Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(=O)CC(CCC)=N1.ClC1C2C(=CC=CC=2)[N+]([O-])=CC=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]/[C:26](=[C:34]2/[C:35]([CH2:41][CH2:42][CH3:43])=[N:36][N:37]([CH3:40])[C:38]/2=[O:39])/[CH:25]=1.[C:44]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([SH:54])=[CH:50][CH:49]=1)(=[O:46])[CH3:45]>C(OC(=O)C)(=O)C.C(O)C>[CH3:40][N:37]1[C:38](=[O:39])/[C:34](=[C:26]2\[NH:27][C:28]3[C:33]([C:24]([S:54][C:51]4[CH:50]=[CH:49][C:48]([NH:47][C:44](=[O:46])[CH3:45])=[CH:53][CH:52]=4)=[CH:25]\2)=[CH:32][CH:31]=[CH:30][CH:29]=3)/[C:35]([CH2:41][CH2:42][CH3:43])=[N:36]1
Reactant: CCCC1=NN(C)C(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: CCCC1=NN(C)C(=O)C1
Agent: [O-][n+]1ccc(Cl)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCCC1=NN(C)C(=O)/C1=C1/C=C(Sc2ccc(NC(C)=O)cc2)c2ccccc2N1
Temperature: 180 °C

Procedure:
1-Methyl-3-n-propyl 2-pyrazolin-5-one (0.2 g, 1.4 mmol) and 4-chloroquinoline N-oxide (1.4 mmol) were stirred in acetic anhydride (2 mL) at ambient temperature for 2-3 hours. The reaction mixture was concentrated and carried out to the next step without further purification. The resulting (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-1-methyl-3-propyl-1H-pyrazol-5(4H)-one (0.71 mmol) was dissolved in ethanol (0.5 mL) and 4-acetamidothiophenol (0.13 g, 0.78 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The mixture was then concentrated and purified by LC-MS to give Example 56. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.67 (t, J=7.45 Hz, 3H) 1.23-1.32 (m, J=7.52, 7.52, 7.52, 7.52 Hz, 2H) 2.00 (t, J=7.58 Hz, 2H) 2.09 (s, 3H) 3.29 (s, 3H) 6.53 (s, 1H) 7.52-7.57 (m, 1H) 7.67-7.76 (m, 3H) 7.80-7.90 (m, 3H) 8.06 (d, J=8.08 Hz, 1H) 10.34 (s, 1H); ESI-MS: m/z calc'd for C24H24N4O2S 432.54. found 433.3 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11].O>C(Cl)Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11])[CH2:2]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: O
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 7.0 g (55.0 mmol) of (R)-3-quinuclidinol were suspended in 100 ml of CH2Cl2. After cooling the suspension to 0° C., a solution of 1,1′-carbonyldiimidazole (10.7 g, 66.0 mmol) in 150 mL of CH2Cl2 was added. The reaction mixture was stirred at 0° C. for 4 hours, then water was added (100 ml). The organic layer was separated, washed with water, dried over sodium sulphate and the solvent was evaporated under reduced pressure. The residue oil (13.1 g) was used without further purification.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([N:34]([CH2:40][CH3:41])[CH2:35][CH2:36][NH:37][CH2:38][CH3:39])[CH3:33]>C(Cl)Cl>[CH2:32]([N:34]([CH2:40][CH3:41])[CH2:35][CH2:36][N:37]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:38][CH3:39])[CH3:33]
Reactant: CCNCCN(CC)CC
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: CCN(C=C1C(=O)OC(COC)C2(C)C1=C(O)C(=O)C1=C2C(OC(C)=O)CC2(C)C(O)CCC12)CCN(CC)CC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added N,N-Diethyl-N′-ethyl-ethane-1,2-diamine (50 μL). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 575 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:21]4[CH2:20][CH2:19][CH2:18][C:17](=O)[C:16]=4[CH:15]=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:23].[C:24]([NH2:28])(=[O:27])[CH2:25][CH3:26].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>FC(F)(F)C1C=CC=CC=1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:21]4[CH2:20][CH2:19][CH:18]=[C:17]([NH:28][C:24](=[O:27])[CH2:25][CH3:26])[C:16]=4[CH:15]=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCC4=O)ccc21
Reactant: CCC(N)=O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: FC(F)(F)c1ccccc1
Product: CCC(=O)NC1=CCCc2c1cncc2-c1ccc2c(c1)CCC(=O)N2C
Temperature: 102 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a stirred suspension of 1-methyl-6-(8-oxo-5,6,7,8-tetrahydro-isoquinolin-4-yl)-3,4-dihydro-1H-quinolin-2-one) (919 mg, 3 mmol, example 70) and propionic acid amide (658 mg, 9 mmol) in trifluorotoluene (30 mL) was added trifluoromethane sulfonic acid (585 mg, 3.9 mmol) and the reaction was stirred at 102° C. After 4 h, a solution of trifluoromethane sulfonic acid (158 mg, 1.05 mmol) in trifluorotoluene (5 mL) was added and the reaction mixture stirred for further 8 h. After this time, propionic acid amide (219 mg, 3 mmol) and a solution of trifluoromethane sulfonic acid (158 mg, 1.05 mmol) in trifluorotoluene (5 mL) were added and the stirring continued at 102° C. over night. The reaction mixture was allowed to cool down to room temperature and aq. NaOH 2 M (30 mL) was added. The resulting mixture was extracted with dichloromethane (3×) and the organic phases washed with aq. sat. NaCl solution (2×). The combined organic phases were dried over Na2SO4, filtered and evaporated. Crystallization of the crude product (dichloromethane/ethyl acetate/heptane) afforded the title compound (915 mg, 84% yield) as off-white crystals. MS: 362.2 (M+H+).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15]O)[CH3:13])[CH3:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH:9]=[C:7]([CH3:8])[CH3:6])[CH3:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: CC(C)=CCCC(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCC(C)CCC=C(C)C
Temperature: 150 °C

Procedure:
24 g of acrylic acid, 31 g of citronellol and 1.5 g of p-toluenesulfonic acid in 500 mL of toluene were heated to reflux at a oil temperature of 150° C. for 19 h. Subsequently, the reaction mixture was quenched by the addition of salt saturated sodium bicarbonate solution. The mixed solution was extracted with ether. The organic layers were combined and washed with salt saturated sodium bicarbonate solution, an aqueous solution of sodium hydroxide, and then salt saturated ammonium chloride solution, and then dried over salt saturated brine and sodium sulfate anhydrous. Finally, the resultant oily product was evaporated under reduced pressure to obtain citronellyl acrylate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][O:14][CH3:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:19]=1[CH:20]=O>>[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([C:28]2[N:29]([CH3:37])[C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:19]=1/[CH:20]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][O:14][CH3:15])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CONS(=O)(=O)c1ccc(C(C)=O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Product: CONS(=O)(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4n3C)c(OC)cc2OC)cc1
Yield: 94 %

Procedure:
The title compound was prepared in an analogous way as Ex-1 using 4-acetyl-N-methoxy-benzenesulfonamide (Ex-30A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 94% yield, yellow solid, mp 214–216° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.11 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=7 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.25–7.26 (m, 1H), 7.11–7.16 (m, 2H), 6.59 (s, 1H), 6.50 (s, 1H), 4.03 (s, 3H) 3.90 (s, 3H), 3.84 (s, 3H), 3.58 (s, 3H). MS m/z: 506 ([M]+, 30%), 476 (100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[C:8]1([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Clc1cnccn1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(-c2cnccn2)cc1
Reaction time: 1.33 h
Yield: 39 %

Procedure:
Chloropyrazine (20.68 gram, 177 mmol) and [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride (41.08 gram, 77.8 mmol) in dry THF (1.5 liter) were mixed and stirred for 80 minutes in a flask (cooled with a water bath) under nitrogen. A solution of phenylmagnesium bromide (3M in Et2O) (103 ml, 309 mmol) was added slowly through a dropping funnel into the cooled brick-red slurry at room temperature under nitrogen over 3.5 hours. After stirring at room temperature overnight, TLC showed that the reaction was complete. 3 N HCI (100 ml) was added slowly through a dropping funnel under nitrogen and the mixture was stirred for one hour. The THF layer was separated from the aqueous layer. The aqueous layer was adjusted to pH 12 with 6 N NaOH and extracted with EtOAc (100 ml, 3×). The organic fractions (THF and EtOAc) were combined and dried over MgSO4, filtered and concentrated to give a solid. The product was purified by flash chromatography on 300 g of flash grade silica gel in 2.5% EtOAc/CH2Cl2 to give 10.79 gram (69 mmol, 39%) of 2-phenylpyrazine, m.p. 69°-70° C.; FAB mass [M+1]+ 157;
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.O>CN(C)C=O>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]([CH2:25][C:26]1[CH:45]=[CH:44][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)[N:10]=1
Reactant: CC(C)CCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of N-(3-methylbutyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (500 mg, 1.59 mmol) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (63.6 mg, 1.59 mmol) and the mixture was stirred for 30 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (462 mg, 1.45 mmol) was added and the obtained mixture was stirred at room temperature for 13 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (490 mg, yield 57%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[C:2](=[CH2:4])[CH3:3].B1C2CCCC1CCC2.[OH-].[Na+].OO.C(=O)([O-])[O-:40].[K+].[K+]>C1COCC1.O.C(O)C>[CH3:4][CH:2]([CH2:3][OH:40])[CH2:1][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: C=C(C)Cc1cc(C(=O)c2ccccc2)ccc1OC(=O)C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)Cc1cc(C(=O)c2ccccc2)ccc1OC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 15.0 g of 3-methallyl-4-pivaloyloxybenzophenone in 30 ml of THF was treated with 100 ml of 0.5M solution of 9-BBN in THF at 0° C. The mixture was stirred at 25° C. for 3 h and at 50° C. for 1 h. To the cooled reaction mixture were added 30 ml of ethanol, 9.5 ml of 6N sodium hydroxide, and 18 ml of 30% hydrogen peroxide. After stirring at 25° C. for 2 h, the oxidation mixture was treated with solid potassium carbonate followed by a small amount of water. The organic layer was separated and dried over MgSO4. The crude product (22 g) was chromatographed on a silica gel column using toluene-ethyl acetate. 8.0 g of product was obtained as an oil. Calcd. for C22H26O4 : C, 74.55; H, 7.39. Found: C, 74.30; H, 7.35.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCC>O.O(C(C)C)C(C)C>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:7]1
Reactant: Clc1ccc2ccccc2n1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)OC(C)C
Solvent: O
Product: Oc1ccc(N2CCN(c3ccc4ccccc4n3)CC2)cc1
Yield: 70 %

Procedure:
A mixture of 10.2 parts of 4-(1-piperazinyl)phenol dihydrobromide, 5.7 parts of 2-chloroquinoline, 6.3 parts of potassium carbonate and 80 parts of 1-butanol is stirred and refluxed overnight. The reaction mixture is diluted with water and 2,2'-oxybispropane is added: the product is crystallized. It is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 6.4 parts (70%) of 4-[4-(2-quinolinyl)-1-piperazinyl]phenol; mp. 198.1° C.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:35](Br)[CH:36]=[CH2:37]>C1COCC1>[CH2:37]([NH:24][C:8]1[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[N:10][C:11]([CH3:13])=[CH:12][C:7]=1[NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:36]=[CH2:35]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCNc1c(NC(CC)CC)cc(C)nc1Oc1c(C)cc(C)cc1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine (500 mg, 1.52 mmol) in dry THF was added 1M in THF of lithium bis(trimethylsilyl)amide (1.6 ml, 1.6 mmol) at −78° C., After stirring at −78° C. for 10 min, allyl bromide (0.13 ml, 1.52 mmol) was added and the resulting mixture was stirred at that temperature for 20 min, then warmed to room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound as a green-blue oil. The oil was purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give a yellow crystal, mp. 86–88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:21])=[CH:4][C:3]=1[CH:22]=O.[C@H:24]12[CH2:33][C@H:27]([N:28]([CH2:30][C:31]#[N:32])[CH2:29]1)[CH2:26][O:25]2.[OH-].[K+]>CS(C)=O>[NH2:32][C:31]1[C:30]([N:28]2[CH2:29][C@@H:24]3[CH2:33][C@H:27]2[CH2:26][O:25]3)=[CH:22][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]3[C:9]([CH3:21])=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:15])[CH:4]=2)[N:1]=1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc(N)c(C=O)c1
Reactant: N#CCN1C[C@@H]2C[C@H]1CO2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(N3C[C@@H]4C[C@H]3CO4)cc2c1

Procedure:
A solution of 4-amino-2′-methyl-6′-(pyrrolidine-1-carbonyl)biphenyl-3-carbaldehyde (0.100 g, 0.324 mmol) in DMSO (3.0 mL) was added to an 80° C. solution of 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)acetonitrile (0.067 g, 0.486 mmol) and potassium hydroxide (0.016 g, 0.28 mmol) (11 M aq., 44 uL) in DMSO (1.25 mL) in 4 portions at 15 min intervals. The resulting mixture was heated for 18 h, cooled, filtered and purified by prep HPLC (12-51% CH3CN/water, 0.1% TFA) to give (2-(2-amino-3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as a yellow solid. MS (ESI, pos. ion) m/z: 429 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH3:16])[N:8]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][N:3]=1.[C-]#N.[Na+].C1N2CC[N:22](CC2)[CH2:21]1>CS(C)=O.O>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:8]1[C:7]([CH3:16])=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:21]#[N:22])=[N:3][CH:4]=2
Reactant: Cc1nc2cnc(Cl)nc2n1CC(C)(C)C
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2cnc(C#N)nc2n1CC(C)(C)C

Procedure:
6.1 g of 2-chloro-9-(2,2-dimethyl-propyl)-8-methyl-9H-purine, 1.25 g of NaCN and 0.57 g of DABCO were heated for 6 hours to 80° C. in 60 ml DMSO/H2O=90:10. The crude mixture was extracted with ethyl acetate and saturated NaHCO3 solution and the organic phases were dried over sodium sulfate and evaporated to dryness. After chromatography on silicagel with ethyl acetate/hexanes=1:1 9-(2,2-dimethyl-propyl)-8-methyl-9H-purine-2-carbonitrile was isolated as a pale brown powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[CH3:28][N:29]([CH3:39])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1>>[CH3:39][N:29]([CH3:28])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)=[CH:34][CH:33]=1
Reactant: CN(C)CCc1ccc(O)cc1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCc1ccc(OCCc2ccc(OC(=O)N(C)c3ccccc3)cc2)cc1
Yield: 92 %

Procedure:
The title compound was prepared as its TFA salt in 92% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-(2-dimethylaminoethyl)-phenol.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:15]O>>[CH3:15][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[NH2:5]
Reactant: CO
Reactant: Nc1ncccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1N
Temperature: 25 °C
Yield: 55 %

Procedure:
42.4 g (356.4 mmol, 26 ml) thionyl chloride was added dropwise to a suspension of 15.0 g (108.6 mmol) 2-aminonicotinic acid in 150 ml abs. Methanol, while cooling. The mixture was heated to reflux and the mixture was refluxed for 19 hours. The evolving SO2 was scrubbed. The solvent was removed under reduced pressure after cooling down to room temperature. The residue was carefully treated with a satured NaHCO3 solution and extracted with ethyl acetate. The organic fraction was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. 9.13 g (55%) of 2-aminonicotinic acid methyl ester was isolated as a pale yellow solid (m.p. 83° C.).
Reaction SMILES: [Cl:1]C1C=C(C2(CC#N)CCCC2)C=CC=1.[ClH:16].FC(F)(F)[C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH2:30][C:31]([NH2:33])=[NH:32])[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[ClH:1].[Cl:16][C:24]1[CH:23]=[C:22]([C:25]2([CH2:30][C:31]([NH2:33])=[NH:32])[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:21]=[CH:20][CH:19]=1
Reactant: N=C(N)CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: N#CCC1(c2cccc(Cl)c2)CCCC1
Agent: Cl
Product: N=C(N)CC1(c2cccc(Cl)c2)CCCC1

Procedure:
2-(1-(3-Chlorophenyl)-cyclopentyl)-acetamidine hydrochloride (499) was synthesized from 2-(1-(3-chlorophenyl)cyclopentyl)acetonitrile (498) following the procedure described for HCl-salt of 2-[1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetamidine hydrochloride (242).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])C.C(OCC)=O.[H-].[Na+].[O-]CC.[Na+].S(O)(O)(=O)=O.[CH3:32][S:33][C:34](=[NH:36])[NH2:35].[CH3:37]SC(=N)N>C1COCC1.CCO>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[O:6][C:5]1[C:4]([OH:3])=[N:36][C:34]([S:33][CH3:32])=[N:35][CH:37]=1
Reactant: CSC(=N)N
Reactant: CCOC(=O)COc1ccc(F)cc1F
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC=O
Product: CSc1ncc(Oc2ccc(F)cc2F)c(O)n1
Yield: 60 %

Procedure:
To a solution of 2-(2,4-difluorophenoxyl)acetic acid ethyl ester (8.0 g, 37.01 mmol) and ethyl formate (4.11 g, 55.51 mmol) in dry THF (200 mL) was added NaH (1.55 g, 38.75 mmol) slowly at 0° C. The mixture was then refluxed for 2 h. In a separate flask, sodium ethoxide (3.02 g, 44.41 mmol) and S-methylthiopseudourea hemisulfate (6.17 g, 44.41 mmol) in EtOH (100 mL) were stirred at 20° C. for 2 h and then the resulting mixture was added to the above THF solution. The combined mixture was refluxed for 12 h. After concentration under vacuum, water (20 mL) and HCl (10 mL, aq. 1N) were added. The suspended solids were collected and washed with water (50 mL×3) and EtOH (50 mL×3) and dried to give the title compound (6.0 g, 60.0% yield) as a light yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.84 (s, 1H), 7.42-7.34 (m, 1H), 7.04-7.01 (m, 1H), 6.95 (t, J=9.6 Hz, 1H), 2.47 (s, 3H). LCMS: 271.1 (M+1)+
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([CH2:10]O)[C:5]=1[CH3:12].S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:10][C:6]1[C:5]([CH3:12])=[C:4]([O:3][CH:2]([F:13])[F:1])[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)ncnc1OC(F)F
Solvent: ClCCl
Product: Cc1c(CCl)ncnc1OC(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6-(difluoromethoxy)-5-methylpyrimidin-4-yl)methanol 49 (15 g, 78.94 mmol) dissolved in DCM (150 ml) added thionyl chloride (8.59 ml, 118.42 mmol). The reaction mixture was stirred for 4 h at RT. The solvent was removed under vacuum pump to afford 4-(chloromethyl)-6-(difluoromethoxy)-5-methylpyrimidine 50 as a brown solid. Yield: 14 g (85%); 1H NMR (400 MHz, DMSO-d6) δ=8.74 (s, 1H), 7.77 (t, 1H, J=95.4 Hz), 4.81 (s, 2H), 2.24 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([SH:12])[C:6]=2[N:7]=1.[CH:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21]>>[CH:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[C:4]([N:13]3[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([SH:12])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: O=CN1CCNCC1
Reactant: O=S1CCN(c2nc(Cl)nc3c(S)ncnc23)CC1
Product: O=CN1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(S)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 93 from 2-chloro-8-mercapto-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: >280° C., decomp.) and N-formyl-piperazine.