Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[N:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([O:41]CC)=[O:40])[CH2:26][C:27]4[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=4)=[O:23])[CH2:18][CH2:17]3)[CH2:11][CH2:10][C:9]=2[CH:44]=1.Cl>O.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[N:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=[O:40])[CH2:26][C:27]4[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=4)=[O:23])[CH2:18][CH2:17]3)[CH2:11][CH2:10][C:9]=2[CH:44]=1
Reactant: CCOC(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3cc(OC)ccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)O)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.11 g (4.50 mmol) LiOH in 50 mL water was added to a solution of 1.80 g (2.94 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-ethoxycarbonyl-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL THF and the reaction mixture was stirred for 3 h at RT. The THF was eliminated i. vac., diluted with 100 mL water and acidified with 1 M HCl. The substance precipitated was suction filtered, washed with 50 mL water and dried in the vacuum drying cupboard at 65° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8]O[C:6](=O)[CH:5]=1)[CH3:2].[C:16]1(=[O:23])C=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1>C1C(Cl)=CC=C(Cl)C=1.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:20](=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:19](=[O:22])[CH:18]=[CH:17][C:16]2=[O:23])[CH3:2]
Reactant: CCOC(=O)c1coc(=O)cc1OCC
Reactant: O=C1C=CC(=O)C=C1
Agent: O=[Mn]=O
Solvent: Clc1ccc(Cl)cc1
Product: CCOC(=O)c1cc2c(cc1OCC)C(=O)C=CC2=O

Procedure:
0.42 g (0.002 mol) of ethyl 4-ethoxy-2-oxo-2H-pyran-5-carboxylate, 1.08 g (0.01 mol) of 1,4-benzoquinone and 0.54 g (0.0062 mol) of MnO2 in 4.8 ml of dichlorobenzene are heated at 180° C. for 12 hours. The resulting reaction mixture is chromatographed over a column of 30 g of silica gel 60 (mobile phase 99:1 CH2Cl2 /acetone, 0.3 bar excess pressure). This gives 0.41 g (75.9%) of crystals of melting point 60°-62° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](=O)[C:9](=O)[NH:10]2)=[CH:6][C:5]=1[F:15])[CH3:2].ClC1C=C(F)C=C2C=1NC=C2>>[CH2:1]([S:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[F:15])[CH3:2]
Reactant: CCSc1cc2c(cc1F)C(=O)C(=O)N2
Agent: Fc1cc(Cl)c2[nH]ccc2c1
Product: CCSc1cc2[nH]ccc2cc1F

Procedure:
6-Ethylthio-5-fluoroindole was prepared from 6-ethylthio-5-fluoroindole-2,3-dione according to the method described in the synthesis of 7-chloro-5-fluoroindole as a pale green oil (0.49 g, 23%): IR νmax (film)/cm−1 3426, 2969, 2927, 1565, 1471, 1454, 1307, 1140 and 1101; NMR δH (400 MHz, CDCl3) 1.26 (3H, t, J 7.5), 2.91 (2H, q, J 7.5 Hz), 6.48-6.51 (1H, m), 7.23 (1H, t, J 2.5 Hz), 7.31 (1H, d, J 10.0 Hz), 7.46 (1H, d, J 6.0 Hz), 8.01-8.25 (1H, brm).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH:11]([C:22](OC)=[O:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[BH4-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:10][CH:11]([CH2:22][OH:23])[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CC(O[Si](C)(C)C(C)(C)C)CN(C(=O)OC(C)(C)C)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-tert-butyl 3-methyl 5-(tert-butyldimethylsilyloxy)piperidine-1,3 from step A in THF (100 mL) was treated with LiBH4 (0.84 g, 38.5 mmol) at 0° C. stirring for 2 hours, warmed to room temperature, and then treated with citric acid (1M) till pH=4. The volatiles were removed in vacuo, and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound. MS (m/z): 246 (M-Boc+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12].C(N(CC)CC)C.N([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N+]=[N-]>C1COCC1>[C:27]([O:26][C:24]([NH:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: NCC1=C(CCC(=O)O)CC=CC1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1=C(CCC(=O)O)CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of β-(2-aminomethyl-1,4-cyclohexadienyl)propionic acid (1.40 L g., 7.7 mmoles) and triethylamine (2.02 g., 20 mmoles) in 50% aqueous THF (20 ml.) was added a solution of t-butyl azidoformate (1.43 g., 10 mmoles) in THF (5 ml.) and the reaction mixture was stirred overnight at room temperature. The mixture was washed with ether (2×20 ml) and the aqueous layer was acidified to pH 2 with dil. hydrochloric acid. The mixture was extracted with chloroform (4×30 ml.) and the combined extracts were washed with water and dried. Evaporation of the extracts under reduced pressure afforded β-(2-tert.-butoxycarbonylaminomethyl-1,4-cyclohexadienyl)propionic acid as a colorless oil. Yield, 2.10 g. (97%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[C:33]([CH3:34])=[CH:32][N:31]=[C:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:34][C:33]1[C:28]([CH3:27])=[N:29][C:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:31][CH:32]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(-c2ccccc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(-c2ccccc2)ncc1CBr
Yield: 92 %

Procedure:
5.54 g (31.1 mmol) of N-bromosuccinimide (NBS) and 6 mg of dibenzoyl peroxide were added to a solution of 5.53 g (30 mmol) of 4,5-dimethyl-2-phenylpyrimidine in 110 ml of CCl4, and the mixture was warmed to the boiling point for 5 minutes with stirring and irradiation with a daylight lamp with increased short-wave content (type: Osram UltraVitalux, 300 W, GUR 53). The NBS had then been consumed and converted into specifically light succinimide. It was filtered off under suction at room temperature and washed with a little CCl4. The filtrate was evaporated in vacuo, the residue was dissolved in 100 ml of diisopropyl ether, the solution was clarified over kieselguhr, and the clear filtrate was again evaporated in vacuo. 7.70 g, 94.5% purity according to the 1H NMR spectrum, of 5-bromomethyl-4-methyl-2-phenylpyrimidine (=92% yield), melting point 65°-66° C., were obtained, analysis: C12H11BrN2 (MW 263.15) calc. C 54.77, H 4.21, Br 30.37, N 10.65; found C 53.5, H 3.9, Br 31.3, N 10.0%.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:11]2[C:6](=[C:7]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>ClCCl>[CH2:3]1[C:11]2[C:6](=[C:7]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36]([N:35]([CH3:39])[CH3:34])=[O:37])[CH2:24][CH2:25]4)[CH2:16][CH2:17]3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CN(C)C(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.4 g (1 mmol) trans-4-{2-[4-(indan-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dichloromethane (30 ml), triethylamine (0.56 ml, 4 mmol) was added followed by 0.12 ml (1.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 24 hours at room temperature. The solution was extracted with water (2×8 ml), dried and evaporated in vacuo. The residue was purified using flash chromatography giving the title compound (0.2 g, 50%), melting at 150-2° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17]C)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cc(Br)ccc2O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 190 mg (0.6 mmol) of 5-bromo-2-methoxy-4'-methylbenzophenone (Compound H) in 15 mL of dichloromethane was added 0.9 mL (0.9 mmol) of boron tribromide (1M in dichloromethane) at ambient temperature. The orange solution was stirred at ambient temperature for 3 hours under a blanket of argon. The reaction mixture was cooled to -78° C., quenched with methanol and then extracted between ethyl acetate and sat. NaHCO3 (aq.) solution. The layers were separated and the organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow solid. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]1[NH:13][CH2:14][CH2:15][C:6]21[CH3:16].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C@H:7]1[N:13]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:15][C@@:6]21[CH3:16]
Reactant: COc1ccc2c(c1)C1(C)CCNC1N2C
Reactant: BrCCc1ccccc1
Product: COc1ccc2c(c1)[C@]1(C)CCN(CCc3ccccc3)[C@@H]1N2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture, under nitrogen, of 8.73 g of 1,2,3,3a,8,8a-hexahydro-5-methoxy-3a,8-dimethylpyrrolo[2,3-b]indole, 9,25 g of 2-(bromoethyl)benzene and 8.29 g of milled, anhydrous potassium carbonate in 75 ml of degassed, dry dimethylformamide is heated at 70°-75° for 8 hours and thereafter stirred at room temperature overnight. The reaction mixture is decanted into 1.5 liters of water and the product is extracted into ethyl acetate (2×250 ml). The combined organic extracts are washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue is subjected to flash chromatography over silica gel using methanol/ethyl acetate mixtures as eluent. The fractions containing the product are combined and concentrated to afford pure (3aS-cis)-1,2,3,3a,8,8a-hexahydro-5-methoxy-1-(2-phenylethyl)-3a,8-dimethylpyrrolo[2,3-b]indole.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH:2]([CH:3]1[CH2:4][CH2:5][CH:6]([CH3:7])[O:8][CH:10]1[CH:11]=[CH:12][CH3:13])([CH3:9])[CH3:1]
Reactant: C/C=C/C=O
Reactant: CC(C)=CCCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC1OC(C)CCC1C(C)C
Temperature: 122 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
6-Methyl-hept-5-en-2-ol (512 g, 3.8 mol, 96%), toluene (750 ml), and p-toluenesulfonic acid (pTSA, 2.6 g) were charged in a flask and heated to 122° C. Crotonaldehyde (350 g, 5 mol) was fed into the mixture for over 3-4 hours at reflux. Water was removed with a Bidwell-Sterling trap. The reaction mixture was aged for 1 hour. Standard addition and gas chromatography (GC) analysis indicated that about 11% of the starting material 6-methyl-hept-5-en-2-ol was left. Additional crotonaldehyde (35 g, 0.5 mol) was added. The reaction mixture was at reflux for another 45 minutes. About 70 ml water was collected and the final temperature was about 118° C. GC analysis indicated that about 8% of the starting material 6-methyl-hept-5-en-2-ol was left. The reaction mixture was quenched with water and wash one time with dilute carbonate solution. The consequent rushover process provided the product 3-isopropyl-6-methyl-2-propenyl-tetrahydro-pyran (493 g) with a boiling point of 109 C at a pressure of 25 mmHg.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Br)=[CH:7]2.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]=O)[CH2:19][CH2:18]1)[CH2:15][CH3:16].CC(C)([O-])C.[K+]>>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:24][CH2:23][C@H:20]1[CH2:19][CH2:18][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:22][CH2:21]1)=[CH:7]2
Reactant: Fc1ccc2cc(Br)ccc2c1F
Reactant: CCCC1CCC(CC=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCC[C@H]1CC[C@H](CCc2ccc3c(F)c(F)ccc3c2)CC1

Procedure:
The procedure of Example 14 was followed except that 5,6-difluoro-2-bromonaphthalene was used instead of 6-fluoro-2-bromonaphthalene, 4-propylcyclohexaneethanal was used instead of 4-propylcyclohexanene and isomerization with potassium t-butoxide was not effected to obtain 5,6-difluoro-2-[2-(trans-4-propylcyclohexyl)ethyl]naphthalene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:41][O:42][NH:43][CH3:44].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([O:34][CH2:35][C:36]([N:43]([O:42][CH3:41])[CH3:44])=[O:37])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CNOC
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetic acid (0.9 g), N-methoxymethanamine hydrochloride (0.25 g), 1-hydroxybenzotriazole (0.39 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.49 g), triethylamine (0.36 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.75 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14]C)=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[BrH:16]>>[BrH:16].[BrH:16].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Agent: Br
Product: Oc1ccc(Cl)cc1N1CCNCC1
Temperature: 25 °C

Procedure:
A suspension of 5.5 g of 1-(5-chloro-2-methoxyphenyl)piperazine in 40 mL of 62% hydrobromic acid was stirred at reflux for 30 hours. After cooling to room temperature the mixture was filtered by suction and the solid was washed on the funnel with acetone affording 6.02 g of the title compound. M.p.>270° C. (ethanol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[CH:10][C:11]1[C:16]([Br:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[Br:19].BrC1C=C(C)C=C(Br)C=1C=O.Cl.[F:32]C1C=CC(NN)=CC=1>>[F:32][C:6]1[CH:5]=[CH:4][C:3]([NH:8][N:9]=[CH:10][C:11]2[C:16]([Br:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[Br:19])=[CH:2][CH:7]=1
Reactant: Cc1cc(Br)c(C=NNc2ccccc2F)c(Br)c1
Reactant: NNc1ccc(F)cc1
Agent: Cc1cc(Br)c(C=O)c(Br)c1
Agent: Cl
Product: Cc1cc(Br)c(C=NNc2ccc(F)cc2)c(Br)c1

Procedure:
Similarly prepared to Intermediate 25 from 2,6-dibromo-4-methylbenzaldehyde and (4-fluorophenyl)hydrazine hydrochloride.
Reaction SMILES: [CH2:1]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.Br[CH2:23][C:24]([O:26]CC)=[O:25]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CCN(CC)CC>[NH2:8][CH2:23][C:24]([OH:26])=[O:25].[CH2:1]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc(CNNCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NCC(=O)O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of dibenzylhydrazine (5.30 g, 25.0 mmol) and THF (50 mL) and TBAI (0.46 g, 1.25 mmol) was added BrCH2CO2Et (2.64 mL, 23.8 mmol) and Et3N (3.32 mL, 23.8 mmol). The reaction mixture was stirred at 60° C. for 7 hours, an additional 0.3 eq. of base and electrophile were added (BrCH2CO2Et, 0.83 mL, 7.5 mmol and Et3N, 1.0 mL, 7.5 mmol). The reaction mixture was held overnight at R/T, an additional 0.3 eq. of each reagent was added and the reaction mixture was stirred at 60° C. for 4 more hours. The reaction mixture was partitioned with CH2Cl2, and the isolated organic fraction was washed with brine three (3 times), dried over Na2SO4, and concentrated in vacuo to afford 7.21 g, 24.2 mmol, (97%) of a crude oil.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21]C(=O)OC(C)(C)C)[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[ClH:1].[ClH:1].[CH2:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH2:21])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(Cc2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1CCCN(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 95 %

Procedure:
A 4N-hydrochloric acid/1,4-dioxane solution (4 ml) was added to a solution of tert-butyl 1-benzyl-3-piperidinylcarbamate (0.448 g, 1.54 mmol) in tetrahydrofuran (4 ml) and stirred overnight. After the solvent was distilled off under reduced pressure, diethyl ether was added to the residue to precipitate a solid, and the supernatant was decanted and then dried under reduced pressure to obtain 1-benzyl-3-piperidinamine dihydrochloride (0.384 g, 95%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH3:34])=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:29]([C:17]1[C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]([CH2:35][CH2:36][N:37]([CH3:38])[CH3:39])[CH3:34])=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cnn4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
A solution of acryloyl chloride (0.087 mL, 1M, THF, 0.09 mmol) was added dropwise to a mixture of 2-{[5-amino-4-(2-dimethylaminoethyl-methylamino)-2-methoxyphenyl]-amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile (Intermediate 121, 0.036 g, 0.08 mmol) and DIPEA (0.017 mL, 0.09 mmol) in THF (5 mL) which was cooled to 0° C. The mixture was stirred at 0° C. for 3 h, then concentrated in vacuo. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 have crude product which appeared to contain the hydrochloride salt of DIPEA. The material was dissolved in CH2Cl2 (10 mL) and stirred with sat. NaHCO3 solution (10 mL). The phases were separated and the organic solution was concentrated in vacuo to give the title compound (24 mg, 60%) as a yellow gum; 1H NMR: (CDCl3) 2.22 (6H, s), 2.26 (2H, dd), 2.67 (3H, d), 2.77-2.86 (2H, m), 3.81 (3H, s), 5.61 (1H, dd), 6.16-6.35 (2H, m), 6.76 (1H, s), 6.88 (1H, d), 7.23 (1H, s), 7.65 (1H, s), 8.50 (2H, dd), 8.59 (1H, s), 9.02 (1H, s), 9.28 (1H, s), 10.08 (1H, s); m/z: ES+ MH+ 512.29.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.C(OCC)(=O)C>[O-:34][N+:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc[n+]([O-])cc1)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Benzyl 4-[(4-pyridinylamino)carbonyl]-1-piperidinecarboxylate (EXAMPLE 1, Step 1) (615 mg, 1.81 mmol) was dissolved in CH2Cl2 and treated with mCPBA (3.12 g, 18.10 mmol) and aged 18 h. The reaction was diluted with ethyl acetate and washed with sat. NaHCO3. The organics were separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to afford benzyl 4-{[(1-oxido-4-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:29]([O:31]CC1C=CC=CC=1)=[O:30])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21](=[O:23])(=[O:22])[N:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19](=[O:28])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[S:21](=[O:22])(=[O:23])[N:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19](=[O:28])[CH2:18]2)=[CH:13][CH:12]=1)[C:29]([OH:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)O
Yield: 65.1 %

Procedure:
To a solution of benzyl N-(tert-butoxycarbonyl)-4-(2-tert-butyl-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)-L-phenylalaninate (1.3 g, 2.4 mmol) in ethanol (35 mL) in a parr shaker, palladium (0.700 g, 6.58 mmol) (Pd, 10% by weight on activated carbon) was added and hydrogenated overnight at 50 psi. The suspension was filtered through celite and concentrated to give the crude product. The crude was purified on preparative LCMS to give the product (0.71 g, 65%). LCMS found for C21H3N2O7S (M+H)+: m/z=455.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].S(Cl)(Cl)=O.[CH3:27]O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]([O:22][CH3:27])=[O:21])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CO
Reactant: CCOc1ccc(-c2nc(CCC(=O)O)cs2)cc1OCC
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(-c2nc(CCC(=O)OC)cs2)cc1OCC
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution (2.3 l) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionic acid (254.5 g) in methanol was ice-cooled, and 58 ml of thionyl chloride was added dropwise. After completion of the addition, the resulting mixture was heated under reflux for 2 hours and cooled to room temperature. The solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent was distilled off under reduced pressure, and the residue was recrystallized from an ethyl acetate/n-hexane mixed solvent, to thereby obtain 219.35 g (yield: 68%) of methyl 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionate as a white powder.