Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl.Cl>CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)N1CCC[C@H]1CN1CCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1
Temperature: 60 °C

Procedure:
Procedure OO: 160 mg of (4′-Nitro-biphenyl-4-yl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (0.43 mmol) is put into the solution of 485 mg of SnCl2.2H2O (2.15 mmol) in 1.0 ml of EtOH. 1.0 ml of conc. HCl is added to the mixture and heated at 60° C. for 30 min. EtOH is removed in vacuo and the solution is made it to pH=12.0 by aqueous NaOH. This mixture is extracted with dichloromethane, dried over Na2SO4 and evaporated. The crude product is applied to SCX column and washed by MeOH and the desired product is eluted with 2M NH3 in MeOH. The elution is concentrated and applied to silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=20:1) to give the title compound. 77 mg (51%) Observed mass; 350 (M+1)
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=1.[Na+].C(O)C.S(O[CH:45]([CH3:51])[C:46]([O:48][CH2:49][CH3:50])=[O:47])(C1C=CC(C)=CC=1)(=O)=O>O>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH3:51])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-[15-(trifluoromethyl)pentadecylamino]benzoate in 100 ml. ethanol is added 4.7 g. of ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield the product as colorless crystals.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[C:19]1([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH2:10][NH:9][CH2:18][CH2:17]3)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCc3cccc(-c4ccccc4)c3C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(-c2cccc3c2CNCC3)cc1
Reaction time: 6 h

Procedure:
A mixture of 6.20 parts of 2-benzyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride and 0.62 parts of 5% palladium-on-carbon catalyst in 100 parts by volume of ethanol is hydrogenated at 2 psi and ambient temperature for about 6 hours. The filtered reaction solution is concentrated to 75 parts by volume and after the addition of ether crystalline solid is formed. This solid is recrystallized from ethanol to yield 8-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, as white crystals melting at about 268°-270° C. This compound has the following formula ##STR17##
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:6]5[O:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:43]=[CH:42][CH:41]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1ncoc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ncoc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 37.7 %

Procedure:
In the same manner as in Example 18-4 and using 4-methyl-1,3-oxazole-5-carboxylic acid (410 mg, 3.22 mmol), tetrahydrofuran (10 mL), oxalyl chloride (420 μL, 4.84 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.647 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (102 mg, 38%) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].CO.O.O[Li].O>C1COCC1>[CH3:31][C:29]([CH3:30])([CH3:32])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]2)[C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)O)s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester is dissolved in a 3:2:1 mixture of THF:methanol:H2O and treated with a 1N solution of LiOH.H2O. After 2 h of stirring at 60° C., the reaction mixture is concentrated under reduced pressure on a rotary evaporator. The mixture is partitioned between ethyl acetate and water. The water layer is acidified using 0.1 N HCl. The EtOAc layer is separated and dried over Na2SO4. The solvent is removed and the residue is purified by column chromatography using methanol and dichloromethane (1:9) as eluent to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nc(O)c2cccc(F)c2n1
Product: CCOC(=O)c1nc(Cl)c2cccc(F)c2n1
Yield: 65 %

Procedure:
A mixture of ethyl 8-fluoro-4-hydroxyquinazoline-2-carboxylate (530 mg, 2.2 mmol) and POCl3 (3 mL) was heated under reflux for 5 h. The mixture was concentrated under reduced pressure, and then toluene was twice added and concentrated under reduced pressure. Thre residue was purified by silica gel chromatography eluting with 0-25% EtOAc/hexanes to afford ethyl 4-chloro-8-fluoroquinazoline-2-carboxylate (365 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ 1.39 (t, J=7.1 Hz, 3 H), 4.46 (q, J=7.1 Hz, 2 H), 7.97-8.06 (m, 1 H), 8.07-8.16 (m, 1 H), 8.18-8.24 (m, 1 H).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]4[CH:33]=[CH:34][C:35]([CH:37]=[O:38])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].O1CC[CH2:51][CH2:50]1>C([Mg]Br)C>[C:1]1([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][N:19]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:23]4[CH:33]=[CH:34][C:35]([CH:37]([OH:38])[CH2:50][CH3:51])=[CH:36][C:22]=4[N:21]=3)[CH2:16][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCN(CC1CCN(Cc2cccc3ccccc23)CC1)c1nc2cc(C=O)ccc2n1COCC[Si](C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.22 h

Procedure:
After dissolving 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboaldehyde (86 mg, 0.131 mmol) in anhydrous tetrahydrofuran (1.2 ml) under a nitrogen stream, ethylmagnesium bromide (0.26 ml, 1M tetrahydrofuran solution) was added at 0° C., and the mixture was stirred at room temperature for 13 minutes. Saturated aqueous ammonium chloride was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-ol.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1.[O-:27][CH2:28][CH3:29].[Na+].O>C(O)C>[CH2:28]([O:27][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1)[CH3:29]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Temperature: 65 °C

Procedure:
2-Chloro-6-(4-fluorophenyl-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example 7) (200 mg, 0.52 mMol) was added to freshly prepared sodium ethoxide (0.57 mMol) (from addition of sodium metal to ethyl alcohol) in ethyl alcohol (50 ml) and heated to 65° C. for 3.5 hours. The reaction mixture was cooled to room temperature. Water (3 ml) was added and the mixture was concentrated. The product was partitioned between water (50 ml) and ethyl acetate (50 ml). The ethyl acetate portion was dried over sodium sulfate, filtered and concentrated to a solid. The product was purified by a silica gel chromatography to give a white solid: m.p. (DSC): 207.22° C. Anal. Calc'd. for C21H17N2O3SF (396.44): C, 63.62; H, 4.32; N, 7.07. Found: C, 63.56; H, 4.32; N, 6.88.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH:19][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH3:18])=[CH:13][CH:12]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(N)c1ccc(Br)cc1
Product: CC(Nc1nc(Cl)ncc1F)c1ccc(Br)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 1-(4-bromophenyl)ethylamine to provide (±)-N4-[1-(4-bromophenyl)ethyl]-2-chloro-5-fluoro-4-pyrimidineamine: 1H NMR (CDCl3): δ 7.88 (d, 1H, J=2.3 Hz), 7.49 (d, 2H, J=8.7 Hz), 7.25 (d, 2H, J=8.7 Hz), 4.45-5.26 (m, 2H), 1.59 (d, 3H, J=7.0 Hz).
Reaction SMILES: [C:1]1(=[O:44])[N:5]([CH:6]2[C:37](=[O:38])[N:8]3[C:9]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:10]([CH2:13][S:14][C:15]4[S:16][C:17]([CH3:20])=[N:18][N:19]=4)[CH2:11][S:12][C@H:7]23)[C:4](=[O:39])[C:3]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:2]12.C1C[O:48]CC1.[S-2].[Na+].[Na+].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[C:1]([C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[C:4]([NH:5][CH:6]1[C:37](=[O:38])[N:8]2[C:9]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[O:39])([OH:48])=[O:44]
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3SC2)s1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Reaction time: 0.25 h

Procedure:
A solution of benzhydryl 7-phthalimido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 25 ml. of THF and 8 ml. of water is cooled in an ice-water bath, and 660 mg. of Na2S.9H2O are then added. The mixture is stirred for 15 minutes, and 10 ml. of water and 40 ml. of ethyl acetate are added. The layers are separated, and a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1N sulfuric acid and is extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried, and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.CI.[C:12]([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:12])[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(Br)cc(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cc1cc(Br)cc(=O)n1C

Procedure:
4-bromo-1,6-dimethylpyridin-2(1H)-one was prepared by methylation of 4-bromo-6-methylpyridin-2(1H)-one with methyl iodide using K2CO3 following a procedure analogous to that described in Example 628 Step 1.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:30])[C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc3ccccc3n2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (150 mg, 0.38 mmol), 2-(methylamino)-1-quinolin-2-ylethanol (Preparation 63)(150 mg, 0.74 mmol) and diisopropylethylamine (134 μL, 0.76 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 6 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (126 mg) as a white solid.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][C:7]([NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)=[O:8])([O-])=O.CO>>[NH2:1][CH2:4][CH:5]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:6][C:7]([NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)=[O:8]
Reactant: CCOC(=O)c1ccc(NC(=O)CC(C[N+](=O)[O-])c2ccccc2)cc1
Solvent: CO
Product: CCOC(=O)c1ccc(NC(=O)CC(CN)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Ref. J. Org. Chem., 2000, 65, 8001. To a stirred solution of nitro compound 47 (0.749 g, 2.10 mmol) and NiCl2.6H2O (1.99 g, 8.40 mmol) in methanol (10 ml) NaBH4 (0.719 g, 18.93 mmol) was added portionwise over 20 min at 0° C. After stirring for 15 at room temperature, the solvent was removed under reduced pressure. Water (20 ml) and ethyl acetate (40 ml) were added to the solid residue. The resulting mixture was filtered through a celite bed which was washed with ethyl acetate (20 ml). After collecting the filtrate, the organic phase was separated, dried over Na2SO4 and the solvent removed under reduced pressure to afford amine 51 as an off white solid (0.596 g, 1.83 mmol, 87%). The amine was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:23][CH:24]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27](/[CH:26]=[CH:25]/[C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:15][C:11]3[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)[CH:14]=[CH:13][CH:12]=3)[N:21]=2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: Oc1cccc(CCCn2ccnn2)c1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccc(/C=C/c2nc(COc3cccc(CCCn4ccnn4)c3)co2)cc1
Yield: 88.4 %

Procedure:
Using 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol(208 mg), 65% oily sodium hydride (39 mg) and 4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg), the same reaction as Example 2 was carried out to yield the titled compound (366 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH2:10](OC(OCC)OCC)C>>[Cl:8][C:7]1[C:2]2[N:1]=[CH:10][S:9][C:3]=2[N:4]=[CH:5][N:6]=1
Reactant: Nc1c(S)ncnc1Cl
Reactant: CCOC(OCC)OCC
Product: Clc1ncnc2scnc12
Temperature: 25 °C

Procedure:
5-Amino-6-chloropyrimidine-4-thiol (E-3) (14.0 g, 86.9 mmol) is dissolved in triethoxy methane (180 mL) and the resulting mixture is stirred at reflux for 3 h. The mixture is allowed to cool to RT and then concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (5-10% ethyl acetate-petro ether) to afford the product, 7-chlorothiazolo[5,4-d]pyrimidine (E-4).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:31]1[O:33][CH2:32]1>CO>[CH3:30][CH:2]([CH3:1])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH3:27])[CH2:20][N:19]1[CH2:31][CH2:32][OH:33])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCC(F)(F)CCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: C1CO1
Solvent: CO
Product: CCC(F)(F)CCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CCO)C1
Temperature: 4 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of the title compound of Example 39 (17.9 mg, 0.039 mmol) in MeOH (2 mL) at 0° C. was added ethylene oxide (0.4 mL). The reaction mixture was stirred at 4° C. overnight. The reaction mixture was concentrated and purified by chromatography to give the title compound as a white solid (8.2 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1)#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC.CN(C)C=O>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: N#Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C#N)cc3)ccc21
Yield: 98.6 %

Procedure:
40.8 g (0.2 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol, 30.4 g (0.2 mol) of 4-cyanobenzyl chloride and 80 g (1.2 mol) of anhydrous potassium carbonate in 400 ml of butanone and 300 ml of dimethylformamide were refluxed for 9 h. The mixture was cooled and then poured into 1.5 l of water, and the solid was filtered off with suction and washed with water. Drying resulted in 63 g of the title compound of melting point 49°-150° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.[H-].[Na+].Br[CH:13]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].N1C=CC=NC=1O>O1CCCC1>[O:18]([CH:13]([O:9][C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=1)[C:14]([O:16][CH3:17])=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: COC(=O)C(Br)Oc1ccccc1
Agent: Oc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccccc1)Oc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,6-Dimethyl-2-pyrimidinol (3.0 g, 24 mmol) and 60 mL of tetrahydrofuran were placed in a dry 250 mL flask and blanketed with argon. Sodium hydride (1.0 g of 60 percent, 24 mmol) was added carefully and the mixture was allowed to stir at ambient temperature for 0.5 hr. A solution of methyl 2-bromo-2-phenoxyacetate (7.2 g, 29 mmol) in a small amount of tetrahydrofuran was added dropwise with stirring and the mixture was then allowed to stir overnight under argon at ambient temperature. The resulting mixture was found by thin layer chromatography to contain only a trace of the starting pyrimidinol. The mixture was concentrated by evaporation under reduced pressure and the residue was diluted with water and ether. The phases that formed were separated and the aqueous phase was extracted twice with ether. The combined ethereal phase was extracted with water and then dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain the title compound in crude form as a reddish oil. This oil was column chromatographed on silica eluting with a 75:25 mixture of hexane and ethyl acetate to obtain 1.2 g (17 percent of theory) of the title compound as a pink oil of 93 percent purity, as determined by gas-liquid chromatography.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10]C(C)C)=[CH:4][C:3]=1[C:14](=[O:17])[CH2:15][CH3:16]>C(OCC)(=O)C.CCCCCC>[OH:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([I:1])=[C:3]([C:14](=[O:17])[CH2:15][CH3:16])[CH:4]=1
Reactant: CCC(=O)c1cc(OC(C)C)c(OC)cc1I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(=O)c1cc(O)c(OC)cc1I

Procedure:
Concentration of fraction B (Rf 0.7 in 1:1 v/v ethyl acetate/hexane) afforded the starting ether 11 (98 mg, 21% recovery) as a pale-yellow oil that was identical, as judged by 1H NMR spectroscopic analysis, with authentic material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][N:14]1[C:18]([OH:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[N:15]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([O:19][C:18]1[N:14]([CH3:13])[N:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=1)(=[O:11])=[O:10]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: Cn1nc(C(F)(F)F)cc1OS(=O)(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
2,4-Dichlorobenzenesulfonyl chloride (245 mg, 1.0 mmol) was added in portions to an ice-cold solution of 1-methyl-3-(trifluoromethyl)pyrazol-5-ol (166 mg, 1.0 mmol) in anhydrous pyridine (5 mL). The resulting solution was stirred at room temperature overnight, and poured onto ice-water. The mixture obtained is stirred for 1 h, and the precipitate formed filtered, yielding 244 mg (65% yield) of the desired product. NMR (δ, CDCl3): 8.0 (1H, d, J=8.5 Hz); 7.65 (1H, d, J=2.1 Hz); 7.4 (1H, dd, J=8.5; 2.1 Hz); 6.1 (1H, s); 3.9 (s, 3H).