Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:13]([O:23][CH3:24])=[CH:12][N:11]=2)=[N:2]1.[H-].[Na+].Br[CH2:28][C:29]1[C:34]([F:35])=[C:33]([CH3:36])[CH:32]=[CH:31][C:30]=1[Cl:37]>O1CCCC1>[Cl:37][C:30]1[C:29]([CH2:28][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]3[N:15]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:13]([O:23][CH3:24])=[CH:12][N:11]=3)=[N:2]2)=[C:34]([F:35])[C:33]([CH3:36])=[CH:32][CH:31]=1
Reactant: Cc1ccc(Cl)c(CBr)c1F
Reactant: COc1cnc(-c2n[nH]c3ccccc23)nc1Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(C)c3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
80 mg of 2-(1H-indazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (1-6-1, 0.251 mmol, 1. eq.) were suspended in dry tetrahydrofuran under a nitrogen atmosphere. 30.2 mg of sodium hydride (60% purity) were added and stirred at room temperature for 10 minutes. Then 59.7 mg of 2-(bromomethyl)-1-chloro-3-fluoro-4-methylbenzene were added. The reaction mixture was stirred for 18 hours at room temperature. Then the mixture was partitioned between half saturated aq. ammonium chloride solution and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. Preparative HPLC purification provided 29 mg (0.06 mmol, 24.1%) of the analytically pure target compound.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]([CH3:46])[CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]([CH3:46])[CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:12]
Reactant: CN(CCN1CCOCC1)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCN1CCOCC1)c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(morpholin-4-yl)ethyl)amino)benzamido)-4-phenylbenzoate (0.12 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.12 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Ethyl acetate was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain 0.074 g of tert-butyl 2-(2-hydroxy-5-(methyl(2-(morpholin-4-yl)ethyl)amino)benzamido)-4-phenylbenzoate.
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH2:7]=[CH:8][CH:9]=[CH2:10]>>[Cl:1][C:2]1([F:6])[C:3]([F:5])([F:4])[CH2:10][CH:9]=[CH:8][CH2:7]1
Reactant: FC(F)=C(F)Cl
Reactant: C=CC=C
Product: FC1(F)CC=CCC1(F)Cl

Procedure:
4-chloro-4,5,5-trifluorocyclohexene was prepared in the same manner as in Comparative Example 4 except that chlorotrifluoroethylene (CTFE), 1,3-butadiene and nitrogen gas were continuously injected into the flow reactor in the rates of 33.8 g/hr, 15.7 g/hr, and 0.4 mol/hr, respectively. Then, 4.7 g of unreacted chlorotrifluoroethylene (CTFE) was recovered. The resultant was purified by steam distillation, and then the water layer was removed to give 29.4 g of the mixture (GC%=53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([NH:23][C:24](=[O:37])[CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=2)[CH:14]=[CH:15][C:16]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]2.O.[C:65]([OH:69])(=[O:68])[CH:66]=O>>[C:60]([O:59][C:57]([N:49]([C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[C:45]1[C:46]2[C:41](=[CH:40][C:39]([NH:38][CH:66]([C:31]3[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][CH2:25][C:24]([NH:23][C:13]4[CH:14]=[CH:15][C:16]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[C:11]([CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:9])[CH:12]=4)=[O:37])=[CH:29][CH:30]=3)[C:65]([OH:69])=[O:68])=[CH:48][CH:47]=2)[CH:42]=[CH:43][N:44]=1)=[O:58])([CH3:63])([CH3:62])[CH3:61]
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C

Procedure:
Using a procedure analogous to that used to prepare 2D, 18C (0.151 g, 0.28 mmol) was reacted with Intermediate 1 (0.101 g, 0.28 mmol) and glyoxylic acid monohydrate (0.026 g, 0.28 mmol) to give, after purification by reverse phase HPLC, 18D (168 mg, 66%) as a yellow glass.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@@H](CSc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CSc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To 62.31 g of an aqueous solution containing 4.55 g of S-phenyl-L-cysteine and maintained at pH 11 with a 30% aqueous solution of sodium hydroxide under constant stirring at about 25° C., 3.94 g of benzyloxycarbonyl chloride (1.0 mole per mole of S-phenyl-L-cysteine) was added dropwise over 1 hour. The mixture was allowed to react for a further 12 hours. The resulting reaction mixture weighed 67.19 g, had a pH value of 10.9, and contained 7.12 g of N-benzyloxycarbonyl-S-phenyl-L-cysteine (concentration 10.6 wt. %; yield 93%). The concentration of sodium chloride in the reaction mixture was 2.7 weight % (based on water). This reaction mixture showed no salting out of N-benzyloxycarbonyl-S-phenyl-L-cysteine sodium salt.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([N+:32]([O-:34])=[O:33])[CH:24]=1>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[C:25]([N+:32]([O-:34])=[O:33])[CH:24]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(Br)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(Br)cc1[N+](=O)[O-]
Yield: 28 %

Procedure:
0.482 g (0.0025 mol) of 1-benzyl-4-hydroxypiperidine and 0.62 ml (0.0045 mol) of triethylamine were dissolved in 20 ml of toluene and treated with the 4-bromo-2-nitro-benzoyl chloride obtained under a) dissolved in 5 ml of toluene. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:7 and 1:4). 0.3 g (28%) of 1-benzyl-piperidin-4-yl 4-bromo-2-nitro-benzoate was obtained as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: OCCCCCCBr
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCCCCCO)cc1
Yield: 56.9 %

Procedure:
5.4 g of p-hydroxybenzoic acid was added to ethanol-dioxane mixture solvent, and an aqueous solution containing 6.6 g of potassium hydroxide was added thereto, followed by dropwise addition of 7.9 g of 6-bromohexanol and 12 hours of heat refluxing. The reaction mixture was then acidified, extracted with ethyl acetate and purified by column chromatography to obtain 5.3 g of the product (Yield: 57 %).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH:42]3[CH2:44][CH2:43]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH:42]3[CH2:44][CH2:43]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CC3CC3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(CC3CC3)c2c1=O
Yield: 69.5 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 6.14 g (9.48 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-cyclopropylmethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 15-(c) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 3.41 g of the title compound was obtained as a white solid. (Yield: 70%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:21]1([CH2:27][C:28](=O)[C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:27]([C:28]1[C:29](=[O:30])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccnc1Nc1cccc(-c2cccnc2)c1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1c(Cc2ccccc2)nc2cccnc2n1-c1cccc(-c2cccnc2)c1
Yield: 56.9 %

Procedure:
A mixture of 3-amino-2-[3-(3-pyridyl)phenylamino]pyridine (150 mg) and 3-phenylpyruvic acid (113 mg) in ethanol (4 ml) was stirred under reflux for 2 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 2-benzyl-4-[3-(3-pyridyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (127 mg).
Reaction SMILES: [CH:1]1([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[CH:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:2]1[C:11]([O:13][CH3:14])=[O:12]>C1(C)C=CC=C(C)C=1.[Pt]>[C:15]([O:17][CH3:18])(=[O:16])[C:1]1[C:2](=[CH:3][C:4](=[CH:5][CH:6]=1)[C:7]([O:9][CH3:10])=[O:8])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1C=CC(C(=O)OC)C(C(=O)OC)C1
Agent: [Pt]
Solvent: Cc1cccc(C)c1
Product: COC(=O)c1ccc(C(=O)OC)c(C(=O)OC)c1
Reaction time: 96 h
Yield: 65 %

Procedure:
Trimethyl cyclohex-5-ene-1,2,4-tricarboxylate (200 mg, 0.78 mmol) is mixed with 305 mg of 5 percent by weight platinum on a carbon support in m-xylene (30 ml). The reaction mixture is refluxed with the reflux apparatus being open to air for 4 days. The residual platinum on carbon is then filtered off and the filtrate is concentrated down to a clear colorless gel. The desired product is obtained with a 65 percent yield. The yield is determined by GC/MS using a dodecane as an internal standard.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:16])=[N:6][C:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:8][CH:9]=1)([O-])=O.O>C1COCC1.O>[NH2:1][C:4]1[C:5]([OH:16])=[N:6][C:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc(-c2cccnn2)nc1O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(-c2cccnn2)nc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a solution of 5-nitro-2-(pyridazin-3-yl)pyrimidin-4-ol, 35i-g, (3.0 g, 13.6 mmol) in THF/H2O (100 mL, VTHF/H2O=1:1) was added Na2S204 (4.77 g, 27.4 mmol) and stirred at room temperature for 4 h. The reaction mixture was extracted with EA (100 mL), washed with brine (50 mL), and concentrated under vacuum. The residue was purified by column chromatography to afford the product, 35i-h, (0.8 g, 30%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ5.66 (s, 2H), 7.39 (s, 1H), 7.80 (dd, J=4.8, 8.4 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 9.26 (d, J=4.8 Hz), LC-MS (M+H)+ 190.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.CCN=C=NCCCN(C)C.[NH2:24][NH:25][C:26]([NH2:28])=[S:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:28][C:26](=[S:27])[NH:25][N:24]=1
Reactant: NNC(N)=S
Reactant: COc1cc(C)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: COc1cc(C)ccc1-c1n[nH]c(=S)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 2-methoxy-4-methylbenzoic acid (1.81 g, 9.22 mmol) in 9 ml of pyridine was added EDCI (1.9 g, 9.3 mmol) and the suspension was stirred at r.t. for 1 h. Then thiosemicarbazide (800 mg, 8.8 mmol) was added and the reaction was stirred at r.t. for 21 h. The mixture was evaporated to dryness and then diluted with water. The white solid was then filtered, washed with water and suspended in 20 ml 1 M aq. NaHCO3 and then heated at reflux for 2 days. The suspension was filtered hot and the aqueous solution was cooled in ice and acidified to pH 3 with conc. HCl. The solid was filtered and washed with water and dried to give a white powder (47%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:20][C:21]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CS(C)=O>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[N:19]=[C:23]([C:22]4[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:21]=4[CH3:20])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1cccc(C=O)c1C
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4cccc(C)c4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (71 mg) and 2,3-dimethylbenzaldehyde (34 mg) in DMSO (1 mL) was added Yb(OTf)3 and the mixture was stirred at room temperature for 4 h. Additional Yb(OTf)3 was added and stirring was continued until starting material was consumed. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using CH2Cl2/EtOAc (2:1) as eluent to furnish 2-(2,3-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a beige solid, MS (m/z) 370 (M−1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH3:8][C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([CH3:12])[CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH3:12][C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)([CH3:8])[CH2:10][OH:11]
Reactant: CC(C)(CO)Oc1ccc(-c2ccc(N)cc2)cc1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)(CO)Oc1ccc(-c2ccc(NCCCCCBr)cc2)cc1

Procedure:
23 g. of 1,5-dibromopentane, 25.7 g. of 2-methyl-2-[4-(4-aminophenyl)-phenoxy]-propanol (obtainable by reaction of 4-hydroxy-4'-nitro-diphenyl with 2-bromo-2-methylpropanol to 2-methyl-2-[4-(4-nitrophenyl)-phenoxy]-propanol and reduction), and 27 g. of potassium carbonate are refluxed in 400 ml. of n-butanol for 12 hours. 2-Methyl-2-[4-(p-5-bromopentylaminophenyl)-phenoxy]-propanol is formed as the intermediate, which is not isolated. Then, the solvent is distilled off, the residue mixed with water and extracted with ethyl acetate. After drying and evaporation, 2-methyl-2-[4-(4-piperidinophenyl)-phenoxy]-propanol is obtained, m.p. 158°-160°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])N(CCCl)CCCl)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].CO>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([CH:23]1[CH2:22][C:20]([C:19]2[CH:27]=[CH:28][C:16]([Cl:15])=[CH:17][CH:18]=2)([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH2:26][CH2:25][NH:24]1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: Clc1ccc(Cc2ccncc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CC(c2ccncc2)(c2ccc(Cl)cc2)CCN1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 0.7 %

Procedure:
Under nitrogen, a solution of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester* (1.54 g, 6.36 mmol) in toluene (10 mL) was cooled in ice. 4-(4-Chloro-benzyl)-pyridine (1.30 g, 6.36 mmol) was added, followed over two minutes by sodium hexamethyldisilazide solution (10 mL, 20 mmol, 2M in THF). The mixture was stirred at 0° C. for 3.5 hours then allowed to warm to room temperature and stirred for a further 20 hours. Methanol was added then the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 1N hydrochloric acid (×3) and brine, dried (MgSO4), filtered and concentrated to afford a residue which was purified by column chromatography (SiO2), eluting with gradient of 2M methanolic ammonia in dichloromethane (1% to 5%). A second purification by column chromatography (SiO2), eluting with 50% ethyl acetate/petrol gave the title compound (16 mg, 0.7%). LCMS (PS-A2) Rt 2.65 min [M+H]+ 373. *This starting material can be made by the method described in J. Chem. Soc., Perkin Trans 1, 2000, p3444-3450
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH2:11](Cl)[C:12]#[CH:13].O>CN(C=O)C.CCOCC>[Cl:1][C:2]1[C:7]([O:8][CH2:13][C:12]#[CH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#CCCl
Reactant: Oc1cccnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cccnc1Cl
Temperature: 15 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of 15.6 g (0.12 mole) 2-chloro-3-pyridinol in 200 ml DMF were added 6.7 g (0.12 mole) powdered potassium hydroxide. After cooling to 15° C., 9.0 g (0.12 mole) propargyl chloride was added dropwise. This mixture was stirred at room temperature for 2 hrs., then 200 ml water and 400 ml ether were added. After agitating, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to leave 16.0 g crude product. Recrystallization from hexane gave 10.5 g pure 2-chloro-3-(2-propynyloxy)pyridine, mp 78°-79°.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.[CH2:13]1COCC1.[Si](C=[N+]=[N-])(C)(C)C>CO>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([O:10][CH3:13])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: C1CCOC1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C[C@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-((R)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (15.8 g, 90.9 mmol) in a 3:1 mixture of THF:MeOH (100 mL) was cooled in an ice bath. After adding 2.0 M TMSCHN2 (50 mL, 100 mmol) the bath was removed, and the mixture was stirred at room temperature for 3 h. The solvent was evaporated, and the crude material was purified via silica gel chromatography using 0-50% EtOAc/hexanes to give methyl 2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate. 1H NMR (400 MHz, CDCl3) d 4.73 (dd, J=6.6, 3.8 Hz, 1H), 3.74 (s, 3H), 2.95 (dd, J=17.0, 3.9 Hz, 1H), 2.81 (dd, J=17.0, 6.6 Hz, 1H), 1.63 (s, 3H), 1.57 (s, 3H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[CH:5][CH:4]=1)=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17]>C(O)C.N1CCCCC1>[C:16]([C:15]([C:14]#[N:18])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:17]
Reactant: COC(=O)Nc1ccc(C=O)cc1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)Nc1ccc(C=C(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
Methyl (4-formylphenyl)carbamate (560 mg) and malononitrile (206 mg) were dissolved in 10 mL of ethanol, and one drop of piperidine was added to the resulting solution, and then the mixture was stirred at room temperature for 3 hours. IPE (10 mL) was added to the reaction mixture, and a precipitated crystal was filtrated to give 441 mg of methyl [4-(2,2-dicyanovinyl)phenyl]carbamate as a yellow powder.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[N:3]=[N:2]1.O>C(O)(=O)C.[Pd].[C]>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[N:3]=[N:2]1
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]nn2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(-c2c[nH]nn2)cc1
Yield: 71 %

Procedure:
A 5 g portion of 4-triazolylnitrobenzene dissolved in 20 ml of acetic acid was mixed with 0.3 g of 10% Pd-carbon and subjected to hydrogenation under a hydrogen pressure of 3 kg/cm2. The reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with sodium bicarbonate aqueous solution and water in that order and dried, and the solvent was removed by evaporation under a reduced pressure to obtain 3 g of 4-triazolylaniline with a yield of 71%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][O:31][CH2:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][C@@H:29]3[CH2:33][CH2:32][O:31][CH2:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCC[C@@H]1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC[C@@H]1CCOC1

Procedure:
Prepared similarly to Intermediate 215 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3S)-3-(2-bromoethyl)tetrahydrofuran.