Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:9][N:8]([C:4]2[CH:3]=[C:2]([CH3:10])[CH:7]=[CH:6][CH:5]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: Cc1cccc(NN)c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2cccc(C)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of m-tolylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of a 50% pyridine in ethanol. The resulting oil was purified by flash chromatography to yield the named product as a solid (m.p. 46.5° C.-47.5° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)N=2)=[CH:6][CH:5]=1)[CH3:2].ClC1N=C(NC2C=CC(OCCCC)=CC=2)[C:33](F)=[CH:32]N=1.[CH2:49]1COC2C=CC(N)=CC=2O1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[CH:49]=2)=[CH:6][CH:5]=1)[CH2:2][CH2:32][CH3:33]
Reactant: CCOc1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1
Reactant: CCCCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: CCCCOc1ccc(Nc2cc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1

Procedure:
In like manner to the preparartion of N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine with 3,4-ethylenedioxyaniline gave N4-(4-n-butyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine. The crude product was purified by chromatography (2:1 CHCl3/EtOAc); (0.17 g, 52%) as a tan solid: Rf 0.51 (4:1 CHCl3/EtOAc); mp 149.6-151.4° C. (DSC); 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=3.4 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.18 (d, J=2.4 Hz, 1H), 6.91-6.86 (m, 3H), 6.78-6.75 (m, 2H), 6.62 (bs, 1H), 4.26-4.22 (m, 4H), 3.96 (t, J=6.5, 2H), 1.82-1.73 (m, 2H), 1.56-1.44 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.1, 150.8, 143.6, 142.8, 140.2, 139.9, 139.5, 139.2, 133.9, 130.7, 123.1, 117.1, 115.0, 113.5, 109.4, 68.2, 64.6, 31.6, 19.4, 14.0; IR (ATR) 3365 cm−1; ESI MS m/z 411 [C22H23FN4O3+H]+; HPLC (Method A) 99.0% (AUC), tR=13.2 min. Anal. Calcd for C22H23FN4O3: C, 64.38; H, 5.65; N, 13.65. Found: C, 63.63; H, 5.60; N, 13.38.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12][PH3+].[CH2:21]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[C:26]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:25]=1[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:22].O>C1COCC1>[Si:33]([O:32][C:26]1[C:27](/[CH:28]=[CH:12]\[C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:30][CH:31]=[C:24]([O:23][CH2:21][CH3:22])[C:25]=1[O:40][Si:41]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:42])[CH3:43])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Reactant: CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
n-Butyl lithium (0.85 mL, 1.36 mmol, 1.6 M in hexanes) was added dropwise over 10 min to a solution of 3,4,5-trimethoxybenzylphosphonium bromide (0.58 g, 1.12 mmol) in THF (7 mL) at −10° C. The reaction mixture was stirred at this temperature for 15 min then cooled to −70 C and a solution of 35 (0.47 g, 1.14 mmol) in THF (3 mL) was added and the reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was cooled to 0° C. and water was added. The reaction mixture was extracted with TBME (3×) and the organic phase was washed successively with water and brine, dried (Na2SO4) and concentrated in vacuo to give crude product (0.67 g). Purification by column chromatography (SiO2 2:98 EtOAc:cyclohexane+1% Et3N) gave 36 (0.21 g, 34%) as an 89:11 mixture of Z:E isomers.
Reaction SMILES: [OH-:1].[K+].[CH3:3][S:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=O.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([C:24](=O)[CH2:25][CH3:26])[CH:21]=[CH:22][CH:23]=1>O.C(O)C>[CH3:26][C:25]1[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:28])[F:29])[CH:19]=2)=[N:10][C:11]2[C:7]([C:8]=1[C:9]([OH:14])=[O:1])=[CH:6][C:5]([S:4][CH3:3])=[CH:13][CH:12]=2
Reactant: [OH-]
Reactant: CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: CSc1ccc2c(c1)C(=O)C(=O)N2
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CSc1ccc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2c1
Yield: 67.4 %

Procedure:
Potassium hydroxide (3.31 g, 59.0 mmol) in water (10 mL) was added slowly to a suspension of 5-(methylthio)-1H-indole-2,3-dione (1.9 g, 9.83 mmol) in ethanol (25 mL). 1-[3-(Trifluoromethyl)phenyl]-1-propanone (1.99 g, 9.83 mmol) was added and the mixture was heated to reflux for 1 h. The solvent was removed under reduced pressure, the residue was dissolved in water, and the aqueous mixture was washed with ether (3 times). The aqueous phase was chilled and was acidified to pH 3 with concentrated HCl. The solid material was collected by filtration, washed with water, and air dried to afford 3-methyl-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.5 g, 67% yield). MS (m/z) 378.0 (M+H+).
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[CH3:12][CH:13]([CH3:33])[C:14]([O:16][CH:17]([O:19][C:20]([CH:22]([NH2:32])[C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]1)=[O:21])[CH3:18])=[O:15].C(=O)(O)[O-].[Na+:38].C(#N)C>O>[CH3:12][CH:13]([CH3:33])[C:14]([O:16][CH:17]([O:19][C:20]([CH:22]([NH2:32])[C@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]([O-:31])=[O:30])[CH2:27][CH2:28]1)=[O:21])[CH3:18])=[O:15].[Na+:38]
Reactant: CC(OC(=O)C(C)C)OC(=O)C(N)[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(OC(=O)C(C)C)OC(=O)C(N)[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 5.03 g (15.94 mmol) of trans-4-{[1-(2-methylpropanoyloxy)ethoxycarbonyl]-aminomethyl}-cyclohexanecarboxylic acid 13 was reacted with 1.34 g (15.94 mmol) of sodium bicarbonate (NaHCO3) in 40 mL of a mixture of acetonitrile and water (1:1) to yield 5.38 g (quant.) of the title compound 14 as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.84 (br. m, 2H), 1.057 (d, J=6.4 Hz, 3H), 1.059 (d, J=6.8 Hz, 3H), 1.20-1.32 (br. m, 3H), 1.38 (d, J=5.2 Hz, 3H), 1.59-1.73 (br. m, 3H), 1.75-1.83 (m, 2H), 2.43-2.53 (m, 1H), 2.72-2.84 (br. m, 2H), 6.62 (q, J=5.6 Hz, 1H), 7.42 (t, J=5.6 Hz, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:24])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.5 %

Procedure:
A mixture of (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}acrylic acid (400 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (159 mg), HOBt (175 mg) and EDCI (202 mg) in DMF (10 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4— The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (170 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[N:16]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:23]>Cl.O>[ClH:23].[NH:1]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15])[NH2:16]
Reactant: COC(=O)c1ccc(N)c(C(F)(F)F)c1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(NN)c(C(F)(F)F)c1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
6.54 g (30 mmol) methyl 4-amino-3-trifluoromethyl-benzoate are suspended in 50 ml 32% hydrochloric acid and cooled to −20° C. A solution of 2.28 g (33 mmol) sodium nitrite in 20 ml of water is added dropwise. The mixture is stirred for 3 hours at −20° to −10° C., then 27.08 g (120 mmol) tin-(II)-chloride dihydrate in 30 ml hydrochloric acid are added dropwise within 0.25 hours. The reaction mixture is stirred for 2 hours at −10° C., then acidified with cooling. The suspension is suction filtered through kieselguhr and washed with chloroform. The phases of the filtrate are separated, the aqueous phase is extracted with chloroform. The combined organic phases are dried and evaporated to dryness. The residue is precipitated as the hydrochloride, then stirred with diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Cl:9])[C:3]=1I.CCCCCC.C([Li])CCC.FC(F)(F)S(O[Si:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[Si:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: Clc1cc(Br)cc(Cl)c1I
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1c(Cl)cc(Br)cc1Cl
Reaction time: 1 h
Yield: 89.5 %

Procedure:
The 2,6-Dichloro-4-bromoiodobenzene (4.48 g, 12.7 mmol) was dissolved in diethyl ether (50 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (1.56 M, 8.2 ml) at −78° C. At the same temperature, the mixture was then stirred for 1 hour. To the mixture was then added dropwise trimethylsilyl trifluoromethanesulfonate (3.2 ml, 16.5 mmol). The mixture was then stirred at −78° C. for 1 hour and at room temperature for 30 minutes. After the quenching of the reaction with water, the mixture was then extracted with ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off. The crude product thus obtained was then distilled under reduced pressure in a glass tube oven so that it was purified to obtain 3,5-dichloro-4-trimethylsilyl-bromobenzene (3.39 g; yield: 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[OH:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[F:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(Br)cn2)c(F)c1
Yield: 91.1 %

Procedure:
2,5-Dibromopyridine (3.0 g; 12.66 mmol), 2,4-difluorophenol (4.11 g; 31.65 mmol) and K2CO3 (5.25 g; 38 mmol) in DMF (40 ml) are stirred at 150° C. for 3 hours. The reaction mixture is poured on water and extracted with TBME three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified via chromatography (SiO2, heptane/TBME 97:3) to yield the title compound as white crystals (3.3 g; 85%). MS (m/z) ES+: 286, 288 (MH+). Retention time: 3.05 minutes (LC-MS method 2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][NH:17][C:18]2[C:27]3[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]3[C:27]4[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:31][CH:32]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)c1cccc2c(NCc3ccc(NC(=O)c4ccc(F)cc4)cc3)ncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4-fluorobenzoyl chloride (220 μL, 0.5 M in anhydrous DCM, 0.10 mmol, 1.1 equiv.) was added to a solution of 4-[(4-aminobenzyl)amino]quinazoline-8-carboxamide (30 mg, 0.09 mmol, 1.0 equiv.) and triethylamine (38 μL, 0.27 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at rt overnight. Ether (2 mL) was added. The precipitate was filtered, washed with ether and DCM to yield the title compound in 72% yield. Mass: M+H+: 416.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.[CH:17]1([C@H:23]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH:35]=[O:36])[CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.N1CCCC1>C1COCC1>[CH:17]1([C@H:23]2[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:25]([C@H:35]([C:15]3[C:14]([Cl:16])=[CH:13][N:12]=[CH:11][C:10]=3[Cl:9])[OH:36])[CH2:24]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1C=O
Reactant: Clc1cncc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1[C@@H](O)c1c(Cl)cncc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 3.51 mL, 7.02 mmol) was added to 3,5-dichloropyridine (820 mg, 5.54 mmol) dissolved in THF (15 mL) cooled at −78° C. and stirred at this temperature for 1 h. (2S,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate (1.04 g, 3.70 mmol) and its epimer at C2 of the pyrrolidine in THF (11 mL) was added and the solution was removed from the cooling bath and allowed to warm to room temperature and stirred for 2 h. The solution was quenched with saturated ammonium chloride, the aqueous layer was extracted with EtOAc (2×50 mL) and the organic layer washed with brine (30 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-80% EtOAc in heptane) affording (2S,4S)-tert-butyl 4-cyclohexyl-2-((S)-(3,5-dichloropyridin-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate (1.20 g, 2.79 mmol, 76% yield) as a mixture of epimers. MS (ESI) 451.1, 453.1 [M+Na]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: FC(F)(F)Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 31 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2,2,2-trifluoroethyl trifluoromethanesulfonate, 154 was obtained as white solid (45 mg, 31%) over two steps. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.060-9.062 (d, J=1 Hz, 1H), 8.76 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 8.05 (s, 1H), 7.60-7.63 (t, J=16 Hz, 1H), 7.26-7.28 (t, J=7.5 Hz, 1H), 6.42-6.43 (d, J=8.5 Hz, 1H), 4.75-4.78 (t, J=16.5 Hz, 2H), 3.86-3.92 (m, 4H), 3.15-3.17 (t, J=10.5 Hz, 2H), 2.90-2.92 (t, J=11.5 Hz, 2H), 2.01-2.03 (t, J=11.5 Hz, 2H); MS (ESI) m/z: 443 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[NH2:7].[O:8]1CCC[CH2:9]1.CO[CH:15]1[C:23](=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[C:16]1C(Cl)=O>C(N(CC)CC)C>[OH:1][C@@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[N:7]1[C:9](=[O:8])[C:15]2=[CH:16][CH:20]=[CH:21][CH:22]=[C:23]2[C:24]1=[O:25]
Reactant: COC1C(=C=O)C=CC=C1C(=O)Cl
Reactant: C1CCOC1
Reactant: N[C@@H]1C=CC[C@H]1O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=CC[C@H]1O

Procedure:
A quantity of dl-trans-4-hydroxy-3-amino-cyclopentene is dissolved in 450 ml. of tetrahydrofuran and 87 ml. (0.60 M) of triethylamine. The solution is cooled to 0° and treated dropwise with 59.6 g. (0.3 M) of o-methoxy-carbonylbenzoylchloride over 50 min. The reaction is then allowed to warm to 25°. After 66 hours the reaction is partitioned between ethyl acetate and water. The ethyl acetate layer is dried over magnesium sulfate and distilled in vacuo to yield 62.4 g. of residual oil. This is chromatographed over 3 kg. of silica gel 60 eluted with 6 l. of (10-90), 2.5 l. of (15-85), and 11 l. of (20-80) acetonemethylene chloride. Two hundred fifty ml. fractions are collected. The product is found in fractions 38-61. These fractions crystallized on standing to yield 25.9 g. of dl-trans-4-hydroxy-3-phthalidocyclopentene.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.[Li]CCCC.[Br:15]Br>C1COCC1.C1CCCCC1>[Br:15][C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1nc(C(=O)O)cs1
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)c(Br)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-thiazole-4-carboxylic acid (13.0 g, 90.8 mmol) was dissolved in 750 ml THF and cooled to −75° C. n-BuLi (1.6M in THF; 120 ml, 190.7 mmol) was added dropwise in 30 minutes. The red suspension was stirred for 15 min. at −75° C. and 30 min. at 0° C. A solution of bromine (5.1 ml, 100 mmol) in 20 ml cyclohexane was added dropwise at −75° C. and stirring was continued at room temperature for 2 hrs. The reaction mixture was quenched with 20 ml water, evaporated and acidified with 2N HCl to pH 2. The aqueous layer was extracted two times with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (16.4 g, 81%) [MS: m/e=223.0 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:9]2N=C[CH:12]=[CH:11][N:10]=2)[CH2:6][C@H:5]1[NH:15][C:16]1[C:21]([CH2:22][CH3:23])=[N:20][C:19]([C:24]2[C:25]([CH3:32])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:18]([CH2:33][CH3:34])[N:17]=1)[CH3:2].BrC1[S:37]C=CN=1>>[CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:9]2[S:37][CH:12]=[CH:11][N:10]=2)[CH2:6][C@H:5]1[NH:15][C:16]1[C:21]([CH2:22][CH3:23])=[N:20][C:19]([C:24]2[C:25]([CH3:32])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:18]([CH2:33][CH3:34])[N:17]=1)[CH3:2]
Reactant: Brc1nccs1
Reactant: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromo-1,3-thiazole provided the title compound as an amporphous solid:
Reaction SMILES: [O:1]1CCOCC1.[CH3:7][O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][CH:18]3[C:23]#[N:24])=[CH:11][CH:10]=1.[Se](=O)=O>O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][CH:18]3[C:23]#[N:24])=[O:1])=[CH:25][CH:26]=1
Reactant: COc1ccc(Cc2cccc3c2CCC3C#N)cc1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Product: COc1ccc(C(=O)c2cccc3c2CCC3C#N)cc1

Procedure:
To 60 ml. of dioxane are added 8.0 g. of 4-(p-methoxybenzyl)indan-1-carbonitrile and 2.8 g. of selenium dioxide and the mixture is refluxed for 12 hours. After cooling, water is added, followed by extraction with chloroform. The extract is washed with water and dried. Then, the solvent is distilled off under reduced pressure and the residue is purified by column chromatography (500 g. silica gel; eluted with chloroform). The crude crystals thus obtained are recrystallized from benzene. The procedure gives 4-(p-methoxybenzoyl)indan-1-carbonitrile as crystals melting at 115.5°-117.5° C.
Reaction SMILES: BrBr.[OH-:3].[Na+].[CH3:5][C:6]1([CH3:22])[C@@H:8]([C:9](=[O:11])C)[C@@H:7]1[CH:12]=[C:13]([Cl:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>O.O1CCOCC1>[CH3:22][C:6]1([CH3:5])[C@@H:8]([C:9]([OH:11])=[O:3])[C@@H:7]1[CH:12]=[C:13]([Cl:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: CC(=O)[C@H]1[C@H](C=C(Cl)c2ccc(Cl)cc2)C1(C)C
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)[C@@H](C=C(Cl)c2ccc(Cl)cc2)[C@@H]1C(=O)O
Reaction time: 3 h
Yield: 75 %

Procedure:
13.8 g of bromine were added dropwise to a solution of 11.5 g of sodium hydroxide in 60 ml of water at 5°-10° C., and a solution of 8.1 g (0.029 mol) of trans-3,3-dimethyl-2-(2-chloro-2-(4-chloro-phenyl)-vinyl)-1-acetylcyclopropane in 30 ml of dioxane was then added dropwise at 0°-5° C. The mixture was subsequently stirred for 3 hours, without cooling, poured onto 250 ml of water and extracted twice with 50 ml of ether each time. The aqueous phase was freed from adhering ether in vacuo and then brought to pH 2 by adding aqueous hydrochloric acid. After crystallization, the product was filtered off and rinsed with water. 6.2 g (77% of theory) of trans-3,3-dimethyl-2-(2-chloro-2-(4-chloro-phenyl)-vinyl)-cyclopropanecarboxylic acid were thus obtained in the form of pale yellow-colored crystals with a melting point of 103°-106° C.
Reaction SMILES: [Br:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[S:24]>CC(C)=O>[BrH:1].[CH2:4]([C:3]1([OH:11])[N:20]2[CH2:21][CH2:22][CH2:23][N:18]=[C:19]2[S:24][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cc1ccccc1)C(Br)c1ccccc1
Reactant: S=C1NCCCN1
Solvent: CC(C)=O
Product: Br
Product: OC1(Cc2ccccc2)C(c2ccccc2)SC2=NCCCN21
Reaction time: 4 h
Yield: 56.8 %

Procedure:
A solution of 2.9 grams of 1-bromo-1,3-diphenyl-2-propanone (Example 93) in 30 ml. of acetone is added to a solution of 1.16 grams of tetrahydro-2-pyrimidinethione in 100 ml. of acetone. A white precipitate forms in a few minutes. After standing at room temperature for four hours, the precipitate is collected, washed with acetone, and dried. Recrystallization from 20 ml. of ethanol yields 2.3 grams of the pure compound, melting at 192°-194° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([Cl:9])=[O:8])[N:6]=1.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:12]=1>>[ClH:9].[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[C:13]([N:25]2[CH2:30][CH2:29][N:28]([C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH2:27][CH2:26]2)[N:12]=1
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)c4csc(C)n4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared from 2-methylthiazole-4-carbonyl chloride (0.49 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.87 g.) following previously described procedures. The product had a m.p. of 260°-263° C. with decomposition.