Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2([OH:20])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.C[O:22][C:23](=[O:46])[C@H:24]([C@@H:43]([CH3:45])O)[NH:25]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2([O:20][C@H:43]([CH3:45])[C@@H:24]([C:23]([OH:46])=[O:22])[NH2:25])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)s2)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: C[C@@H](OC1(c2ccc(Cl)s2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(5-chlorothien-2-yl)-9H-fluoren-9-ol (Example 31) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [N:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH:5]1[OH:15])=[N+:2]=[N-:3].[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20].O>CN(C=O)C>[CH2:20]([O:15][C@@H:5]1[CH2:6][C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C@H:4]1[N:1]=[N+:2]=[N-:3])[CH:19]=[CH2:18]
Reactant: COc1ccc2c(c1)C(N=[N+]=[N-])C(O)C2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1Cc2ccc(OC)cc2[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Step AA (5): To a solution of (1RS,2RS)-1-azido-6-methoxy-2,3-dihydro-1H-inden-2-ol (64 mg) from Step AA (4) in DMF (0.30 mL) at rt was added sodium hydride (95% purity, 20 mg), and the resulting mixture was stirred at rt for 5 min. Allyl bromide (40 μL) was added, and the reaction mixture was stirred for 5 min. Water was added, the aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give trans-2-(allyloxy)-1-azido-6-methoxy-2,3-dihydro-1H-indene as a slightly yellowish oil (71 mg). 1H NMR (400 MHz, CDCl3) δ 7.09 (1H, d), 6.84 (2H, m), 5.96 (1H, m), 5.34 (1H, d), 5.23 (1H, d), 4.75 (1H, d), 4.23 (1H, q), 4.16 (2H, q), 3.80 (3H, s), 3.21 (1H, dd), 2.78 (1H, dd).
Reaction SMILES: [NH2:1][C:2]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15](Cl)(=[O:19])[O:16][CH2:17][CH3:18]>CC1C=CC=CC=1C>[Cl:13][C:12]1[C:2]([NH:1][C:15]([O:16][CH2:17][CH3:18])=[O:19])=[C:3]([CH:9]=[C:10]([Cl:14])[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)Nc1c(Cl)cc(Cl)cc1C(=O)OCC
Reaction time: 8 h

Procedure:
To a stirred mixture of 25 parts of ethyl 2-amino-3,5-dichlorobenzoate and 180 parts of dimethylbenzene are added dropwise 30 parts of ethyl carbonochloridate. Upon completion, stirring is continued for 8 hours at reflux temperature. The reaction mixture is evaporated and the residue is crystallized from petroleumether. The product is filtered off and dried, yielding 30 parts of ethyl 3,5-dichloro-2-(ethoxycarbonylamino)benzoate.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[H-].[Na+].Br[CH2:15][C:16]([CH3:23])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>CN(C=O)C.CCOCC>[CH3:15][C:16]([CH2:23][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C=C(C)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)COc1ccc(C=O)cc1OC
Reaction time: 0.17 h

Procedure:
Vanillin (3.43 g, 22.5 mmol) in 10 ml of DMF is added portionwise, at 0°, to sodium hydride (21.5 g, 23.6 mmol) in ml of DMF. The mixture is stirred for 10 min. and then ethyl 4-bromo-3-methyl-2-butenoate (4.87 g, 23.5 mmol) in 3 ml of DMF is added. After 3 hours, the reaction mixture is poured into ether and 5% sodium hydroxide solution. The aqueous layer is extracted with ether, and the organic layers are combined and washed with 5% sodium hydroxide, with water and with brine and dried. Solvent is removed in vacuo and the crude product is chromatographed to give ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate. To isopropyltriphenylphosphonium iodide (2.26 g, 5.23 mmol) in 15 ml of tetrahydrofuran (THF) is added n-butyllithium (1.6 M; 3.10 ml, 5.0 mmol) at -5°. The mixture is cooled to -60°, and ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate (0.70 g, 2.51 mmol) in 10 ml of THF is added. After 45 min. the reaction mixture is poured into ether and water, and the aqueous phase is extracted with ether. The combined ether layers are washed with water and with brine and dried. Solvent is removed in vacuo, and the crude product is triturated with hexane and the hexane-soluble fraction is purified by prep. TLC to give ethyl 3-methyl-4-[2-methoxy-4-(2-methyl-1-propenyl)phenoxy]-2-butenoate, MS m/e 304 (M+).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[NH:31][CH:30]=[N:29][C:28]=1[C:32]#[N:33]>C1COCC1>[NH2:33][C:32]1[C:28]2[N:29]=[CH:30][NH:31][C:27]=2[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:11][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=1
Reactant: N#Cc1nc[nH]c1N
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3ccccc3[nH]2)c(=O)[nH]c2[nH]cnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiHMDS (4.4 eq) was added to ethyl 1H-benzimidazol-2-ylacetate (1.0 eq) and 5-amino-1H-imidazole-4-carbonitrile (1.0 eq) in THF at 0° C. After 1 hour, the resulting mixture was warmed to room temperature and then stirred overnight. The mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. LC/MS m/z 267.1 (MH+), Rt 1.47 minutes.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].Br[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19](=[O:20])[O:18]1>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([O:12][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19](=[O:20])[O:18]1)=[O:11])([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Reactant: O=C1OC(Br)c2ccccc21
Product: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)[nH]1
Yield: 94.8 %

Procedure:
Following a procedure similar to that described in Preparation 31, but using 1.06 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in Preparation 22(i)] and 1.15 g of 3-bromophthalide, 1.63 g of the title compound were obtained as an amorphous solid.
Reaction SMILES: C([NH:4][CH:5]([CH2:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:11])[C:6]([OH:8])=[O:7])(=O)C>Cl>[NH2:4][C@H:5]([CH2:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:11])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(CC(=O)c1cc(Cl)ccc1N)C(=O)O
Agent: Cl
Product: Nc1ccc(Cl)cc1C(=O)C[C@@H](N)C(=O)O
Yield: 61.7 %

Procedure:
A solution of (-)-2-acetamido-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (0.76 g, 2.67 mmol) in 2N HCl (90 ml) was heated at reflux temperature for 3 h. The aqueous solution was evaporated to dryness, the residue was dissolved in water, washed with CH2Cl2 and evaporated again. The residue was dissolved in water (30 ml) and adjusted to pH 6.5 with 1N NaOH: a light yellow solid separated. The solid was filtered and washed with cold water to obtain (R)-(+)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (0.40 g; 59.7%; m.p. 210°-211° C. (dec.); [α]20D =+11.5 (1%, CH3COOH); ee=96%).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:12][O:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>C1COCC1>[OH:19][C:18]([C:17]1[CH:28]=[CH:29][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)(CC#N)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Yield: 74.4 %

Procedure:
Acetonitrile (3.2 ml, 0.058 mol) was added dropwise to a solution of lithium diisopropylamide (1.5 M in THF, 36.7 ml, 0.055 mol) stirred at -78° C. under argon. After 5 min. a solution of 4,4'-dimethoxybenzophenone (10.0 g, 0.048 mol) in dry THF (130 ml) was added slowly. The mixture was allowed to warm up to -35° C. and after 20 min. was quenched by the cautious dropwise addition of a solution of acetic acid (3.0 g) in water (6 ml) . Brine (50 ml) was added, the organic layer separated washed with brine (50 ml) and the combined aqueous phases were extracted with DCM (2×50 ml). The combined organics were dried over anhydrous magnesium sulphate, filtered and concentrated. The residue was crystalised from ethyl acetate to give 3-hydroxy-3,3-di(4-methoxyphenyl)propanenitrile (10.12 g, 85%) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:6].[CH2:14]=[O:15]>>[CH3:1][O:2][CH2:3][O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][OH:15])=[N:11][CH:12]=1)[CH3:6]
Reactant: C=O
Reactant: COCOC(C)c1ccc(C)nc1
Product: COCOC(C)c1ccc(CCO)nc1
Yield: 31.9 %

Procedure:
The mixture of 5-(1-methoxymethoxyethyl)-2-methylpyridine (21.0 g) and formalin (37% aq. HCHO, 14.1 g) was heated at 150° to 160° C. for 8 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure and then the residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (25:1, v/v) gave 2-[5-(1-methoxymethoxyethyl)-2-pyridyl]ethanol (7.8 g, yield: 32%) as oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]#[CH:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(NC(C)C)(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:9][C:4]1[C:3]([C:25]#[C:24][CH:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[C:2]([Cl:1])[N:7]=[C:6]([CH3:8])[N:5]=1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N)c(I)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1nc(N)c(C#CC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)n1
Temperature: 52.5 °C
Yield: 86.8 %

Procedure:
Dissolve 6-chloro-5-iodo-2-methyl-pyrimidin-4-amine (20 g, 74.22 mmol), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (18.64 g, 89.06 mmol), and diisopropylamine (10.44 mL, 74.22 mmol) in THF (200 mL) in a 3-neck flask. Alternately evacuate and charge the flask with nitrogen 3 times. Add bis(triphenylphosphine)palladium(II) chloride (2.63 g, 3.71 mmol) and copper(I) iodide (0.713 g, 3.71 mmol) to the solution. Heat the mixture to between 50 to 55° C. for 16 h. Cool the mixture to RT and add more bis(triphenylphosphine)palladium(II) chloride (1.31 g, 1.86 mmol), copper(I) iodide (0.356 g, 1.86 mmol) and 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.55 g, 7.42 mmol). Heat the mixture to 60° C. for 3.5 h. Cool the mixture to RT and concentrate under reduced pressure. Dilute the material with DCM (300 mL) and wash with saturated aqueous ammonium chloride solution (100 mL), water (100 mL), and saturated aqueous sodium chloride (100 mL). Dry the solution over MgSO4, filter, and concentrate under reduced pressure. Purify the residue using silica gel chromatography (800 g silica gel column) eluting with 20% to 100% EtOAc in hexanes. Concentrate the purified fractions to give the title compound as a pale orange powder (22.6 g, 86%). LC-ES/MS m/z (35Cl/37Cl) 351.2/353.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[N:32]=[C:31]([CH3:36])[N:30]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:29]=4[C:28]4[CH:44]=[CH:45][CH:46]=[CH:47][C:27]3=4)=[O:25])=[CH:20][C:19]=2[F:48])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:49]>CO.O1CCOCC1>[ClH:49].[ClH:49].[CH2:37]([N:30]1[C:29]2[C:28]3[CH:44]=[CH:45][CH:46]=[CH:47][C:27]=3[N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:19]([F:48])[CH:20]=3)=[O:25])[CH2:35][CH2:34][C:33]=2[N:32]=[C:31]1[CH3:36])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCN(C(=O)OC(C)(C)C)CC3)c(F)c1)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2c(n1Cc1ccccc1)-c1ccccc1N(C(=O)c1ccc(OCCCN3CCNCC3)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
4-{3-[4-(1-Benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-fluoro-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E69.1 (110 mg, 0.17 mmol) was dissolved in methanol (5 ml) and 4M HCl in dioxan (2 ml) was added. The mixture was stirred for 20 h at room temperature then concentrated in vacuo to yield the title compound (105 mg, 100%).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[O:8][N:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:39][C:40](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:41]F>>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:30][CH2:31][N:32]([CH:40]([CH3:41])[CH3:39])[CH2:33][CH2:34]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[O:8][N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)on1
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)no4)cc3)nc2)CC1
Yield: 52 %

Procedure:
N-(4-(3-(3-tert-Butylisoxazol-5-yl)ureido)phenyl)-5-(1-isopropylpiperidin-4-yloxy)picolinamide (63 mg, 52%) was prepared using a procedure analogous to that described in Example 20, substituting N-(4-(3-(3-tert-butylisoxazol-5-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 521 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH:34](C(N5CCN(C)CC5)=O)[CH2:33]4)=[CH:28][CH:27]=3)=[N:23]2)=[CH:18][CH:17]=1.NC1C=CC(N2CCC([C:60]([N:62]3[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]3)=[O:61])CC2)=CC=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH:35]([C:60]([N:62]5[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]5)=[O:61])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: CN1CCN(C(=O)C2CCN(c3ccc(N)cc3)CC2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCCC(C(=O)N5CCN(C)CC5)C4)cc3)nn12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCC(C(=O)N5CCN(C)CC5)CC4)cc3)nn12

Procedure:
The titled compound (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-4-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid was prepared in an analogous fashion to (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid of Example 443c after replacing [1-(4-Amino-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with [1-(4-Amino-phenyl)-piperidin-4-yl]-(4-methyl-piperazin-1-yl)-methanone, to give after purification via reverse phase HPLC (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-4-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid as a brown lyophylate (38 mg, 42%). LC/MS (E/I+) 526.21 (M+H). NMR 1H (DMSO-d6)-10.0 (bs, 1H), 9.5 (bs, 1H), 8.97 (s, 1H), 7.81-7.74 (m, 3H), 7.50-7.11 (m, 5H), 6.97-6.93 (m, 2H), 4.2-3.85 (bm, TFA salt and water provided poor resolution), 3.81 (s, 3H), 3.62-2.85 (bm; smeared as TFA salt), 2.83 (s, 3H), 1.88 (bs, 4H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:9])[N:7]=1
Reactant: C1CCNCC1
Reactant: CC(=O)c1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(c1cccc(Br)n1)N1CCCCC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(6-bromo-pyridin-2-yl)-ethanone (600 mg, 3.01 mmol) in dry CH2Cl2 (20 mL) was added piperidine (0.5 mL) followed by NaBH(OAc)3 (1.3 g, 12.06 mmol) and HOAc (0.7 mL, 6.03 mmol). The mixture was heated at 40° C. for 72 h. The reaction was quenched with 2M Na2CO3 and stirred 1 h. The organic layer was collected, dried over MgSO4 and concentrated in vacuo. This crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (90:10) gave a light yellow solid. MS m/z: 269.2 (M+H). Calc'd. for C12H17BrN2-268.06.
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8].N1C=CN=C1.O>CN(C)C=O>[N:1]([CH2:4][CH2:5][O:6][Si:11]([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [N-]=[N+]=NCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
2. 2-Azidoethanol, 1, (105 g, 1.21 mol), crude from above preparation, and tert-butylchlorodimethylsilane (200 g. 1.33 mol) were dissolved in 200 mL of dry N,N-dimethylformamide (DMF) and stirred under nitrogen. Over a period of 20 min, imidazole (204 g, 3.00 mol) was added portionwise with stirring and the temperature of the reaction rose to about 40° C. The solution was stirred at 40° C. under nitrogen for 24 h. The reaction mixture was cooled to room temperature, poured into 1 L of water, and extracted with pentane (4×300 mL). The pentane layers were dried over anhydrous sodium sulfate, concentrated on a rotary evaporator at 25° C., and distilled at reduced pressure through a 4 in. Vigreux column to give 230 g (1.14 mol, 94.7%) of 1-azido-2-(tert-butyldimethylsiloxy)ethane, 2: bp 37°-39° C. (0.02 mm); IR (CH2Cl2) 2940, 2860, 2120, 1115, 940, 840 cm10-1,1H NMR (CDl3, Me4Si) δ 0.09 6H,s), 0.92 (9H,s), 3.27 (2H,t,J=5 Hz), 3.80 (2H,t,J=5 Hz); proton decoupled 13C NMR (CDCl3, Me4Si)) δ-5.54, 18.18, 25.77, 53.16, 62.59.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][C@@H:8]([C:10]([OH:12])=O)[NH2:9])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:15]([N:19]=[C:20]=[O:21])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([N:19]1[C:10](=[O:12])[CH:8]([CH2:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:9][C:20]1=[O:21])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN=C=O
Reactant: Cc1ccc(C[C@H](N)C(=O)O)s1
Agent: [Na+]
Agent: [OH-]
Product: CCCCN1C(=O)NC(Cc2ccc(C)s2)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
DL-β-(5-Methylthiophen-2-yl)alanine (4.1 g; 0.022 mole) was dissolved in 2 N sodium hydroxide solution (11 ml; 0.022 mole), cooled to 0° C. and n-butylisocyanate (3.75 ml; 0.033 mole) added gradually maintaining the temperature at 0° C. for 2 hours. The mixture was allowed to come to room temperature and stirred overnight. The mixture was filtered (solid discarded) and the filtrate washed with ether. The washed filtrate was acidified with concentrated hydrochloric acid (11 ml) and heated on a steam bath for 1 hour. After cooling to room temperature the resultant solid was separated by filtration, water washed and dried. Recrystallisation from ethyl acetate gave the title compound. Yield 4.2 g (72%), m.p. 107° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1cccc(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1cccc(OC)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3-methoxy-phenyl)-acetic acid methyl ester (1.07 g, 5.94 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (14.8 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.37 g, 6.53 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.16 mL). The reaction mixture was stirred at −78° C. for 3 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. At this time, the reaction was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. This solution was diluted with water (100 mL) and extracted into ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid methyl ester (1.39 g, 89.1%) as a clear oil: EI-HRMS m/e calcd for C16H22O3 (M+) 262.1568, found 262.1561.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C=O.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1]([N:11]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:22])[O:21][CH2:25]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Product: O=C1OCN(C(=O)OCc2ccccc2)[C@H]1Cc1ccccc1

Procedure:
Following the procedure of Ben-Ishai (J. Am. Chem. Soc., 1957, 79, 5736), N-Cbz-L-phenylalanine (10.0 gm, 33.4 mmol), paraformaldehyde (3.0 gm, 100.2 mmol), and p-toluenesulfonic acid (0.64 gm, 3.3 mmol) were suspended in toluene (150 ml). The reaction was brought to reflux and water removed azeotropically through the agency of a Dean-Stark trap until collection of water ceased (0.5-2.0 h). After cooling, the reaction mixture was diluted with ethyl ether, washed (1X, saturated aqueous NaHCO3 ; 1X, brine), dried (Na2SO4), filtered, and concentrated in vacuo to provide a solid after cooling. Recrystallization from ethyl acetate/hexanes provided, after the collection of two crops, the pure title compound (9.26 gm, 89%). m.p.=85.5°-86.5° C.; MS (CI) (M+NH4)+ =329, (M+H)+ =312; Anal. Calcd. for C18H17NO4 : C, 69.44; H, 5.50; N, 4.50. Found: C, 69.33; H, 5.48; N, 4.40.