Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.[C:13](OCC)(=[O:16])[CH2:14][CH3:15]>C1COCC1>[CH3:7][C:5]1[N:6]=[C:2]([CH2:1][C:13](=[O:16])[CH2:14][CH3:15])[S:3][CH:4]=1
Reactant: CCOC(=O)CC
Reactant: Cc1csc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)Cc1nc(C)cs1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
3.00 g (26.5 mmol) of 2,4-dimethylthiazole are dissolved in 30 ml of THF and, at −78° C., 11.6 ml (29.2 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for 2 hours, 4.60 g (45.1 mmol) of ethyl propionate are added as solution in 15 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. 3.5 g (39% of theory) of the title compound are obtained in 50% purity (GC-MS) and are employed without further purification.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[NH2:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([NH:16][C@H:17]([C:19]2[N:23]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:22]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=3[N:20]=2)[CH3:18])[N:11]=[CH:10][N:9]=1.OO>CS(C)=O>[NH2:7][C:8]1[C:13]([C:14]([NH2:15])=[O:2])=[C:12]([NH:16][C@H:17]([C:19]2[N:23]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:22]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=3[N:20]=2)[CH3:18])[N:11]=[CH:10][N:9]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cccnc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](Nc1ncnc(N)c1C(N)=O)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of potassium carbonate (0.027 g, 0.19 mmol) and (S)-4-amino-6-(1-(6-fluoro-1-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethylamino)pyrimidine-5-carbonitrile (0.060 g, 0.16 mmol) in DMSO (1.60 mL) was added hydrogen peroxide (31.3% in water, 0.078 mL, 0.80 mmol) dropwise under nitrogen atmosphere. The solution was stirred at 0° C. for 1 h then was partitioned between water and EtOAc. Organic extracts were concentrated under reduced pressure then purified by MPLC (eluted with a gradient of 0-10% MeOH in DCM) to afford 4-amino-6-(((1S)-1-(6-fluoro-1-(3-pyridinyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarboxamide as an off-white foam. 1H NMR (400 MHz, DMSO-d6) d ppm 1.48 (d, J=6.85 Hz, 3H) 5.26 (quin, J=6.94 Hz, 1H) 6.57 (s, 2H) 6.98 (dd, J=8.90, 2.45 Hz, 1H) 7.14 (ddd, J=9.78, 8.80, 2.54 Hz, 1H) 7.46 (s, 2H) 7.65-7.70 (m, 1H) 7.74 (dd, J=8.80, 4.89 Hz, 1H) 7.77 (s, 1H) 7.94 (d, J=7.63 Hz, 1H) 8.05-8.12 (m, 1H) 8.78 (dd, J=4.79, 1.47 Hz, 1H) 8.82 (d, J=2.15 Hz, 1H). LC-MS (ESI) m/z 393.2 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[C:1]1([NH:7][N:8]=[C:10]([CH3:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)CC(C)=NNc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of phenyl hydrazine (125 g, 1150 mmol) and ethyl 3-oxobutanoate (100 g, 770 mmol) in terbutyl dimethyl ether (1000 mL) acetic acid (2 mL) was added. The resulting mixture was stirred at 0° C. for 1 h. The solvent was evaporated under vacuum. The residue (220 g) was used as such for next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH2:25][CH3:26])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1

Procedure:
A mixture of 3-hydroxy-5-nitro-4-phenylbenzoic acid (22 g; prepared as in Example 2, step B), conc. sulfuric acid (10 ml) and ethanol (400 ml) is refluxed for 20 hours. The resulting solution is concentrated in vacuo to about 100 ml and is then diluted with water (about 300 ml). The separated ethyl 3-hydroxy-5-nitro-4-phenylbenzoate is collected by filtration, washed with water and dried. After recrystallization from carbon tetrachloride, the ester is obtained with a melting point of 128°-130° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]1[CH2:63][CH2:62][N:61](C(OC(C)(C)C)=O)[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:57][CH:58]5[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and tert-butyl 4-aminopiperidine-1-carboxylate, where Boc was removed using TFA in DCM. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (qd, J=11.9, 3.8 Hz, 2 H) 1.54-1.66 (m, 5 H) 1.66-1.77 (m, 4 H) 1.98 (br. s, 2 H) 2.52 (d, J=1.8 Hz, 2 H) 2.98 (d, J=11.9 Hz, 2 H) 3.79-3.87 (m, 1 H) 3.93 (s, 3 H) 4.04 (t, J=14.2 Hz, 2 H) 4.76 (quin, J=8.1 Hz, 1 H) 7.48 (d, 1 H) 7.50 (s, 1 H) 7.96 (s, 1 H) 8.13 (d, J=8.1 Hz, 1 H) 8.26 (d, J=8.1 Hz, 1 H) 8.26 (s, 1 H). [M+H] calc'd for C26H33F2N7O3, 530; found 530.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)[C:15]2=[O:20].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][N:14]([CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(N)cccc3C2=O)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCN2Cc3c(NC(=O)c4ccc(Cl)s4)cccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 0.97 g (5.35 mmol) of 5-chlorothiophene-2-carbonyl chloride is added dropwise to a suspension of 1.48 g (4.12 mmol) of tert-butyl 4-[2-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) ethyl]-1-piperidinecarboxylate, 1.7 ml (20.6 mmol) of pyridine and 25 mg (0.206 mmol) of 4-DMAP in 21 ml of absolute THF. The mixture is slowly warmed to room temperature and stirred overnight. The reaction mixture is concentrated and then separated by chromatography on silica gel (dichloromethane/methanol 97:3).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.Cl.[CH3:15]O>>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:15])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: CO
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Product: COC(=O)c1ccc2[nH]c(C)nc2c1

Procedure:
46.6 g (0.202 mol) of 18a are reacted with methanol and gaseous hydrogen chloride in analogy to Example 14b.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:32])=[CH:4][CH:5]1[N:9](C(OCC)=O)[C:8](=[O:15])[N:7]([CH2:16][C:17]2[N:24]3[C:20]([S:21][C:22]([CH2:25][O:26]C)=[N:23]3)=[N:19][C:18]=2[C:28]([F:31])([F:30])[F:29])[CH2:6]1>>[Cl:1][C:3]([F:32])([F:2])[CH2:4][CH:5]1[CH2:6][N:7]([CH2:16][C:17]2[N:24]3[C:20]([S:21][C:22]([CH2:25][OH:26])=[N:23]3)=[N:19][C:18]=2[C:28]([F:31])([F:30])[F:29])[C:8](=[O:15])[NH:9]1
Reactant: CCOC(=O)N1C(=O)N(Cc2c(C(F)(F)F)nc3sc(COC)nn23)CC1C=C(F)F
Reactant: Cl
Product: O=C1NC(CC(F)(F)Cl)CN1Cc1c(C(F)(F)F)nc2sc(CO)nn12
Temperature: 100 °C
Reaction time: 60 h
Yield: 12 %

Procedure:
HCl (37%, 4 ml) is added to ethyl 5-(2,2-difluoroethenyl)-3-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-2-oxoimidazolidine-1-carboxylate a22 (226 mg, 0.48 mmol) at room temperature then stirred at 100° C. for 60 h. After cooling and neutralization by sodium carbonate, the reaction mixture is extracted with CH2Cl2 (2×30 ml), dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by chromatography (basic conditions; gradient; eluent: H2O/CH3CN/NH4CO3/NH4OH 95/5/0.1/0.005 to 40/60/0.1/0.005; 7 min) to afford 25 mg of pure 4-(2-chloro-2,2-difluoroethyl)-1-{[2-(hydroxymethyl)-6-(trifluoromethyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}imidazolidin-2-one 18.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11](Br)=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNCC1
Reactant: CCCCn1c(=O)c2[nH]c(Br)nc2n(CCCC)c1=O
Solvent: Cc1ccccc1
Product: CCCCn1c(=O)c2[nH]c(N3CCCCC3)nc2n(CCCC)c1=O

Procedure:
1,3-Di-n-butyl-8-bromo xanthine (2 g, 0.0029 mol) was dissolved in toluene (50 ml). After addition of piperidine (5 g, 0.0058 mol) the mixture was refluxed for 9 hours. The reaction mixture was then extracted with water (4'30 ml), the organic layer dried over anhydrous sodium sulphate and the solvent removed in vacuo. The residue was recrystallised from ethanol to give the title product, yield 0.4 g (20%), m.pt. 221° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH3:21])[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH3:21])[C:9]2[N:10]=[C:11]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2cnc(S(C)(=O)=O)nc2n(C)c1=O
Reactant: C1CCNC1
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cnc(N3CCCC3)nc2n(C)c1=O

Procedure:
A stirred mixture of 3.27 g. (0.01 mole) of 7,8-dihydro-5-hydroxy-8-methyl-2-(methylsulfonyl)-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester and 0.71 g. (0.01 mole) of pyrrolidine in 50 ml. of ethanol was heated under reflux for 1 hour. The mixture was cooled and was filtered. The filter cake was recrystallized twice from ethyl acetate to afford 1.1 g. of title product--m.p. 174°-177° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6]CC)=[O:5].CO.[OH-].[Na+]>O>[CH3:1][CH:2]([CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCCCCCC(C)CC(C)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCC(C)CC(C)CC(=O)O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere, the crude product (1.22 g, 0.00452 mol) of ethyl 3,5-dimethyldodecanoate (7Et) produced in the method of Example 3-1, methanol (1 ml), a 25% by weight aqueous sodium hydroxide solution (3 ml) were placed in a reaction vessel and stirred at 65° C. for 2 hours. After addition of water, the resulting mixture was washed with a hexane-tetrahydrofuran mixture. The aqueous phase was made acidic in addition of 20% by weight hydrochloric acid, followed by extraction with a hexane-tetrahydrofuran mixture. The organic phase thus obtained was dried over magnesium sulfate and then concentrated under reduced pressure. The concentrate thus obtained was distilled under reduced pressure (bp: from 130 to 140° C./2 mmHg) to obtain 3,5-dimethyldodecanoic acid (5) (1.03 g, 0.00452 mol). A total yield of the three steps from the 2-methylnonyl chloride (1 Cl) was 60%.
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].Cl>>[C@@H:11]12[O:12][CH2:2][C@H:3]([O:4]1)[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]2[OH:10]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Product: O[C@@H]1[C@H](O)[C@@H]2OC[C@H](O2)[C@H]1O
Yield: 35.5 %

Procedure:
A mixture of L-gulose (1) (33 g,0.127 mol) and 0.5 N HCl (330 mL, 0.165 mol) was refluxed for 20 hours. The mixture was cooled and neutralized to pH 6 by a resin (Dowex-2, HCO3-form) with air bubbling. The resin was recycled by washing with 10% HCl, water, methanol, water and saturated NaHCO3 solution. The reaction mixture was filtered and the resin was washed with water (500 mL). The combined filtrate was concentrated to dryness and dried in vacuo overnight. The residue was purified over a column (5 cm depth, silica gel, mesh, CHCl3—CH3OH, 10:1) to give a slightly yellow solid, which was recrystallized from absolute alcohol to give a colorless solid (2) [Rf=0.43 (CHCl3—CH3OH, 5:1), 7.3 g, 35.52%]. The L-gulose Rf=0.07, 11 g) obtained was recycled to give (2) (5 g, total yield 60%):mp 142.5-145° C.; 1H NMR (DMSO-d6) δ 3.22-3.68 (m, 4H, H-2, -3, -4 and -6a), 3.83 (d,J6b,6a=7.25 Hz, 1H, Hb-6), 4.22 (pseudo t, J5,6a=4.61 and 4.18 Hz, H, H-5), 4.46 (d, J2-OH, 2=6.59 Hz, 1H, 2-OH, exchangeable with D2O), 4.62 (d, J3-OH,3=5.28 Hz, 1H, 3-OH, exchangeable with D2O), 5.07 (d, J4-OH,4=4.84 Hz, 1H, 4-OH, exchangeable with D2O), 5.20 (d, J1,2=2.19 Hz, 1H, H-1). [α]D25−50.001 (c, 1.61, CH3OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(C(O)c2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCC(C(Cl)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-fluorophenyl 1-methylpiperidin-4-yl methanol 1.2 g (4.98 mmol) in toluene (5 ml) was added thionyl chloride (0.44 ml) dropwise. The resulting mixture was stirred at room temperature over night. The mixture was then made alkaline with NaOH solution and extracted with ethyl acetate (3×40). The combined organic solution was dried and concentrated to give 1.1 g of desired product.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]2([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].[NH:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1.N12CCCN=C1CCCCC2>C(#N)C>[C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:5][N:6]([C:8]2([CH3:21])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CC(=CC#N)C2)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1

Procedure:
A 2 L round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl 4-[3-(cyanomethylene)azetidin-1-yl]-4-methylpiperidine-1-carboxylate (9.17 g, 0.0472 mol), 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (14.9 g, 0.0472 mol) and acetonitrile (300 mL). The resulting solution was heterogeneous. To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.48 mL, 0.0567 mol) portionwise via a syringe over 3 minutes at room temperature. The solution slowly became homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 hours. The solution was concentrated on a rotovap to remove ˜150 mL of acetonitrile. After addition of 100 mL of EtOAc and 100 mL of 20% brine, the organic phase was separated. The aqueous layer was extracted with 150 mL of EtOAc. The combined organic phase was dried over MgSO4, filtered and concentrated to yield an orange oil. Purification by flash chromatography (150 grams of silica, 60% EtOAc/hexanes, loaded with CH2Cl2) yielded the title compound as a white foam. LC-MS: 607.2 (M+H)+.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:15]([CH2:14][CH2:13][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCOc1ccccc1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCCOc1ccccc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a solution of methyl salicylate (100.0 g, 657 mmol) in N,N-dimethylformamide (100 ml) were added β-bromophenetole (138.8 g, 690 mmol) and potassium carbonate (136.3 g, 986 mmol), and the mixture was stirred at 80° C. for 10 hr. After cooling the reaction mixture, water (1000 ml) was added, and the precipitated insoluble material was filtered to give methyl 2-(2-phenoxyethoxy)benzoate. This was suspended in methanol (250 ml), aqueous solution (200 ml) of sodium hydroxide (32 g, 800 mmol) was added at room temperature, and the mixture was stirred at 70° C. for 2 hr. After cooling, the mixture was neutralized with 6N-aqueous hydrochloric acid solution, and the precipitated insoluble material was filtered to give a carboxylic acid compound 2-(2-phenoxyethoxy)benzoic acid (160.8 g, 623 mmol, yield 95%). The obtained carboxylic acid compound (160.8 g, 623 mmol) was suspended in toluene (320 ml), thionyl chloride (81.5 g, 685 mmol) was added, and the mixture was stirred at 40° C. for 4 hr. N,N-Dimethylhydrazine (82.2 g, 1.37 mol) was added under ice-cooling, and the mixture was further stirred at room temperature for 0.5 hr. The reaction mixture was added dropwise to water (1000 ml), and the precipitated insoluble material was filtered to give an acylhydrazine compound N′,N′-dimethyl-2-(2-phenoxyethoxy)benzohydrazide 131.6 g (yield 70%) as a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)CCN
Product: CCN(CC)C(=O)c1ccc(NCCC(C)C)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 103.5 %

Procedure:
Following general procedure 2B, N,N-diethyl-4-fluoro-3-nitrobenzamide (1.077 g, 4.48 mmol) and 3-methyl-1-butanamine (0.68 mL, 5.83 mmol) were stirred at 85° C. for 14 h to provide the title compound (1.425 g) as an orange oil. The crude product was used in subsequent steps. 1H-NMR (CD3OD): δ 8.22 (d, J=2.0 Hz, 1H), 7.56 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 7.09 (d, J=9.2 Hz, 1H), 3.52–3.40 (br m, 6H), 1.83–1.72 (m, 1H), 1.64 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 6H), 1.01 (d, J=6.8 Hz, 6H). MS (ESI) (M+H)+=308.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20](OCC)=[O:21])=[N:16][N:15]4[C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[NH3:32]>CO>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20]([NH2:32])=[O:21])=[N:16][N:15]4[C:25]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 130 °C
Yield: 72 %

Procedure:
A mixture of ethyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Example 4, (1.00 g, 93% purity) and ammonia (17.3 mL of a 7M solution in methanol) was heated at 130° C. under microwave irradiation for 5 hours. The volatile components were removed by distillation under reduced pressure. Crystallization from methanol/diisopropyl ether gave the title compound (672 mg, 72% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13].Cl[S:22]([C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][C:26]=1[O:41][CH3:42])(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:22]([C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[CH:27][C:26]=1[O:41][CH3:42])(=[O:24])=[O:23])[C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[NH:12][CH3:13]
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)Cl
Reactant: CNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Product: CNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(C(=O)OCc3ccccc3)cc2OC)c2ccc(Cl)cc21
Yield: 86.2 %

Procedure:
This compound is prepared according to the procedure described in step A of EXAMPLE 28 from 6 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)-indol-2-one and 6.66 g of benzyl 4-chlorosulfonyl-3-methoxybenzoate. 10.3 g of the expected product are obtained after crystallization from iso ether.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[Cl:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[Cl:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CCCO
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 422 (0.21 mmol) and but-3-yn-1-ol (0.21 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 30:70 to 100:0 as the eluent to afford the title compound as light yellow foam.