Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][OH:15])[CH2:20][CH2:21]2)=[CH:6][CH:7]=1
Reactant: OCCCN1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: OCCCN1CCN(c2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
3,6-dichloropyridazine (14.90 g, 100 mmol), sodium carbonate (10.60 g, 100 mmol) and DMA (80 mL) were placed in a 250 mL three-necked bottle, and the solution of 1-(3-hydroxypropyl)piperazine (14.4 g, 100 mmol) in DMA (20 mL) was added slowly in dropwise within 30 min under an ice-bath condition. The mixture was stirred at room temperature overnight, distilled under a reduced pressure to remove the solvent to obtain a brown solid, which was subjected to a column chromatography (gradient elution: petroleum/acetone system, v/v 2: 1 to acetone) to obtain a white solid, 13 g, yield 50.8%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[S:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[C:28]2[CH:35]=[CH:36][CH:37]=[CH:38][C:27]1=2>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:31]([C:29]3[C:28]4[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=4[S:26][CH:30]=3)(=[O:32])=[O:33])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S(=O)(Cl)c1csc2ccccc12
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)c3csc4ccccc34)CC2)nc1N

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, Example 59, and benzo[b]thiophene-3-sulfonyl chloride (Maybridge) by the procedure described in Example 152. HR-MS (ES, m/z) calculated for C25H25FN5O4S2 [(M+H)+] 542.1327, observed 542.1331.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2=[C:9]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:10]=[C:11]([C:13]([OH:15])=O)[CH:12]=[C:7]2[C:6]([CH3:26])=[C:5]1[CH3:27])[CH:2]=[CH2:3].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:60][C:61]1[CH:68]=[CH:67][C:64]([CH2:65][NH2:66])=[CH:63][CH:62]=1>ClCCl>[CH2:1]([N:4]1[C:8]2=[C:9]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:10]=[C:11]([C:13]([NH:66][CH2:65][C:64]3[CH:67]=[CH:68][C:61]([CH3:60])=[CH:62][CH:63]=3)=[O:15])[CH:12]=[C:7]2[C:6]([CH3:26])=[C:5]1[CH3:27])[CH:2]=[CH2:3]
Reactant: C=CCn1c(C)c(C)c2cc(C(=O)O)nc(N3CCc4ccccc4C3)c21
Reactant: Cc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=CCn1c(C)c(C)c2cc(C(=O)NCc3ccc(C)cc3)nc(N3CCc4ccccc4C3)c21
Yield: 23.6 %

Procedure:
A solution of 1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (30 mg, 0.083 mmol) prepared in Example 732, 1-hydroxybenzotriazole hydrate (16.9 mg, 0.125 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.9 mg, 0.125 mmol), diisopropylethylamine (43.4 μl, 0.25 mmol), and 4-methylbenzylamine (15.9 μl, 0.125 mmol) in dichloromethane (1 ml) was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 9.1 mg of the titled compound as a white solid. (Yield: 45%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[O:16]=[C:17]1[C:25]2([C:29]3=[CH:30][C:31]4[O:32][CH2:33][CH2:34][O:35][C:36]=4[CH:37]=[C:28]3[O:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:43](=[O:44])[C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3([C:29]4[C:28](=[CH:37][C:36]5[O:35][CH2:34][CH2:33][O:32][C:31]=5[CH:30]=4)[O:27][CH2:26]3)[C:17]2=[O:16])=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Reactant: Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1F)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 50.1 %

Procedure:
To a stirred solution of 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (0.400 g, 0.93 mmol) in anhydrous chloroform (20 mL) was added thionyl chloride (0.27 mL, 3.7 mmol). The solution was heated at reflux for 2 h and concentrated in vacuo to afford 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoyl chloride (0.45 g) as a pale yellow solid. To a solution of 2-fluoroaniline (0.1 mL, 1.0 mmol) and triethylamine (0.43 mL, 3.1 mmol) in anhydrous dichloromethane (10 mL) at 0° C. under nitrogen was added 4-((2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.46 g, 1.0 mmol). The reaction mixture was stirred at ambient temperature for 42 h and was washed with 10% w/v hydrochloric acid (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with hexanes/ethyl acetate (1/1) to afford N-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.262 g, 49%) as a colorless solid: mp 245-251° C.; 1H NMR (300 MHz, CDCl3) δ 8.48-8.43 (m, 1H), 8.11-8.04 (m, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.24-7.02 (m, 6H), 6.75 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.16 (d, J=15.9 Hz, 1H), 4.95 (d, J=8.7 Hz, 1H), 4.89 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.21-4.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 164.9, 155.3, 152.7 (d, J=241.4 Hz), 144.7, 141.7, 140.0, 138.3, 134.1, 132.2, 128.8, 127.8 (d, J=4.1 Hz), 126.4 (d, J=9.8 Hz), 124.7-124.6 (m), 124.1, 123.7, 121.8, 120.8, 114.8 (d, J=19.1 Hz), 111.4, 109.1, 99.5, 80.1, 64.5, 63.9, 58.0, 43.8; MS (ES+) m/z 523.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:55]=[CH:54][CH:53]=[CH:52][C:5]=1[CH2:6][O:7][C:8]([NH:10][CH:11]1[CH:14]([CH2:15][CH2:16][OH:17])[N:13]([P:18]([CH2:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N+:48]([O-:50])=[O:49])=[O:39])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]1=[O:51])=[O:9])([O-:3])=[O:2].CC(C)=[O:58].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>C(Cl)Cl>[N+:1]([C:4]1[CH:55]=[CH:54][CH:53]=[CH:52][C:5]=1[CH2:6][O:7][C:8]([NH:10][CH:11]1[CH:14]([CH2:15][C:16]([OH:58])=[O:17])[N:13]([P:18]([CH2:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N+:48]([O-:50])=[O:49])=[O:39])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]1=[O:51])=[O:9])([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=C(CP(c1ccccc1)(c1ccccc1)(c1ccccc1)N1C(=O)C(NC(=O)OCc2ccccc2[N+](=O)[O-])C1CCO)OCc1ccccc1[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(O)CC1C(NC(=O)OCc2ccccc2[N+](=O)[O-])C(=O)N1P(CC(=O)OCc1ccccc1[N+](=O)[O-])(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
One gram of 3-(o-nitrobenzyloxycarbonylamino)-1-(o-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4-(2-hydroxyethyl)-2-azetidinone is dissolved in 20 ml. acetone and cooled to 0° C. Jones Reagent (1 ml., 4 N solution) is added dropwise over 5 min. and the resulting solution is stirred at 0° C. for 10 min. Isopropanol (0.1 ml.) is added. The mixture is stirred for another 2 min. The reaction mixture is diluted with CH2Cl2 and filtered. The filtrate is washed with saturated NaCl solutin, dried and evaporated to give the title compound which is used without further purification in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)=[O:12])[CH:3]=[CH:2]1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Product: O=C(c1cccc2cc[nH]c12)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Indole-7-carboxylic acid (3.20 g, 0.02 mole) was dissolved in 30 ml of dimethylformamide (DMF) and chilled with ice-water. N,N'-Carbonyldiimidazole (3.30 g, 0.02 mole) was then added and the reaction mixture was allowed to stir for 1 hour. At the end of this time N-phenylpiperazine (4.0 g, 0.025 mole) was added, the cold bath was removed., and the reaction mixture was allowed to come to room temperatureover 3 hours. The product was filtered off and recrystallized form toluene to give 3.30 g (54%) of 1-(1H-indol-7-ylcarbonyl)-4-phenylpiperazine, m.p.217°-219° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:16]#[C:17][Si](C)(C)C)=[O:5])[CH3:2].[OH:22]S(O)(=O)=O.CC(C)=O>O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:16](=[O:22])[CH3:17])=[O:5])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C#C[Si](C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C(C)=O
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-1,5-dimethyl-6-oxo-2-trimethylsilanylethynyl-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent), HgSO4 (1.00 equivalent) and H2SO4 (2.00 equivalents) in 6:1 acetone:water is refluxed for 3 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with a mixture of THF and ethyl acetate and washed with water and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure. The desired product is obtained by flash column chromatography as necessary.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]2[O:8][CH:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[N:10]=2)[CH2:12][CH2:13]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)c1coc(C2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1coc(C2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Ethyl 2-(4-piperidino)-1,3-oxazole-4-carboxylate (500 mg, 2.230 mmol) and triethylamine (0.466 ml, 3.34 mmol) were dissolved in dry DCM and cooled down to 0° C. Methanesulfonyl chloride (0.190 ml, 2.453 mmol) was added slowly at 0° C. and the reaction mixture was stirred at RT overnight. Small amount of water was added carefully and organic phase was washed with 1M Na2CO3 and water. Organic phase was dried and evaporated to yield the title compound 89%. 1H-NMR (400 MHz; CDCl3): δ 1.38 (t, 3H), 1.97-2.11 (m, 2H), 2.15-2.24 (m, 2H), 2.81 (s, 3H), 2.88-3.07 (m, 3H), 3.72-3.82 (m, 2H), 4.39 (q, 2H), 8.17 (s, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH:29]1[C:34]([NH2:35])=[CH:33][CH:32]=[C:31]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)[CH:30]=1>Cl>[CH:26]1[C:25]([NH2:28])=[CH:24][CH:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:4]4[CH:5]=[CH:6][C:1]([NH:35][C:34]5[CH:29]=[CH:30][C:31]([NH:36][C:37]6[CH:42]=[CH:41][C:40]([NH:43][C:44]7[CH:49]=[CH:48][C:47]([NH:50][C:1]8[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=8)=[CH:46][CH:45]=7)=[CH:39][CH:38]=6)=[CH:32][CH:33]=5)=[CH:2][CH:3]=4)=[CH:13][CH:12]=3)=[CH:16][CH:17]=2)[CH:27]=1
Reactant: Nc1ccc(Nc2ccc(Nc3ccc(Nc4ccccc4)cc3)cc2)cc1
Reactant: Nc1ccc(Nc2ccc(Nc3ccc(N)cc3)cc2)cc1
Agent: Cl
Product: Nc1ccc(Nc2ccc(Nc3ccc(Nc4ccc(Nc5ccc(Nc6ccc(Nc7ccc(Nc8ccc(N)cc8)cc7)cc6)cc5)cc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ferric chloride hexahydrate 5.4 g (0.02 mole) was dissolved in 20 ml 0.1 M HCl at room temperature. The tetraaniline in the leucoemeraldine oxidation state from Example 3 above 3.66 g (0.01 mole) was suspended in 250 ml 0.1 M HCl solution with magnetic stirring for 0.5 hours at room temperature. The ferric chloride solution was added very quickly (within 1~2 seconds) to the tetraaniline suspension with strong stirring. The suspension was then stirred magnetically for 2 hours. The reaction mixture was filtered, washed and neutralized following the general procedure described herein.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:51]([Cl:52])=[C:50]([Cl:53])[CH:49]=[CH:48][N:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:51]([Cl:52])=[C:50]([Cl:53])[CH:49]=[CH:48][N:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccnc(CBr)c1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloropyridine hydrobromide and isolated as white solid. MS (m/e): 442.2 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:39][CH:36]([CH3:38])[CH3:37])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Reactant: CC(C)N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNC(C)C)CCC2)c1=O

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268 g) and isopropylamine using a similar method to that described for example 167f.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.ClCCl.C(O)C.N>ClCCl.CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:4]2)=[O:28])=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCC1CN(C(=O)OCc2ccccc2)CCO1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: O=C(NCC1CN(C(=O)OCc2ccccc2)CCO1)Nc1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of Intermediate 5 (2.0 g) in dichloromethane (100 ml) was added 4-chlorophenylisocyanate (1.35 g). The mixture was stirred at 22° C. for 18 h before 10% 0.880 ammonia solution in methanol (10 ml) was added. Stirring was continued for a further 30 min before the solvent was removed in vacuo. The residue was purified by Biotage flash chromatography on silica gel, eluting with 33% ethyl acetate/cyclohexane; further purification by Biotage flash chromatography on silica gel, eluting with 500:8:1 dichloromethane/ethanol/0.880 ammonia solution gave the impure title compound as a buff solid (3.6 g).
Reaction SMILES: C(O)(=O)C.[O-:5][C:6]#[N:7].[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([S:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[NH:24][C:25](=[O:36])[C@:26]([O:32][C:33](=[O:35])[CH3:34])([CH3:31])[C:27]([F:30])([F:29])[F:28]>C1COCC1.O>[Cl:9][C:10]1[CH:15]=[C:14]([S:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:6]([NH2:7])=[O:5])=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]=1[NH:24][C:25](=[O:36])[C@:26]([O:32][C:33](=[O:35])[CH3:34])([CH3:31])[C:27]([F:30])([F:28])[F:29]
Reactant: N#C[O-]
Reactant: CC(=O)O[C@](C)(C(=O)Nc1ccc(Sc2ccc(N)cc2)cc1Cl)C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@](C)(C(=O)Nc1ccc(Sc2ccc(NC(N)=O)cc2)cc1Cl)C(F)(F)F
Reaction time: 2 h
Yield: 65.3 %

Procedure:
Water (0.34 ml), acetic acid (0.54 ml) and sodium cyanate (0.104 g dissolved in 0.3 ml of water) were added to a solution of (R)-N-[2-chloro-4-{4-aminophenylsulphanyl}phenyl]-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (0.432 g) (Method 22) in THF (0.8 ml. The mixture was stirred for 2 hours then diluted with water (5 ml) and extracted with ethyl acetate (2×20 ml). The extracts were poured onto a Varian Chem Elut column and eluted with ethyl acetate. Volatile material was removed by evaporation and the residue was triturated with ether to give the title compound (0.31 g) as a solid. NMR: 1.8 (s, 3H), 2.2 (s, 3H), 5.9 (s, 2H), 7.1 (s, 3H), 7.4 (d, 2H), 7.5 (d, 2H). 8.8 (s, 1H), 9.9 (s, 1H); MS (ESP−): 474.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].[Br:8]CC([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=O.C[O:18][C:19](C)(C)[CH3:20]>C(O)C>[Br-:8].[SH:13]1([C:19](=[O:18])[CH2:20][N+:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][CH:4]=2)[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC(C)(C)C
Reactant: Cc1ncsc1C
Reactant: O=C(CBr)c1cccs1
Solvent: CCO
Product: Cc1sc[n+](CC(=O)[SH]2C=CC=C2)c1C
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4,5-dimethylthiazole (2.2 g, 19.4 mmol) and 2-bromoacetylthiophene (4 g, 19.4 mmol) in ethyl alcohol (20 mL) was refluxed for 3 hours. It was cooled to room temperature and t-butyl methyl ether (10 mL) was added. The reaction mixture was left at room temperature overnight with stirring. The white product separated and was filtered and dried. It was crystallized from ethyl alcohol (4.42 g, 73%), m.p. 203-205° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C@@H:14]1([OH:20])[CH2:18][CH2:17][CH2:16][C@H:15]1[OH:19]>CN(C=O)C>[O:19]([C@@H:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[OH:20])[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O[C@@H]1CCC[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of t-butyldimethylsilyl chloride (5.08 g, 33.7 mmol) and imidazole (2.30 g, 33.7 mmol) in DMF (10 mL), a solution of trans-1,2-cyclopentanediol in DMF (4 mL) was added. The reaction mixture was stirred overnight at 25° C. The reaction mixture was diluted with ice water and extracted with ether. The ether extract was washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, 9:1 hexane:ethyl acetate) to the title compound as an oil (3.44 g, 49%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]([CH3:32])[CH3:31])[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]([CH3:32])[CH3:31])[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC(C)C)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OC(C)C)c23)c1
Yield: 64.4 %

Procedure:
Using an analogous procedure to that described in Example 20, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-isopropoxyquinazoline (0.33 g) was reacted with trifluoroacetic acid. There was thus obtained the title compound (0.17 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.55 (d, 6H), 3.85 (s, 3H), 5.1 (m, 1H), 6.8 (s, 1H), 6.92 (s, 1H), 7.0 (m, 1H), 7.58 (d, 1H), 7.65 (d, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 360 and 362.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[OH:11].[CH3:19]I>C1COCC1>[CH3:19][O:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:9][CH2:8][CH:4]1[O:5][CH2:6][CH2:7][O:3]1
Reactant: CI
Reactant: Cc1ccccc1C(O)CCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CCC1OCCO1)c1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a suspension of NaH (468 mg of a 60% dispersion in mineral oil, 11.7 mmol) in 35 mL THF was slowly added 3-[1,3]Dioxolan-2-yl-1-o-tolyl-propan-1-ol (290.0 mg, 1.3 mmol) as a solution in 15 mL THF at room temperature followed by the dropwise addition of methyl iodide (624 L, 1.4 g, 9.6 mmol). The mixture was stirred for 3 h at room temperature before being quenched by the careful addition of saturated aqueous NH4Cl (40 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL) and dried over sodium sulfate. The solvents were evaporated under reduced pressure and the product isolated by flash column chromatography eluting with 0% to 30% ethyl acetate/hexane to give 285 mg of the title compounds as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH:3]=[O:4].C(N(CC)CC)C.[C:23]([O-])(=[O:25])[CH3:24].[Na+].O>C(OC(=O)C)(=O)C>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:2]([CH3:1])=[CH:3][O:4][C:23](=[O:25])[CH3:24])=[CH:11][CH:10]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Yield: 459.7 %

Procedure:
A solution of 200 g 2-methyl-3-(4-tert-butylphenyl)-propanal, 280 ml triethylamine and 13.4 g sodium acetate in 800 ml of acetic anhydride was stirred at 120° C. for 5.5 hours. Then the solution was cooled, water was added and the water phase was extracted with hexane. The organic phase was washed with 2N NaOH and water to neutrality, dried and evaporated to dryness. The residue was distilled to yield 185 g of a colorless liquid.