Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)C)nn4-c4ccccc4)c3)c2cc1OC
Yield: 71.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (125 mg, 0.4 mmol), prepared as described in Example 115B, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-isopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (129 mg, 0.4 mmol) described in Example 324A. The suspension was filtered and triturated with anhydrous diethyl ether to afford 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea (154 mg, 71%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, J=7.2 Hz, 6H), 2.88 (m, 1H), 3.99 (s, 6H), 6.32 (s, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.25-7.53 (m, 10H), 7.79 (m, 1H), 8.47 (s, 1H), 8.69 (s, 1H), 9.21 (s, 1H); LC-MS (ESI) m/z 541 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH:13]=[CH2:14].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C1(C=CC(O)=CC=1)O.O>C(O)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][CH2:14][NH:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)=[CH:29][CH:28]=1
Reactant: C=Cc1cc(OC)c([N+](=O)[O-])cc1Cl
Reactant: CN1CCN(c2ccc(CN)cc2)CC1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: CCCCO
Product: COc1cc(CCNCc2ccc(N3CCN(C)CC3)cc2)c(Cl)cc1[N+](=O)[O-]
Yield: 42.8 %

Procedure:
A mixture of 1-chloro-4-methoxy-5-nitro-2-vinylbenzene (0.42 g, 1.95 mmol), 4-(4-methyl-piperazin-1-yl)-benzylamine (1.2 g, 5.85 mmol) and quinol (0.043 g, 0.39 mmol) in n-butanol (8 mL) was heated to reflux for 12 hours under a N2 atmosphere. Water (100 mL) was added and the reaction mixture extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 3-5% methanol in DCM to give the title compound (0.35 g, 43%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]([NH:40][CH2:41][CH:42]3[CH2:44][CH2:43]3)[S:38][CH:39]=2)=[CH:31][N:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]([NH:40][CH2:41][CH:42]3[CH2:44][CH2:43]3)[S:38][CH:39]=2)=[CH:31][N:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(-c2csc(NCC3CC3)n2)cn1
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(-c4csc(NCC5CC5)n4)cn3)c2CC1)C(F)(F)F
Yield: 30.3 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (316 mg, 0.74 mmol) with 2-aminomethyl-5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine (290 mg, 1.11 mmol) in toluene (8 mL). Filter the crude mixture over Celite®, followed by activated charcoal and wash with dichloromethane. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel (12 g) eluting with hexane/(EtOAc with 1% methanol) (20:1 to 3:2 gradient) to obtain 7-chloro-6-{[5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridin-2-ylmethyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (120 mg, 30%). MS (ES+) m/z: 536.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH:8]=2)[CH:3]=[CH:2]1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:16]4[N:17]=[CH:18][C:19]([C:20]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:21])=[C:15]4[N:14]=[CH:13][C:12]=3[C:23]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:24])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(Nc3ccc4cc[nH]c4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc4cc[nH]c4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 35 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(6-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.092 g, 0.84 mmol), the title compound (0.020 g, 36%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8]O)=[N:4][N:5]([CH3:7])[CH:6]=1.[Br:10]P(Br)Br>ClCCl>[Br:10][CH2:8][C:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH3:7])[N:4]=1
Reactant: BrP(Br)Br
Reactant: Cn1cc(Cl)c(CO)n1
Solvent: ClCCl
Product: Cn1cc(Cl)c(CBr)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-chloro-1-methyl-1H-pyrazol-3-yl)methanol (680 mg, 4.7 mmol) in anhydrous dichloromethane (25 mL) was added dropwise a solution of tribromophosphane (450 μL, 4.7 mmol) in anhydrous dichloromethane (5 mL) at 0° C. The mixture was stirred for 1 hour at room temperature and then was evaporated to yield 3-(bromomethyl)-4-chloro-1-methyl-1H-pyrazole, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:21]=[C:19]1[NH:18][C:17](=[O:22])[C:16](=[CH:15][C:12]2[CH:11]=[CH:10][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[C:30](=[O:31])[CH2:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:4]=3)=[CH:14][CH:13]=2)[S:20]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Product: CN(C(=O)Cc1ccccc1)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (3.2 mmol) of 5-(3′-methylaminobiphenyl-4-ylmethylene)thiazolidine-2,4,dione with 470 μl (3.5 mmol) of phenylacetyl chloride, and after purification, 1.4 g (50%) of N-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-yl]-N-methyl-2-phenylacetamide are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Brc1cccs1
Reactant: Oc1ccc(F)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Fc1ccc(Oc2cccs2)cc1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
A solution of 4-fluorophenol (22.42 g, 200 mmol), 2-bromothiophene (65.22 g, 400 mmol), potassium carbonate (42.84 g, 310 mmol), and copper powder (6.35 g, 100 mmol) in pyridine (200 mL) was refluxed for 18 hours. It was then cooled to ambient temperature and filtered through Celite. The filtrate was diluted with ethyl acetate (500 mL) and washed with water (3×300 mL). The organic phase was dried over MgSO4 and concentrated. The resulting residue was chromatographed (silica gel; hexanes) to afford 3.67 g (9%) of 2-(4-fluorophenoxy)thiophene as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][NH:103][CH2:102]1)([CH3:97])([CH3:96])[CH3:95]>>[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][N:103]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:3]=2)[CH2:102]1)([CH3:97])([CH3:95])[CH3:96]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA7) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 46) by replacing trans-1,4-diaminocyclohexane with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[O:12](S(C(F)(F)F)(=O)=O)[S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14].O>ClCCl>[F:17][C:16]([F:19])([F:18])[S:13]([O:4][CH2:3][CH2:2][F:1])(=[O:14])=[O:12]
Reactant: OCCF
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(OCCF)C(F)(F)F
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of 2-fluoroethanol (3.2 g, 50 mmol) and triethylamine (5.5 g, 55 mmol) in dichloromethane (60 mL) was added dropwise (CF3SO2)2O (15.5 g, 55 mmol) at −78° C. under N2. The mixture was stirred at 10˜20° C. for 1 h, and treated with water (100 mL). The organic layer was washed with satd aq NaHCO3 (100 mL) and brine (100 mL), dried, and concentrated to give 2-fluoroethyl trifluoromethanesulfonate (8 g, yield 82%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][C@@H:18]([CH2:37][C:38]#[C:39][CH2:40][CH3:41])/[CH:19]=[CH:20]/[C@H:21]1[C@H:28]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:27][C@H:26]2[C@@H:22]1[CH2:23][C:24](=[O:36])[O:25]2.C(O)(C)C.O>C1(C)C=CC=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][C@@H:18]([CH2:37][C:38]#[C:39][CH2:40][CH3:41])/[CH:19]=[CH:20]/[C@@H:21]1[C@@H:22]2[C@@H:26]([O:25][CH:24]([OH:36])[CH2:23]2)[CH2:27][C@H:28]1[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1
Reactant: CCC#CC[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CCC#CC[C@@H](/C=C/[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
17.9 ml of a diisobutylaluminium hydride solution (20% in toluene) are added dropwise, under argon, to a solution of 4.3 g of the lactone prepared in Example (23f) in 84 ml of toluene cooled to -70° C. After 0.5 hour, 1.0 ml of isopropanol and 8.97 ml of water are added to the reaction mixture and the whole is stirred at room temperature for 2.5 hours. The precipitate is filtered off and washed with methylene chloride, and the combined organic phases are dried over magnesium sulphate and concentrated; 4.15 g of the title compound are obtained in the form of an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=2[NH2:14])[CH2:4][CH2:3]1.O.[N:21]#[C:22]Br.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:12]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=3[N:14]=[C:22]2[NH2:21])[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCNc2ccc(Cl)cc2N)CC1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(CCCn2c(N)nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 2-[3-(4-methyl-1-piperazinyl)propylamino]-5-chloroaniline (70 g., 0.248 mole) in 350 ml. of water and 150 ml. ethanol was added, with stirring, 59.0 g. (0.557 mole) of cyanogen bromide in portions over 1 hour. The temperature was maintained at 40°-50° C. After the addition was completed the mixture was allowed to cool to room temperature and stirred overnight. After pouring into 1500 ml. ice water and making strongly alkaline with 20% NaOH, the precipitated solid was collected on a Buchner funnel, washed with water and dried in the vacuum oven to obtain 45.0 g. (59% yield) of crude 1-[3-(4-methyl-1-piperazinyl)propyl]-2-amino-5-chlorobenzimidazole, m.p. 223°-227° C. A portion was recrystallized from acetone as colorless needles, m.p. 228°-229.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[I:16]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([I:16])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cn1c(N)nc(-c2ccccc2)cc1=O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Cn1c(N)nc(-c2ccccc2)c(I)c1=O
Temperature: 25 °C

Procedure:
To 1.8 g (8.95 mM) of 2-amino-3-methyl-6-phenyl-4-pyrimidinone was added 75 ml glacial acetic acid and 1.98 g N-iodosuccinimide (8.8 mM). The reaction mixture was heated to 70° for 5 hours. The mixture was allowed to cool to room temperature and evaporated to dryness under vacuum. The residual solid was azeotroped twice from absolute EtOH, heated to reflux with 50 ml absolute EtOH and allowed to cool to room temperature. The solids were filtered, washed well with absolute EtOH, and dried at 80° for 18 hours. Yield of yellow crystals was 1.6 g (56%).
Reaction SMILES: [C:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[CH:16](=[O:19])[CH2:17][CH3:18].C(O)(=O)C>CO>[C:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:17]([CH3:18])[CH:16]=[O:19])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC=O
Reactant: CCC(C)(C)c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(C)(C)c1ccc(C=C(C)C=O)cc1
Temperature: 40 °C

Procedure:
162.2 g of p-tert.amyl-benzaldehyde are added under nitrogen gasification to a solution of 1.56 g of potassium hydroxide in 113 ml of methanol and 48.8 g of propionaldehyde are subsequently added dropwise at 40° C. over a period of 6 hours. The mixture is subsequently stirred at 40° C. for an additional hour, 2 ml of acetic acid are added and the mixture is concentrated on a rotary evaporator. The oily suspension is taken up in ether, washed neutral with water, dried and evaporated. By distillation there is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-acrolein of boiling point 117°-120° C./0.035 Torr.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:16]=[C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:14][N:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(OC(N1[CH2:37][CH2:36][CH:35]([C:38]2O[N:41]=[C:40](COC3C=CC(S(C)(=O)=O)=CC=3)[N:39]=2)[CH2:34]C1)=O)(C)(C)C.CCN(C(C)C)C(C)C.ClC1N=CC(CC)=CN=1>O1CCOCC1.CC(O)C>[CH2:36]([C:35]1[CH:38]=[N:39][C:40]([N:20]2[CH2:21][CH2:22][CH:17]([C:15]3[O:14][N:13]=[C:12]([CH2:11][O:10][C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:24][CH:23]=4)[N:16]=3)[CH2:18][CH2:19]2)=[N:41][CH:34]=1)[CH3:37]
Reactant: CS(=O)(=O)c1ccc(OCc2noc(C3CCNCC3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)no2)CC1
Agent: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(c3nc(COc4ccc(S(C)(=O)=O)cc4)no3)CC2)nc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To the crude HCl salt (0.18 g, ˜0.5 mmol) of 4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine, prepared by treatment of 4-[3-(4-methanesulfonyl-phenoxymethyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 81) in dioxane with 4N HCl, was added 2-propanol (3 mL), followed by DIPEA (0.13 g, 1 mmol) and 2-Chloro-5-ethyl-pyrimidine (0.14 g, 1 mmol). The resulting mixture was stirred at 70° C. overnight. After concentration in vacuo, the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product. 1H NMR (CDCl3): δ 8.18 (2H, s), 7.89 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 5.24 (2H, s), 4.75˜4.65 (2H, m), 3.3˜3.2 (1H, m), 3.2˜3.1 (2H, m), 3.03 (3H, s), 2.47 (2H, q, J=7.6 Hz), 2.22˜2.16 (2H, m), 1.96˜1.84 (2H, m), 1.19 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1](Cl)([CH3:4])([CH3:3])[CH3:2].[Mg].[Sn:7]([Cl:11])(Cl)(Cl)[Cl:8].[Cl-].[Mg+2].[Cl-]>CCCCCCC.O1CCCC1>[C:1]([Sn:7]([Cl:11])([Cl:8])[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: CC(C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)[Sn](Cl)(Cl)C(C)(C)C

Procedure:
The Grignard reagent from t-butyl chloride (92.5 g., 1 mole), magnesium (24.3 g., 1 mole) and tetrahydrofuran (11.) was added dropwise to a solution of tin(iv) chloride (104 g., 0.4 mole) in heptane (11.). A vigorous reaction started at once and magnesium chloride precipitated. After completion of the addition, the mixture was refluxed for 4 hrs. Cooling and work-up gave a yellow oil. This was distilled to give the desired product as a clear oil which solidified readily (70.0 g., 58%), m.p. 42°-43° (lit., 142°); b.p. 66°/3 mm.; n.m.4. 81.45(s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])(=O)[CH3:2].Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][NH2:31])=[CH:26][CH:25]=1.CC([O-])=O.[Na+]>CCO>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][N:31]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=2[NH:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH3:2])=[CH:26][CH:25]=1
Reactant: NOc1ccc(F)cc1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1ccc(F)cc1)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Yield: 81 %

Procedure:
A solution of N-(2-acetyl-5-trifluoromethylphenyl)trifluoromethanesulfonamide 35 (280 mg, 0.84 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (150 mg, 0.92 mmol) and anhydrous NaOAc (75 mg, 0.92 mmol) in EtOH (15 mL) was stirred for 24 hours at RT. The reaction mixture was concentrated under vacuum, the residue purified by column chromatography (eluting with CH2Cl2/PE; 1:1 to 4:1) and the solvent removed under reduced pressure. Recrystallization from CH2Cl2/PE afforded N-{2-[1-(4-fluorophenoxyimino)ethyl]-5-trifluoromethylphenyl}trifluoromethanesulfonamide 200 (300 my, 81%), as colorless crystals. M.p. 95-96° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.48, br s, 1H, 8.01, s, 1H, 7.76, d, J=8.4 Hz, 1H, 7.55, m, 1H, 7.19-7.04, m, 4H, 2.60, s, 3H.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Br)=[O:8].[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20]>C(=S)=S>[Br:5][CH:6]([CH3:10])[C:7]([C:18]1[CH:17]=[CH:16][C:15]2[S:11][C:12](=[O:20])[NH:13][C:14]=2[CH:19]=1)=[O:8]
Reactant: CC(Br)C(=O)Br
Reactant: O=c1[nH]c2ccccc2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2sc(=O)[nH]c2c1
Temperature: 0 °C
Yield: 85.3 %

Procedure:
To a suspension of aluminum chloride (91.8 g) in carbon disulfide (200 ml) was added 2-bromopropionyl bromide (50 g) and 2-benzothiazolinone (20 g) and the resulting solution was refluxed for 6 hours with stirring. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to give a residue, which was washed with diisopropyl ether and recrystallized from a mixture of ethyl acetate and diethyl ether to give 5-(2-bromopropionyl)-2-benzothiazolinone (32.3 g).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13]Cl)[CH:7]=1)[C:3]([OH:5])=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>CO>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][N:15]=[N+:16]=[N-:17])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCc1cc(C(N)C(=O)O)ccc1O
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid (252 mg, 1 mmole) in 4 ml of methyl alcohol is added sodium azide (156 mg, 2.4 mmole). The mixture is stirred at about 40° C. for 15 minutes. After about 10 minutes the title compound begins to precipitate. The mixture is cooled, filtered and the product is washed with a small amount of methyl alcohol and acetone. The title compound is collected (210 mg, 95% yield). M.P.>300°; [α]D18 =-73.03° (c 1.7, water), NMR (DMSO-D6) ppm (δ) 4.22 (s,1), 4.35 (s,2), 6.7-7.5 (superimposed q and s,3).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)C=O)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].CO[CH:29]([O:32][CH3:33])[O:30][CH3:31].C(=O)(O)[O-].[Na+]>CO>[CH3:33][O:32][CH:29]([O:30][CH3:31])[C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])[CH:20]=1
Reactant: CC(C)(C)C(=O)Oc1cccc(C=O)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cccc(OC(=O)C(C)(C)C)c1
Reaction time: 1 h

Procedure:
Four hundred mg of p-toluenesulfonic acid dissolved in 25 ml of methanol was added, with stirring, to the 3-pivaloyloxybenzaldehyde of Example I. Trimethylorthoformate (224 ml; 2.05 mol) was then added dropwise. The minor exotherm that resulted was allowed to proceed unchecked while the mixture was stirred for 1 hour. One half gram of sodium bicarbonate was added, and the flask was placed on the rotary evaporator (bath temperature 40° C.) to remove all volatiles. The resulting oil was passed through a short silica gel column under nitrogen pressure to give an orange-brown oil which was pumped under vacuum (1.0 mm Hg) with stirring to yield 426 g of crude 3-pivaloyloxybenzaldehyde dimethyl acetal. Infrared analysis revealed no aldehyde carbonyl absorption (1695 cm-1).
Reaction SMILES: C1(P(=[CH:20][CH:21]=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]=O)=[N:28][CH:29]=1>>[Br:23][C:24]1[CH:25]=[CH:26][C:27](/[CH:30]=[CH:20]/[CH:21]=[O:22])=[N:28][CH:29]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C/C=C/c1ccc(Br)cn1

Procedure:
818 mg of (triphenylphosphoranylidene)acetaldehyde and 500 mg of 5-bromopyridinecarbaldehyde are stirred at RT overnight. The volatile fractions are removed under reduced pressure, and the residue is purified by column chromatography (silica gel, MeOH:DCM=99:1).