Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH3:23][NH2:24]>CO.C(Cl)Cl>[CH3:23][NH:24][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with methylamine HCl (2.0 equiv, 23 mg, 0.34 mmol) as described in General Procedure X to afford 5-methylaminomethyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide, Ic (18 mg, 34.6%) as a yellow solid, tlc Rf=0.2 (15% MeOH/CH2Cl2), m/z obs312 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C=CC(S(O[CH2:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH:32]1([CH2:31][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:35][CH2:34][CH2:33]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCC2)c1
Yield: 41 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and (cyclobutyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (147 mg, yield: 41.0%).
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10].[S:23](=[O:27])(=[O:26])([OH:25])[OH:24].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1C=CC=CC=1>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[S:23]([O:25][S:23]([OH:26])(=[O:25])=[O:24])([OH:24])(=[O:27])=[O:26].[OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10]
Reactant: O=S(=O)(O)O
Agent: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(O)OS(=O)(=O)O

Procedure:
Following the same manner as in Example 26, the reaction was conducted with 3.0 g of (E,Z,E) and (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol and 5.0 g of anhydrous sulfuric acid-pyridine reagent in anhydrous benzene and after-treatment was conducted to afford 4.4 g of the end product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:28][CH2:29][CH2:30][OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(=O)OCC>CN(C=O)C>[CH2:21]([O:28][CH2:29][CH2:30][O:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCOCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (5 g, 23.91 mmol) in DMF (50 mL) was added K2CO3 (6.61 g, 47.8 mmol) and 2-(benzyloxy)ethanol (4.00 g, 26.3 mmol) at rt. The mixture was stirred at 110° C. for 12 h. LCMS and TLC (PE/EA=5:1, Rf=0.4) showed the reaction was finished. The mixture was filtrated, and the filtrate was concentrated to give crude product, which was purified by silica gel column to obtain 1-(2-(benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene (7.1 g, 18.18 mmol, 76.0% yield): 1H NMR (400 MHz, CDCl3) 8.49 (d, J=2.4 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 7.54-7.28 (m, 5H), 7.13 (d, J=8.4 Hz, 1H), 4.56 (s, 2H), 4.36 (t, J=4.8 Hz, 2H), 3.89 (t, J=3.6 Hz, 2H); ES-LCMS m/z 342 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6].O>C(O)(=O)C>[C:5]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[C:19]([N+:1]([O-:4])=[O:2])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCC2(CC1)Cc1ccccc1O2
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCC2(CC1)Cc1cc([N+](=O)[O-])ccc1O2
Temperature: 100 °C

Procedure:
3.8 g of nitric acid (sp gr 1.42) in 30 ml of glacial acetic acid are added dropwise to a stirred solution of 4.7 g of 2,3-dihydro-1'-acetylspiro[benzofuran-2,4'-piperidine], Example 16, in 65 ml of glacial acetic acid. After total addition, the reaction mixture is slowly heated to 100° C. over a 2 hour span and then cooled and poured into 500 ml of water. The diluted mixture is extracted with chloroform and the chloroform extracts are washed sequentially with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and then dried. The chloroform is removed under reduced pressure. The residue is triturated with ether, causing an orange precipitate which is collected and recrystallized first from an ethyl alcohol-ether mixture and then from ethyl alcohol to provide the product, 2,3-dihydro-1'-acetyl-5-nitrospiro[benzofuran-2,4'-piperidine], mp 149°-150° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][C:16]([CH3:29])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][C:16]([CH3:29])([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: CC(CN)(CC1CC1)c1cnc(C(F)(F)F)nc1
Product: CC(CNC(=O)c1cccc(F)c1Cl)(CC1CC1)c1cnc(C(F)(F)F)nc1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=416.1, tR (minutes, Method G)=2.48
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O>O1CCCC1>[Br:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCc1sc(C(=O)OC)cc1-c1c(Br)cnn1C
Yield: 85.2 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (980 mg, 3.92 mmol) [prepared in Example 98] and N-bromosuccinimide (697 mg, 3.92 mmol) in tetrahydrofuran (19.6 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated then purified via column chromatography (silica, 10-40% EtOAC in hexanes) yielding methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (1.1 g, 3.34 mmol, 85% yield) as a yellow oil: LCMS (ES) m/e 329, 331 (M, M+2)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.S([N:32]=[N+:33]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[N+:32](=[C:10]1[C:9](=[O:14])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][C:11]1=[O:13])=[N-:33]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)CC(c2ccccc2)CC1=O
Yield: 36.9 %

Procedure:
A solution of 20.0 g (0.106 mol) of 5-phenylcyclohexane-1,3-dione in 75 ml ethanol was cooled to -10° C. and stirred magnetically under nitrogen. To the mixture was added 10.75 g (0.106 mol) of triethylamine. The tosyl azide (20.95 g 0.106 mol) was added all at once, and the mixture stirred for one hour at C-5° C. The solvent was removed under vacuum at a temperature less than 40° C. To the residue was added 200 ml ether, and the mixture extracted with a solution containing 3.1 g potassium hydroxide in 200 ml of water. The ethereal solution was dried over anhydrous MgSO4 filtered and the solvent removed to give a yellow solid which was recrystallized from ethanol-hexane to give 8.38 g (32%) of 2-diazo-5-phenylcyclohexane-1,3-dione as yellow crystals, mp 122°-124° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)=[O:26].[OH-].[Na+]>CN(C=O)C.CO>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)(=[O:26])[CH3:24]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-aminoacetophenone in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: CS(N)(=O)=O.[CH3:6][O:7][CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:41][C:42]1[C:43]([O:52][CH2:53][C:54]2([C:64]#[N:65])[CH:61]3[CH2:62][CH:57]4[CH2:58][CH:59]([CH2:63][CH:55]2[CH2:56]4)[CH2:60]3)=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47](O)=[O:48]>>[Cl:41][C:42]1[C:43]([O:52][CH2:53][C:54]2([C:64]#[N:65])[CH:55]3[CH2:56][CH:57]4[CH2:58][CH:59]([CH2:60][CH:61]2[CH2:62]4)[CH2:63]3)=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47]([NH:13][S:10]([CH2:9][CH2:8][O:7][CH3:6])(=[O:12])=[O:11])=[O:48]
Reactant: COCCS(N)(=O)=O
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2Cl)C2CC3CC(C2)CC1C3
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: COCCS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with 2-methoxyethanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid, the title compound was obtained following trituration with a 5:1 mixture of hexanes in diethyl ether (10 mL) as a colorless powder (0.094 g, 63%): 1H NMR (300 MHz, DMSO-d6) δ 12.13 (br s, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.40 (d, J=12.2 Hz, 1H), 4.54 (s, 2H), 3.70 (s, 4H), 3.18 (s, 3H), 2.15-2.07 (m, 4H), 1.97-1.78 (m, 6H), 1.70-1.60 (m, 4H); MS (ES−) m/z 483.2, 485.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCCCNc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Aminobenzophenone (25 g.) is heated with octadecyl bromide (70 g.) in dry hexamethylphosphoramide (100 ml.) containing anhydrous potassium carbonate (30 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (10 ml.). The solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethance provides the product of the Example.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7]([Cl:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[Cl:12][C:7]1[C:8]([C:10]#[N:11])=[N:9][C:4]([C:1](=[O:3])[CH:2]=[CH:15][N:16]([CH3:18])[CH3:17])=[CH:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(Cl)c(C#N)n1
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ccc(Cl)c(C#N)n1
Yield: 34.9 %

Procedure:
Compound 64 (633 mg, 2.7 mmol) and N,N-dimethylformamide dimethyl acetal (1.1 mL, 8.1 mmol) in toluene was heated to reflux for 5 h. After which time the solvent was evaporated and the crude product triturated with isoxane/diethylether to give compound 67 as an orange solid (222 mg, 35%); LCMS Rt=2.35 min (MeOH-FA method), m/z 236 (MH+).
Reaction SMILES: [CH2:1]([C:3]1([CH3:21])[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[O:4]1)[CH3:2].CCN(CC)CC.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].[NH4+].[Cl-]>C(Cl)Cl>[CH2:1]([C:3]1([CH3:21])[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:13][N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:39]([C:33]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[CH:32]=3)(=[O:41])=[O:40])[CH:9]=2)[O:4]1)[CH3:2]
Reactant: CCC1(C)C=Cc2cc(CNc3ccccc3)ccc2O1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(C)C=Cc2cc(CN(c3ccccc3)S(=O)(=O)c3ccc(OC)c(OC)c3)ccc2O1
Reaction time: 24 h
Yield: 30.6 %

Procedure:
To a solution of 9 (80 mg, 0.29 mmol) in DCM (3 mL) was added Et3N (0.12 mL, 0.85 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (135 mg, 0.573 mmol). After 24 h, sat. NH4Cl was added to the reaction mixture and the aqueous layer was extracted with DCM (5×2 mL). The organic layers was combined, dried over MgSO4 and concentrated under vacuum. The crude product was purified by column (silica gel, 5:1 Hx/EtOAc) to give a white solid (42.6 mg). Yield: 32%. 1H NMR (CDCl3): δ 7.35 (dd, J=6.4 Hz, 2.0 Hz, 1H), 7.25-7.23 (m, 3H), 7.02-6.98 (m, 3H), 6.94 (d, J=8.4 Hz, 1H), 6.91-6.88 (m, 2H), 4.62 (s, 2H), 3.98 (s, 3H), 3.77 (s, 3H), 1.71-1.65 (m, 2H), 1.43 (s, 3H), 0.94 ppm (t, J=7.6 Hz, 3H). 13C NMR (CDCl3): δ 152.8, 152.5, 148.7, 139.2, 130.5, 129.8, 129.3, 129.2, 128.8, 127.9, 127.8, 126.6, 122.8, 121.4, 121.1, 115.8, 110.4, 79.0, 56.2, 56.1, 54.3, 34.0, 26.0 ppm. MS (ESI) m/z 502 [(M+Na)+]. HPLC: ret. time=5.9 min, 98.9%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:14][C:15]#[N:16]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:14][C:15]#[N:16])[CH2:11][CH2:12]1
Reactant: N#CCBr
Reactant: c1ccc(N2CCNCC2)nc1
Product: N#CCN1CCN(c2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-2-yl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=203.2: 1HNMR(DMSO-d6) 8.05 (dd, 1H), 7.50 (dd, 1H), 6.80 (d, 1H), 6.60 (dd, 1H), 3.80 (s, 1H), 3.50 (t, 4H), 2.50 (t, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([OH:11])=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].[C:17]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[C:17]([O:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][O:11][C:6]2[C:7]([O:9][CH3:10])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])[CH:5]=2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OCCN1CCC(CCO)CC1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCCC1CCN(CCOC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
N′-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylimidoformamide (876 mg, 4 mmol) in dichloromethane (2 ml) was reacted with 2-(1-(2-tert-butoxyethyl)piperidin-4-yl)ethanol (916 mg, 4.4 mmol) in the presence of triphenylphosphine (1.2 g, 4.6 mmol) by slow addition of a solution of di-tert-butyl azodicarboxylate (1.058 g, 4.6 mmol) in dichloromethane (5 ml). The mixture was stirred for 2 hours at ambient temperature and purified by chromatography. Elution with dichloromethane:ethyl acetate:methanol (5:4:1) yielded N′-(5-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (720 mg, 42% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Cl)[N:10]=[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[N:8]=1.[N:30]1[CH:31]=[CH:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][C:34]=12.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:36]2[CH2:37][CH2:38][N:33]3[CH:32]=[CH:31][N:30]=[C:34]3[CH2:35]2)[N:10]=[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[N:8]=1
Reactant: COC(=O)c1c(Cl)nc(N2CCC(O)CC2)nc1NCc1ccc(OC)c(Cl)c1
Reactant: c1cn2c(n1)CNCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCC(O)CC2)nc1N1CCn2ccnc2C1
Reaction time: 5 h

Procedure:
To a solution of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-(4-hydroxypiperidin-1-yl)pyrimidine (prepared in the above (3)) 56 mg in N,N-dimethylacetamide 0.5 ml are added a solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 31 mg in N,N-dimethylacetamide 0.5 ml and triethylamine 27 μl at room temperature, and the mixture is stirred at 80–90° C. for 5 hours. The reaction mixture is diluted with an aqueous citric acid solution, made basic with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-(4-hydroxypiperidin-1-yl)pyrimidine as a pale yellow powder, 66 mg.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[O:6][C:7]=1[CH3:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:3]2[CH:4]=[C:5]([C:9]3[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[O:6][C:7]=2[CH3:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(-c2cc(C(Cl)C3CCCCC3)c(C)o2)nn1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)nn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A mixture of 3-{4-[chloro(cyclohexyl)methyl]-5-methylfuran-2-yl}-6-methylpyridazine (107 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (175 mg), sodium carbonate (74 mg) and sodium iodide (210 mg) in N,N-dimethylacetamide (5 mL) was stirred at 80° C. for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (30% ethyl acetate/hexane to 100% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.3 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (56 mg, 33%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH:12]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:30][CH2:11]1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(O)(C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1)C(F)(F)F

Procedure:
Following the procedure of Example 14, making variations only as required to use 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (55% yield). m.p. 181-183° C. 1H NMR (300 MHz, CDCl3) δ 8.07, 7.98, 7.01, 4.86, 3.92-3.81, 3.55, 1.74, 1.51, 0.81-0.68, 0.46, 0.09. 13C NMR (75 MHz, CDCl3) δ 167.2, 163.1, 160.0, 145.4, 127.1, 126.3, 122.5, 112.5. 76.8-75.6 (q, J=117 Hz, C-19F), 44.6, 39.7, 35.3, 20.5, 8.5, 4.8. MS (ES+) m/z 416 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][NH:16][C:15](=[N:19]N)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1>C(N)CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:12][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=4)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN=c1cc(-c2c[nH]nc2-c2cccc(Cl)c2)cc[nH]1
Agent: NCCc1ccccc1
Product: Clc1cccc(-c2n[nH]cc2-c2ccnc(NCCc3ccccc3)c2)c1
Yield: 163.6 %

Procedure:
A solution of the bromopyridine compound prepared in step 3 of Example A-219 (250 mg, 0.75 mmol) in phenethylamine (5 ml) was heated at 175° C. for six hours under a nitrogen atmosphere. The excess amine was distilled off under high vacuum and the residue was dissolved in ethyl acetate and washed with water. After drying over magnesium sulfate and removal of solvent, the residue was chromatographed on silica gel with mixtures of ethyl acetate and toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylethyl)-2-pyridinamine (230 mg, 81%) as a solid, m.p. 185–186° C.