Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([N+:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(=O)C.[NH4+:25].O>C(O)(=O)C>[C:5]1([C:3]2[N:25]=[C:20]3[CH2:19][C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH2:12][N:11]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: O=C(C[n+]1ccc2ccccc2c1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(-c2cn3c(n2)Cc2ccccc2C3)cc1

Procedure:
A solution of 2-phenacylisoquinolinium bromide prepared as above (13.1 g) and ammonium acetate (28 g) in glacial acetic acid (36 ml) was heated under reflux for 2 hours. The cooled reaction mixture was poured, with stirring, into water (600 ml). The resultant solid was filtered off and washed well with water. The solid was dissolved in methanol (20 ml), and added dropwise, with stirring, to a solution of sodium hydroxide (1.6 g) in water (100 ml). A further 300 ml of water was added to the suspension, and the granulated solid filtered off, washed well with water, dried, and crystallised from methanol. Yield 2.1 g (21%) m.p. 195°-197°. (Found C 82.8; H 6.0; N 11.4, Required C 82.9; H 5.7; N 11.4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.C(N(C(C)C)CC)(C)C.[CH3:31][O:32][CH2:33]/[CH:34]=[CH:35]/[C:36](Cl)=[O:37].C(=O)(O)[O-].[Na+]>>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:36](=[O:37])[CH:35]=[CH:34][CH2:33][O:32][CH3:31])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: COC/C=C/C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COCC=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 1.5 h

Procedure:
To a solution of 1.0 g (2.95 mmol) of of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile and 0.57 g (4.42 mmol) of diisopropylethyl amine at 0° C. with stirring was added 0.43 g (3.24 mmol) of 4-methoxycrotonyl chloride. After 1.5 hr at 0° C., the mixture was poured into a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. The organic solution was dried over magnesium sulfate and the sovent was removed. The residue was recrystallized from 1-butanol giving 1.3 g of 4-Methoxy-but-2-enoic acid [4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow solid: mass spectrum (electrospray, m/e,): M+H 436.4, 438.9.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f32) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H][H]>C(O)(C)C>[CH3:9][O:8][C:6]([CH:5]1[CH2:10][CH2:11][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: [H][H]
Solvent: CC(C)O
Product: COC(=O)C1CCC(=O)CC1

Procedure:
One mole of methyl 4-hydroxybenzoate was reacted with two moles of hydrogen in the presence of 5% palladiun-carbon catalyst. This reaction was carried out in isoproyl alcohol at a temperature of 170°-180° C. and a hydrogen pressure of 20-40 kg/cm2. After the reaction mixture was filtered to recover the catalyst therefrom, the filtrate was distilled to obtain cyclohexanone-4-carboxylic acid methyl ester as the distillate at 140° C./20 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[CH:4]=[C:5]1[S:9]C(=S)N[C:6]1=[O:11].[OH-:17].[Na+].Cl>O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1/[CH:4]=[C:5](\[SH:9])/[C:6]([OH:17])=[O:11]
Reactant: [OH-]
Reactant: O=C1NC(=S)SC1=Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)/C(S)=C/c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
A suspension of 2,6-dichlorobenzylidenerhodanine (160.4 g) and water (800 ml) was stirred at room temperature, and sodium hydroxide (83.0 g) was added over a period of 1 hour. The resulting mixture was heated with stirring for another 0.5 hours. The reaction mixture was cooled with ice (10° C.), and concentrated hydrochloric acid (192 ml) was added. After the mixture was stirred while cooling with ice for 0.5 hours, the precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with water and then dried to obtain an equivalent amount of (Z)-3-(2,6-dichlorophenyl)-2-mercapto-2-propenoic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[CH:7]=1.[CH2:19]([O:21][C:22](=[O:34])[C@@H:23]([O:32][CH3:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:34])[CH:23]([O:32][CH3:33])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:18]=[CH:17][C:9]3[O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:8]=3[CH:7]=2)=[CH:29][CH:30]=1)[CH3:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OC
Reactant: BrCCCOc1ccc2oc3ccccc3c2c1
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc3oc4ccccc4c3c2)cc1)OC

Procedure:
A mixture of 2-(3-Bromo-propoxy)-dibenzofuran and (2S)-3-(4-hydroxy-phenyl)-2-methoxy propionic acid ethyl ester were allowed to react under the Standard Procedure I to give the title compound.
Reaction SMILES: OCCC1C=CC([NH2:8])=CC=1C(F)(F)F.N1C(C)=CC=CC=1C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[NH2:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(CCO)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141.9 %

Procedure:
4-(2-Hydroxyethyl)-3-(trifluoromethyl)aniline (408 mg, 2.0 mmol) was dissolved in DCM (10 mL), and 2,6-lutidine (426 mg, 4.0 mmol) and then benzyl chloroformate (678 mg, 4.0 mmol) were dropwise added thereto. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was quenched with a saturated sodium bicarbonate solution, and the organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=3:1) to give 4-(2-hydroxyethyl)-3-(trifluoromethyl)phenyl]carbamic acid benzyl ester (429 mg, 64%) as a light-yellow oil.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>O1CCCC1.CO>[CH:12](=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C(=Cc2ccccc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 250 mL flask was charged with tetralone (4 g, 27.4 mmol) and benzaldehyde (3.88 g, 36.6 mmol). This was dissolved in warm tetrahydrofuran (15 mL), and to this yellow solution was slowly added a 4 wt % solution of KOH in methanol (125 mL). The reaction was stirred for 4 days at room temperature. The solvent was then removed under reduced pressure, and it was poured into 150 mL of water and extracted with methylene chloride. The organic extract was dried over magnesium sulfate and filtered, and the solvent was removed at reduced pressure to afford 4.1 g (64%) as white powder.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH2:25][CH2:26][CH3:27]>>[CH2:24]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])=[CH:33][CH:34]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCCCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 40.1 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-butylaniline (51.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-butylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (28.2 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH2:24]([N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:29]=2[CH2:28][CH2:27]1)[CH3:25].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:37][C:34]2[CH:35]=[CH:36][C:29]3[CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:32][CH2:31][C:30]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc2CC1
Temperature: 120 °C
Reaction time: 6 h
Yield: 17 %

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (104 mg, 0.293 mmol) was added into a vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (55.0 mg, 0.289 mmol) in 2-Methoxyethanol (3 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.10 mL) was added and the reaction was heated at 120° C. After 6 h, Macroporous carbonate resin (3.16 mmol/g loading; 150 mg, 0.474 mmol) was added and the reaction was cooled to room temperature, stirred overnight, then was concentrated in vacuo onto Celite, and chromatographed (2×24 g ISCO Amine column, 0-0.5% MeOH:DCM). Product is ca. 75% pure; rechromatograph, (2×4 g ISCO Amine column, DCM) to isolate 5-Chloro-N*2*-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as a beige powder (25 mg, 17%). m.p.=157-162° C.; LCMS (m/e) 509 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.25 (d, 1H, J=8.8 Hz), 8.00 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.18 (m, 1H), 7.02 (m, 1H), 6.83 (s, 1H), 6.54 (s, 1H), 6.49 (d, 1H, J=9.1 Hz), 3.92 (s, 3H), 3.89 (t, 4H, J=4.8 Hz), 3.15 (t, 4H, J=4.8 Hz), 2.91 (m, 4H), 2.64 (m, 4H), 2.57 (q, 2H, J=7 Hz), 1.10 (t, 1H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[NH:4][C:3]1=[O:25].[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:27]1([NH:33][C:34]([N:4]2[C:5]3[CH:6]=[C:7]4[N:22]=[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)[NH:11][C:8]4=[CH:9][C:10]=3[C:2]([CH3:26])([CH3:1])[C:3]2=[O:25])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)C3(C)C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4C(=O)Nc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 21.7 %

Procedure:
A solution of N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methoxy-benzamide (100 mg) and phenyl isocyanate (35 mg; 0.3 mmol) in dry toluene (2 ml) is stirred in a microwave apparatus at 150° C. for 900 s. The mixture is filtered and concentrated in vacuo. The residue is dissolved in acetic acid (2 ml), iron (115 mg; powder) is added and the mixture is again stirred in a microwave apparatus at 150° C. for 900 s to achieve reduction of the nitro function and ring closure. The mixture is filtered and concentrated in vacuo. The desired compound (26 mg) is obtained by preparative RP-HPLC.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH:15]=[O:16])([CH3:14])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])([CH3:4])([CH3:3])[CH3:2].P([O-])(O)(O)=[O:27].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:14])([C:15]([OH:27])=[O:16])[O:13][C:9]=2[CH:8]=[C:7]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:6]=1[O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=P([O-])(O)O
Reactant: CC1(C=O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1(C(=O)O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a solution of 0.5 g of 4,6-di-t-butyl-2-formyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran in 5 ml of t-butyl alcohol were added 5 ml of a saturated aqueous sodium dihydrogenphosphate solution and 0.73 ml of 2-methyl-2-butene, and the mixture was cooled to -5° C. To this solution was added dropwise a solution of 0.14 g of sodium chlorite in 5 ml of distilled water, and the mixture was stirred for 20 minutes, then further stirred at room temperature for 15 minutes. The reaction solution was extracted with diethyl ether, and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was recrystallized from hexane to give 0.38 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid as a colorless powder (yield 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([F:15])([F:14])[F:13].[CH3:16][O:17]C1C=CC(CC(F)(F)F)=CC=1C=O>>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([CH2:11][C:12]([F:14])([F:13])[F:15])=[CH:5][C:6]=1[CH:16]=[O:17]
Reactant: COc1ccc(CC(F)(F)F)c(OC)c1
Reactant: COc1ccc(CC(F)(F)F)cc1C=O
Product: COc1cc(OC)c(CC(F)(F)F)cc1C=O

Procedure:
This compound was prepared from Compound 84 in the same manner of Compound 46.
Reaction SMILES: C(=O)(O)[O-].[Na+].O.[C:7]1([C:13]2[NH:18][C:17](=[S:19])[NH:16][C:15](=[O:20])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:18]=1)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: O=c1cc(-c2ccccc2)[nH]c(=S)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CSc1nc(O)cc(-c2ccccc2)n1

Procedure:
To a stirred solution of 8.4 g of sodium bicarbonate in 450 ml. of water and 100 ml. of ethanol was added 20.4 g of 6-phenyl-2-thiouracil. The mixture was heated on a hot plate until a clear solution was obtained then 16.7 g of ethyl bromoacetate was added. A precipitate was deposited which was removed by filtration and washed with water. The dried product amounted to 28.1 g, mp. 214°-218°C. decomp. The analytical sample of (4-hydroxy-6-phenyl-2-pyrimidinylthio)acetic acid ethyl ester was obtained by recrystallization from dimethyl formamide, mp. 217°-219°C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.CCN=C=NCCCN(C)C.Cl.O>CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cnc(C=O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 3.2 %

Procedure:
In methanol (15 ml), 5-methylpyrazine-2-carboxylic acid (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.25 g) was dissolved. Then, the solution was added with WSCI hydrochloride (2.59 g) and N,N-dimethylaminopyridine (1.65 g) in this order, followed by stirring at room temperature for 3 hours. The reaction solution was added with water and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. The solvent was distilled off and the resulting crude product was then purified through silica gel column chromatography (chloroform/methanol). The purified product was dissolved in ethanol (15 ml) and THF (8 ml) and added with calcium chloride (1.11 g). After that, the reaction solution was cooled to 0° C. and then gradually added with sodium borohydride (757 mg), followed by stirring at room temperature for 19 hours. The reaction solution was added with a 1 mol/l citric acid solution (40 ml), followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate, followed by distilling the solvent off. The residue was dissolved in chloroform (10 ml) and then added with manganese dioxide (chemically processed product) (2.2 g), followed by stirring at room temperature for 1 hour. After completion of the reaction, the catalyst was filtrated out through Celite and the solvent was then distilled off. The crude product obtained was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (35.9 mg) as a colorless oily substance.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([NH:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].[C:18]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC1C=CC=CC=1>[CH2:16]([O:15][CH2:14][CH2:13][NH:12][C:11]1[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:26][CH2:27]2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:17]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOCCNc1cccnc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOCCNc1cccnc1NC(=O)CN1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of 3.62 parts of 2-chloro-N-[3-[(2-ethoxyethyl)amino]-2-pyridinyl]acetamide, 10.6 parts of 1-(phenylmethyl)piperazine, 6.4 parts of sodium carbonate and 90 parts of methylbenzene was stirred for 20 hours at 80° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 7.9 parts (100%) of N-[3-[(2-ethoxyethyl)amino]-2-pyridinyl]-4-(phenylmethyl) -1-piperazineacetamide as a residue (int. 25).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH2:10][Cl:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cc(C(F)(F)F)ccc1Sc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: FC(F)(F)c1ccc(Sc2ccccc2)c(CCl)c1

Procedure:
96 g of 2-(phenylthio)-5-trifluoromethyl-benzyl alcohol are dissolved in 450 ml of absolute benzene and heated to reflux. The solution thus obtained is treated dropwise over a period of 20 minutes with 48 ml of thionyl chloride and the mixture is subsequently stirred at reflux for 30 minutes. After cooling, the mixture is evaporated under reduced pressure. There is obtained 2-(phenylthio)-5-trifluoromethyl-benzyl chloride as a brown-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1>[N:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1N1CCCC1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
4-Chloro-3-nitropyridine (2.02 g, 12.7 mmol) was suspended in 15 ml of 1,4-dioxane. The suspension was cooled a little in an ice bath, and then pyrrolidine (2.1 ml, 25.3 mmol) was added dropwise thereto. The temperature of the suspension was returned to room temperature, and the suspension was stirred for 30 minutes, followed by removal of the solvent by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 2.34 g of a yellow solid (yield: 95.4%).
Reaction SMILES: [C:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.NN.C(O)CO[CH2:19][CH2:20]O.[OH-].[K+]>O>[CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:8][CH2:1][CH2:2][CH2:3][CH2:19][CH3:20]
Reactant: CCCCCC(=O)c1cccs1
Reactant: OCCOCCO
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCc1cccs1
Temperature: 50 °C

Procedure:
In a 5 liter-five-necked flask, 266 g (1.0 mol) of 2-hexanoylthiophene, 392.4 ml of 60% hydrazine hydrate and 3 liter of diethyleneglycol were placed and reacted for 6 hours at 195° C. with distilling-off of excessive water and hydrazine hydrate. The mixture was cooled to 50° C. and 210.6 g of KOH was added thereto, followed by heating again to react for 2.5 hours at 155° C. After the reaction, the reaction mixture was poured into 10 liter of water, extracted two times with 2 liter of isopropyl ether, followed by drying with CaCl2 and distilling-off of the solvent to obtain 229 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 168 g of a pure product (yield: 66.7 b.p.: 121.5° C./0.7 mmHg
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1.[Cl:15]C1C=CC(N)=C(C)C=1>>[Cl:15][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(F)ccc1N1CCNCC1
Reactant: Cc1cc(Cl)ccc1N
Product: Cc1cc(Cl)ccc1N1CCNCC1
Yield: 73 %

Procedure:
The title compound was prepared following the method described for the Compound 31A of Example 31 but starting from 4-chloro-2-methylaniline instead of 4-fluoro-2-methylaniline. Purification by flash chromatography (chloroform-2N ammonia in methanol 100:3 to 100:5) afforded the title compound (73%) as an oil.
Reaction SMILES: Br[C:2]1[C:3](Cl)=NC(Cl)=N[CH:7]=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])C)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C:19]2([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:29][CH2:31][CH2:3][CH2:2][CH2:7]2)=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)NCC1(Nc2nc(Cl)ncc2Br)CCCCC1

Procedure:
tert-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclohexyl]methyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate K using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.18-1.54 (m, 17H) 2.23 (d, J=14.35 Hz, 2H) 3.36 (d, J=6.44 Hz, 2H) 5.82 (s, 1H) 6.93 (s, 1H) 8.22 (s, 1H). LCMS (ESI) 419 (M+H).