Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN1CC[O:18][CH2:17][CH2:16]1.C(Cl)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:17](=[O:18])[CH3:16])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCOCC1
Reactant: Nc1cc(-c2cccc(F)c2)n[nH]1
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2cccc(F)c2)n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
To a solution of 3-(3-fluorophenyl)-1H-pyrazol-5-amine (6.5 g, 36 mmol) and N-methylmorpholine (9.7 mL, 88 mmol) in CH2Cl2 (150 mL) was added acetyl chloride (6 mL, 85 mmol) dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1 d. The reaction mixture was concentrated in vacuo. MeOH (50 mL) and THF (50 mL) were added to the residue, followed by the addition of NaOH solution (aq. 2.5 M, 42.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 min and HCl solution was added until pH reached ˜6. The organic solvents were evaporated in vacuo. The solid from the resulting aqueous suspension was collected by filtration, yielding the title compound as a solid (7.6 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([Cl:22])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.CO.C[C:27](C)([O-:29])C.[K+].O1CCOCC1>O>[CH3:27][O:29][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([Cl:22])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(Cl)nc3ccc(Cl)cc23)cc1Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(NCc2ccc(OC)c(Cl)c2)c2cc(Cl)ccc2n1
Yield: 75.9 %

Procedure:
A mixture comprising 200 mg of 2,6-dichloro-4-(3-chloro-4-methoxybenzyl)aminoquinoline, 0.5 ml of methanol, 200 mg of potassium t-butoxide and 3 ml of 1,4-dioxane was heated under reflux for one hour and cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 10 to 30% ethyl acetate/hexane and recrystallized from ethyl acetate/hexane to give 150 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=2)O1>>[C:43]([C:40]1[N:41]=[CH:42][C:37]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:12][CH:11]=2)=[O:8])=[CH:38][N:39]=1)#[N:44]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Product: N#Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile to afford a yellow solid. UPLC-MS (condition 1) tR=2.54 min, m/z=485.0 [M+H]+, m/z=4831.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.67 (m, 1H) 1.82-1.93 (m, 1H) 2.21-2.30 (m, 1H) 2.98 (dd, J=11.00, 7.09 Hz, 1H) 3.14-3.30 (m, 4H) 3.33-3.41 (m, 1H) 4.62 (t, J=5.26 Hz, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.17 (d, J=2.20 Hz, 1H) 8.82 (d, J=2.20 Hz, 1H) 9.10 (s, 2H) 10.20 (s, 1H).
Reaction SMILES: [NH:1]([C:8]1[N:12]=[C:11]([SH:13])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[NH:1]([C:8]1[N:12]=[C:11]([S:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1nc(Nc2ccccc2)n[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CSc2nc(Nc3ccccc3)n[nH]2)cc1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a stirring solution of the compound of Example 1 (c) (23 mg, 0.12 mmol) in 1.2 mL of DMF was added K2CO3 (17 mg, 0.12 mmol), followed by benzyl bromide (20 mg, 0.12 mmol). The mixture was stirred overnight, filtered, and purified by preparative HPLC to afford the title compound as a white solid (30 mg, 70%). 1H-NMR (400 MHz, d6-DMSO) δ9.30 (broad singlet, 1H), 7.47 (d, 2H, J=8.1 Hz), 7.39 (d, 2H, J=7.3 Hz), 7.31 (t, 2H, J=7.3 Hz), 7.23 (quartet, 3H, J=7.3 Hz), 6.82 (t, 1H, J=7.3 Hz), and 4.3 (s, 2H).
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].[CH2:33]1COCC1>O>[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:33][C:7]2[CH:8]=[CH:3][CH:4]=[C:5]([O:9][CH3:10])[N:6]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(CBr)ccn1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(OC)n1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 100-mL round-bottomed flask were added 4-(bromomethyl)-2-methoxypyridine (1.98 g, 9.80 mmol), ethyl N-(diphenylmethylene)glycinate (2.62 g, 9.80 mmol, Acros, N.J.) and 5N sodium hydroxide (9.80 mL, 49.0 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 24 h, diluted with water (30 mL), and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give ethyl N-(diphenylmethylidene)-3-(6-methoxy-2-pyridinyl)alaninate (2.58 g) as a light-yellow oil.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7].[H-].[Na+].S(O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)[CH:25]=1)(=O)(=O)C.C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[Cl:1]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[CH:25]=2)[CH:10]=1)[CH2:6][CH3:7]
Reactant: CS(=O)(=O)OCc1cccc(-c2ccsc2)c1
Reactant: CCN(C/C=C/Cl)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C/C=C/Cl)Cc1cccc(OCc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a solution of 280 mg (1.24 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-hydroxybenzylamine in 2.5 ml of tetrahydrofuran was added 74.4 mg (1.86 mmol) of 60% oily sodium hydride under ice cooling. The mixture was stirred for 20 minutes at room temperature, ice-cooled, treated with a solution of 333 mg (1.24 mmol) of 3-(3-thienyl)benzyl mesylate in 2.5 ml of dimethylformamide, and stirred for 1.5 hours at room temperature. The reaction mixture was poured into 40 ml of ethyl acetate, washed with 20 ml ×2 of water and 20 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate =9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 460 mg (yield: 93%) of the above identified compound as an oil.
Reaction SMILES: [CH3:1][CH:2]([S:11][C:12]#[N:13])[C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[BrH:15].C(O)(=O)C>>[Br:15][C:12]1[S:11][C:2]([CH3:1])=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: Br
Reactant: CC(SC#N)C(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc(Br)nc1-c1ccccc1
Yield: 73.1 %

Procedure:
A solution of 1-methyl-2-oxo-2-phenylethyl thiocyanate (1.00 g, 5.23 mmol) in 25% hydrogen bromide/acetic acid (10 ml) was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 971 mg (73.1%) of the desired product as an oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][CH:9]=[CH:8][NH:7][C:6]1=[O:20])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][Cl:31]>C(OCC)(=O)C.O>[ClH:31].[C:1]([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:6]1=[O:20])(=[O:3])[CH3:2]
Reactant: COc1ccc([C@H]2SC=CNC(=O)[C@H]2OC(C)=O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@H]2SC=C(c3ccccc3)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Product: Cl
Temperature: 25 °C
Yield: 167.7 %

Procedure:
A mixture of 3.9 g (0.01 mol) of rac.-cis-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-1, 4-thiazepin-5(4H)-one, 1.5 g of powdered potassium carbonate and 1.3 g (0.011 mol) of 2-dimethylaminoethyl chloride in 100 mL of ethyl acetate was stirred and heated at reflux for 2 hrs, then twice an additional 0.5 g of 2-dimethylaminoethyl chloride was added at 2 hr intervals. The mixture was heated at reflux for a total of 12 hrs, cooled to room temperature and diluted with water. The organic solution was separated, washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure. The residue in acetone was treated with hydrogen chloride (anhydrous) and the crude hydrochloride salt after recrystallization from acetone afforded 4.0 g (80%) of rac.-cis-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-4 -[2-(dimethylamino)ethyl]-3-phenyl-1,4-thiazepin-5(4H)-one hydrochloride, mp 125°-127°.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH2:20][CH2:19][CH:18]([C:21](=O)[CH2:22][F:23])[C:17]1=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:9]([N:16]1[CH2:20][CH2:19][CH:18]([CH:21]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:22][F:23])[C:17]1=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: O=C(CF)C1CCN(Cc2ccccc2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1C(C(CF)NCc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Benzylamine (3.9 mL, 35.7 mmol) was added to a solution of 1-benzyl-3-(2-fluoro-acetyl)pyrrolidin-2-one (7.00 g, 29.8 mmol, Example 15) in dichloroethane (150 mL). The solution was cooled to 0° C. and sodium triacetoxyborohydride (8.20 g, 38.7 mmol) added. The reaction mixture was warmed to room temperature and stirred overnight, then washed with aqueous sodium bicarbonate solution and brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (99:1 to 97:3 dichloromethane/methanol) to afford the title compound (7.2 g) as a mixture of diastereomers. MSCI: m/z 327 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[CH3:24])=[CH:9][N:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl.Cl>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:32]([C:9]2[N:10]3[C:15]([CH:14]=[CH:13][CH:12]=[CH:11]3)=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]=2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[CH3:24])=[O:34])[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(F)cccc1Cc1cn2ccccc2c1C1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1c(F)cccc1Cc1c(C2CCCCC2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
The compound of step 2 (0.488 g, 1.52 mmol) was dissolved in DCM (15.2 ml) under argon and cooled at 0° C. Pyridine (0.12 ml, 1.52 mmol) and triphosgene (0.45 g, 1.52 mmol) were added and the mixture stirred at room temperature for 2 h. The mixture was then cooled to 0° C. and triethylamine (0.85 ml, 6.07 mmol) and 1-tert-butoxycarbonyl-piperazine (1.13 g, 6.07 mmol) were added. The mixture was stirred at room temperature overnight, then diluted with 1 N hydrochloric acid and extracted with DCM. The organic phases were washed with a saturated solution of sodium hydrogencarbonate and twice with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (cyclohexane/EA, 100:0, then 50:50) to give 0.686 g of 4-[1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a beige foam. The obtained product was dissolved in 10 ml of DCM, the solution cooled to 0° C. under a nitrogen atmosphere and a solution of TFA (1.91 ml, 25.7 mmol) in 1.91 ml of DCM added. After stirring at room temperature overnight, the mixture was evaporated to dryness under reduced pressure and the residue two times admixed with toluene and evaporated to dryness again. The residue was purified by chromatography on silica gel (DCM/MOH, 9:1, containing 1% of ammonia) to give 0.600 g of [1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizin-3-yl]-piperazin-1-yl-methanone. For conversion into the hydrochloride, the obtained product was dissolved in 15 ml of DCM and a 4 N solution of hydrogen chloride in dioxane (0.69 ml, 2.77 mmol) was added. The solution was stirred for 1 h at room temperature and concentrated to dryness under reduced pressure. The solid was triturated three times with diethyl ether, filtered and dried in vacuo at 65° C. to give 0.422 g of the title compound in the form of [1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizin-3-yl]-piperazin-1-yl-methanone hydrochloride as an off-white powder with the following characteristics:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.Cl.[OH:34][C:35]1([C:39]([NH:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH2:38][NH:37][CH2:36]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:37]2[CH2:38][C:35]([OH:34])([C:39]([NH:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH2:36]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: C=CCNC(=O)C1(O)CNC1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCNC(=O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 0.08 h
Yield: 9.2 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (1.20 g, 3.05 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (1.20 g, 9.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (701 mg, 3.66 mmol) were dissolved in DMF (10 mL). The mixture was stirred at ambient for 5 minutes and then 3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05 mmol) in DMF (5 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 60-85% ethyl acetate in hexanes) and then reverse phase HPLC gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide (150 mg, 0.282 mmol, 9% yield): 1H NMR (400 MHz, d6-DMSO): 8.64 (br s, 1H), 8.13 (t, 1H), 7.58 (dd, 1H), 7.38 (dd, 1H), 7.34-7.28 (m, 1H), 7.21-7.12 (m, 1H), 6.84 (br s, 1H), 6.72 (ddd, 1H), 5.83-5.72 (m, 1H), 5.10-4.99 (m, 2H), 4.38 (d, 1H), 4.20 (d, 1H), 4.02 (d, 1H), 3.86 (d, 1H), 3.73-3.68 (m, 2H); MS (EI) for C20H17F3IN3O3: 532 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11]1[N:16]=[C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])[N:14]=[C:13]([Cl:28])[CH:12]=1.CN(C)C=O>ClCCl>[ClH:28].[CH3:10][C:11]1[N:16]=[C:15]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])[N:14]=[C:13]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[CH:12]=1
Reactant: Cc1cc(F)ccc1N
Reactant: Cc1cc(Cl)nc(N2CCc3ccccc3C2C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Nc2ccc(F)cc2C)nc(N2CCc3ccccc3C2C)n1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methyl-4-fluoroaniline(1.1 ml, 10.2 mmol) was added to a mixture solution of 6-methyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(1.5 g, 5.5 mmol) and dimethylformamide(10 ml). The reaction solution was stirred for 3 hours and cooled to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. Dichloromethane layer was separated, basified with aqueous sodium hydroxide solution, washed with water, and dried and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography to give a free base form of titled compound as an oily form. The free base form of titled compound was dissolved in ethyl ether, then hydrochloric acid was added thereto. The resulting solid was filtered, dried under reduced pressure to give 0.9 g of titled compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][C:3]=1[F:17].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CS(C)=O>O>[F:17][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)[N:9]([CH3:12])[CH:8]=[C:7]([C:13]([OH:15])=[O:14])[C:6]2=[O:16]
Reactant: CN1CCNCC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C)CC1
Yield: 40.7 %

Procedure:
2.55 g (0.01 mol) of 7-chloro-6-fluoro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 4.5 cm3 of 1-methylpiperazine (0.011 mol) and 32 cm3 of DMSO were heated at 110° C. for 4 hours. After cooling, the mixture was taken up in 150 cm3 of water. The crystalline precipitate was filtered off, washed and recrystallised from 100 cm3 of methylcellosolve. 1.3 g of 6-fluoro-1-methyl-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, m.p. 304° C. (decomposition), were obtained.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:17]2[C:18]3[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:27]([C:24]1[S:23][C:19]2[N:20]=[CH:21][N:22]=[C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[O:8][CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:30])[CH2:7][CH2:6]3)[C:18]=2[C:25]=1[CH3:26])=[O:28]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Reactant: CN(C)CCCN
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12

Procedure:
Prepared analogously to 33.3 from 0.050 g 4-[2-(4,4-difluoro-cyclohexyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 33.2) and 0.126 ml N,N-dimethyl-propane-1,3-diamine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:46])[CH2:44][CH3:45]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:46][CH2:43][CH2:44][CH3:45])=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCCN
Product: CCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and propylamine (10.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-propylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (28.7 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]([CH3:43])=[CH:10][C:11]1[N:12]([CH2:41][CH3:42])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:40])(=[O:39])[N:30]([CH2:35][CH2:36][O:37][CH3:38])C(C)(C)C)=[CH:25][CH:24]=3)[N:17]=2)=[CH:14][N:15]=1.C1(OC)C=CC=CC=1>>[CH3:8][C:9]([CH3:43])=[CH:10][C:11]1[N:12]([CH2:41][CH3:42])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29](=[O:39])(=[O:40])[NH:30][CH2:35][CH2:36][O:37][CH3:38])=[CH:27][CH:28]=3)[N:17]=2)=[CH:14][N:15]=1
Reactant: CCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)N(CCOC)C(C)(C)C)cc3)n2)cnc1C=C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)cnc1C=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Aqueous TFA (90%) was added to a mixture of 4-[2-(2-methylprop-1-enyl)-1-ethylimidazol-5-yl]-2-{4-[N-(2-methoxyethyl)-N-t-butylsulphamoyl]anilino}pyrimidine (Method 111; 70 mg, 0.14 mmol), and anisole (90 μl, 0.83 mmol), and the mixture stirred at ambient temperature for 1 hour. The volatiles were evaporated and the residue dissolved in water. The solution was neutralised (NaHCO3), and extracted with EtOAc. The extracts were dried, and the solvent evaporated to give the title compound (30 mg, 41%). NMR: 1.19 (t, 3H), 1.99 (s, 3H), 2.15 (s, 3H), 2.89 (q, 2H), 3.18 (s, 3H), 3.30-3.28 (m, 2H), 4.65 (q, 2H), 6.28 (s, 1H), 7.25 (d, 1H), 7.50 (t, 1H), 7.70 (d, 2H), 7.85 (s, 1H), 7.89 (d, 2H), 8.45 (d, 1H), 9.85 (s, 1H); m/z: 457.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([C:12]1[N:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][N:13]=1)C(=O)OC(C)(C)C.FCCNC1C=CC(C2OC3C=C(OC)C=CC=3N=2)=CN=1>>[F:1][CH2:2][CH2:3][NH:4][C:12]1[N:13]=[CH:14][C:15]([C:18]2[O:19][C:20]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:16][N:17]=1
Reactant: COc1ccc2nc(-c3cnc(N(CCF)C(=O)OC(C)(C)C)nc3)oc2c1
Agent: COc1ccc2nc(-c3ccc(NCCF)nc3)oc2c1
Product: COc1ccc2nc(-c3cnc(NCCF)nc3)oc2c1

Procedure:
The title compound was synthesized from tert-butyl (2-fluoroethyl)[5-(6-methoxy-1,3-benzoxazol-2-yl)pyrimidin-2-yl]carbamate according to the procedure described for N-(2-fluoroethyl)-5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine to give 29.8 mg. MS m/z 289 (M+H).