at 0° C. under N2 atmosphere was added a solution of compound 7 (394 mg, 1.2 mmol) in dry THF (5 mL) and reaction mixture was allowed to stir for 30 min at room temperature. Compound 11 (300 mg, 1.2 mmol) in THF (2 mL) was then added and stirring was continued for 12 h at room temperature [reaction was followed by TLC]. Reaction mixture was quenched with water (5 mL), extracted with CH2Cl2 (40 mL), washed with brine, dried over Na2SO4 and concentrated. The crude mass was purified by column chromatography over silica gel using 10% methanol in chloroform as eluant to give 11a (110 mg, 28%) as pale yellow solid, mp 76.7-78.8° C.