Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]>>[C:35]([C:38]1[CH:43]=[CH:42][C:41]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=3)[CH:13]=2)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(CC(C)C)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-acetyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (300 MHz, MeOD) δ ppm 0.88 (dd, J=6.78, 2.26 Hz, 6H), 1.42-1.52 (m, 1H), 1.67 (ddd, J=13.75, 7.16, 6.97 Hz, 1H), 1.91-2.01 (m, 1H), 2.55 (s, 3H), 3.76 (t, J=7.72 Hz, 1H), 7.59 (t, J=5.84 Hz, 2H), 7.66-7.81 (m, 7H), 8.01 (d, J=8.29 Hz, 2H);
Reaction SMILES: [S:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[NH:3]1.[CH3:16]I>CCO>[CH3:16][S:1][C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COC(=O)c1ccc2c(c1)NC(=S)NC2
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)N=C(SC)NC2
Yield: 84.6 %

Procedure:
To a suspension of methyl 2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (110 mg, 0.5 mmol) in anhydrous EtOH (5 mL) was added MeI (0.125 mL, 2 mmol). The reaction mixture was stirred at reflux for 1 hr. After cooling, the solid was isolated by filtration to afford methyl 2-(methylthio)-3,4-dihydroquinazoline-7-carboxylate (100 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51]>>[Cl:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1OCCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4Cl)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.060 g of 1-(4-bromobutoxy)-2-chlorobenzene are used to prepare the title compound. Rf=0.28 (2:1 EtOAc-heptane); Rt=6.17.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:10][C:9]([NH:8][C:6]1[CH:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=1)([CH3:12])[CH3:11]
Reactant: C1CNCCN1
Reactant: CC(C)(C)Nc1cc(Cl)nc(N2CCCC2)n1
Product: CC(C)(C)Nc1cc(N2CCNCC2)nc(N2CCCC2)n1
Yield: 67.5 %

Procedure:
4-Chloro-6-(1,1-dimethylethylamino)-2-pyrrolidinopyrimidine is reacted with piperazine as described in Example 4 to give the title product in a yield of 67.5%, m.p.: 140°-145° C.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([C:5](=[O:10])[CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>C1COCC1>[CH2:1]1[CH:9]2[CH:4]([C:5]([O:10][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=C1CCCC2CCCC12
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CCCC2CCCC12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
Add dropwise hexahydro-1H-inden-4(2H)-one (1.6 g, 11.6 mmol) in dry THF (5 mL) to a solution of LDA (23.2 mL, 23.2 mmol) in THF (30 mL). Stir the reaction mixture for 30 min and then add dropwise TMSCl (3.5 g, 32.0 mmol) to the reaction mixture. Stir the resultant solution for additional 1 hour. Pour the mixture into ice water (50 mL) and extract the aqueous mixture with EtOAc (50 mL×3). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford crude (2,3,3a,6,7,7a-hexahydro-1H-inden-4-yloxy)trimethylsilane (2.45 g, 100%) as yellowish oil, MS (m/z): 209 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.[Br:47][CH2:48][C:49](Cl)=[O:50]>ClCCl>[Br:47][CH2:48][C:49]([NH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])=[O:50]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)CBr)c(C(=O)N(C)C)c3)cc12
Temperature: 0 °C
Yield: 87.3 %

Procedure:
285 mg (0.55 mmol) of 2-amino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 25 mL of dichloromethane. 175 μL (132 mg, 1.02 mmol) of di-iso-propylethylamine was added and the solution cooled to 0° C. 110 μL (208 mg, 1.32 mmol) of bromoacetyl chloride was added in two portions within 2 h while stirring at 0° C. Upon complete addition the mixture was stirred for 19 h, allowing to warm to ambient temperature. The resulting solution was evaporated and the residue directly purified by flash chromatography on silica gel using a gradient of ethyl acetate containing 15% of methanol in hexanes to afford 306 mg (0.48 mmol, 87%) of 2-(2-bromo-acetylamino)-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a tan solid. MS: m/z 637.9+640.0 (M+H+).
Reaction SMILES: [NH:1]([C:8]1[CH2:17][C:16]([C:18]([O:20]C)=O)=[C:15]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14][C:9]=1[C:10]([O:12]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH:26]1[CH:27]=[C:28]2[C:18]([C:16]3[C:15]([NH:22][C:23]2=[CH:24][CH:25]=1)=[CH:14][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:17]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])=[O:20]
Reactant: COC(=O)C1=C(Nc2ccccc2)CC(C(=O)OC)=C(Nc2ccccc2)C1
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Yield: 3 %

Procedure:
A suspension of 200 g of dimethyl 2,5-dianilino-3,6-dihydroterephthalate in 1 l of water was introduced by means of a two-material nozzle and 1.5 m3 of nitrogen into a tubular reactor (50 mm in diameter, 300 mm in length) at 395° C. Using a solids filter, 170 g of dihydroquinacridone (purity 95%, includes about 3% of quinacridone) were obtained.
Reaction SMILES: C[O:2][C:3]([CH:5]([N:13]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15](OCC2C=CC=CC=2)[C:14]1=[O:31])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C[OH:33]>[Pd]>[OH:33][C@@:5]([C:3]([OH:2])=[O:4])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:13][C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C(Cc1ccccc1)N1C(=O)C(OCc2ccccc2)C1c1ccccc1
Reactant: CO
Agent: [Pd]
Product: O=C(CCc1ccccc1)N[C@@](O)(Cc1ccccc1)C(=O)O
Reaction time: 48 h
Yield: 100 %

Procedure:
According to the same procedure as in Example 1, 1-(1-methoxycarbonyl-2-phenylethyl)-3-benzyloxy-4-phenylazetidin-2-one (1.0 g.) was subjected to hydrogenolysis at 50° C. in methanol (50 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (255 mg.). The reaction was completed in 48 hours. The same after-treatment as in Example 1 was followed to give methyl ester of α-hydroxy-β-phenylpropionylphenylalanine (784 mg., yield: 100%), which was an oil.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[N:7]1([S:13](Cl)(=[O:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CO.C(O)(C)C>[N:7]1([S:13]([N:3]2[CH2:2][CH2:1][NH:6][C:4]2=[O:5])(=[O:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: O=C1NCCN1
Solvent: CO
Solvent: CC(C)O
Product: O=C1NCCN1S(=O)(=O)N1CCCCC1
Reaction time: 3 h

Procedure:
To 17.4 of ethyleneurea is added with shaking 36 g of piperidinosulfonyl chloride (b.p. 130°/11m) and the mixture kept under nitrogen at 100° for 3 hrs. The mixture is cooled and the gummy material treated with methanol-isopropanol (1:1) to give a granular product of 1-piperidinosulfonyl-2-oxo-tetrahydroimidazole which melts at 201° on recrystallization from methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[C:26]([C:28]([OH:37])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:3]=1[O:4][C@@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.[OH-].[Li+:39]>C1COCC1>[CH3:1][C:2]1[CH:27]=[C:26]([C:28]([OH:37])([C:29]([F:30])([F:31])[F:32])[C:33]([F:35])([F:36])[F:34])[CH:25]=[CH:24][C:3]=1[O:4][C@@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([O-:14])=[O:13])=[CH:10][CH:9]=1.[Li+:39]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1O[C@H](COc1ccc(C(=O)O)cc1)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1O[C@H](COc1ccc(C(=O)[O-])cc1)Cc1ccccc1
Yield: 98.2 %

Procedure:
20.2 mg (0.04 mmol) of 4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-3-phenyl-propoxy}-benzoic acid (example 36) in 3 mL of THF were treated with 1 mg (0.04 mmol) of lithium hydroxide. The solvent was evaporated to give 21 mg (quantitative) of lithium 4-{(S)-2-[2-methyl-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-3-phenyl-propoxy}-benzoate as a light yellow oil, MS: 527 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH:10]([CH3:15])[C:11]([O:13]C)=[O:12].Cl>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:10]([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(C)Cl
Reactant: Oc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(Oc1cccc(F)c1)C(=O)O
Temperature: 80 °C
Yield: 42 %

Procedure:
To a solution of m-fluorophenol (24.2 g, 0.22 mol) in 79.2 ml of 25% aqueous sodium hydroxide heated to 45° C. with an oil bath was added 29.5 ml (0.26 mol) methyl 2-chloropropionate. The reaction mixture was heated to 80° C. for 17 hours and then allowed to cool. When the temperature reached about 40° C., concentrated HCl (25 ml) was added and the reaction mixture was allowed to cool to room temperature. The reaction mixture was extracted twice with 100 ml ethyl ether. The organic layers were combined and washed with 200 ml of 1.5M aqueous sodium carbonate. The aqueous layer was separated and acidified to pH 1, by pH test paper, by adding concentrated HCl. The acidified aqueous layer was extracted with 200 ml ethyl ether. The organic layer was separated, dried with MgSO4 and filtered. The solvent was removed in vacuo to yield 17 g (41% yield) of 2-(3' -fluorophenoxy)propionic acid as a yellow solid (m.p. 72.5°-74° C.).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[CH:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>C(O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([NH:1][N:2]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: NNc1ccc([N+](=O)[O-])cn1
Solvent: CCO
Product: CC(C)c1ccc(C=NNc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 90 °C
Yield: 62.8 %

Procedure:
In 50 ml of ethanol were dispersed 3.03 g of 2-hydrazino-5-nitropyridine and 3.08 g of 4-isopropylbenzaldehyde. The dispersion was refluxed at 90° C. for one hour. The reaction solution was allowed to cool at room temperature and further cooled down to 5° to 10° C. to cause crystals to fully precipitate, which were collected by suction filtration. The crystals were washed with a small amount of ethanol and dried in vacuum at 60° C. for 1.5 hours, obtaining 3.51 g (yield 62%) of dark yellow acicular crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: ClCc1cccc(Cl)c1
Solvent: C1CCOC1
Product: Clc1cccc(CN2CCNCC2)c1

Procedure:
Synthesized according to General Procedure A: 3-chlorobenzyl chloride (4{8}, 5 mL, 39.3 mmol, 1 equiv.), piperazine (20.3 g, 235.7 mmol, 6 equiv.), THF (85.4 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{8} (5.41 g, 65%) as a light yellow liquid. 1H-NMR (400 MHz, CDCl3): δ 7.28 (br s, 1H) 7.19-7.12 (m, 3H), 3.39 (s, 2H), 2.82 (t, 4H, J=5.6 Hz), 2.34 (br s, 4H), 1.54 (br s, 1H). 13C-NMR (100 MHz, CDCl3): δ 140.2, 133.9, 129.2, 128.8, 127.0, 126.9, 62.8, 54.3, 45.9.
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](O)=[C:6](N)[CH:5]=1)([O-])=O.COC1C=CC=CC=1[NH2:19]>>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]([NH2:19])=[CH:4][CH:9]=1)([O-:12])=[O:11]
Reactant: COc1ccccc1N
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Product: Nc1ccc([N+](=O)[O-])cc1

Procedure:
If, in Example 10, the 4,6-dinitro-2-amino-phenol is replaced by 12.3 parts of 2-methoxy aniline and the 4-nitro aniline by 30.9 parts of 4-amino-4'-nitro-diphenylamine-2'-sulphonic acid, one obtains a dyestuff which dyes leathers from different tanning processes in shades which are much more yellow.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:28])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.[NH3:29]>O1CCOCC1>[NH2:29][C:2]1[C:7]2[C:8](=[O:28])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: N
Reactant: COC(=O)C(C)(C)COc1ccc(N2CCOc3ncnc(Cl)c3C2=O)cn1
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)COc1ccc(N2CCOc3ncnc(N)c3C2=O)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
Methyl 3-(5-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-20 was dissolved in a 0.5 M solution of ammonia in 1,4-dioxane and stirred at room temperature for 20 h. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (7 N ammonia solution in methanol:CH2Cl2 gradient) to give methyl 3-(5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-21 (55.0 mg, Yield=57% from B-19). MS (ESI) [M+1]+ 388.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[C:9]=1[OH:10])[CH:5]=O.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[C:9]=1[OH:10]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1cc(O)c(O)c(C(F)(F)F)c1
Product: O=C(C=Cc1cc(O)c(O)c(C(F)(F)F)c1)c1ccccc1

Procedure:
The procedure described in Example 8 was repeated using 2.06 g of 3,4-dihydroxy-5-trifluoromethylbenzaldehyde and 1.20 g of acetophenone. Yield 2.19 g (71%), m.p. 196°-210° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1.[CH3:14][Si:15]([CH3:24])([CH3:23])[C@@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:22][C@H:19]2[CH2:18][CH2:17][C@@H:16]([Si:15]([CH3:24])([CH3:23])[CH3:14])[CH2:21][CH2:20]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:13]
Reactant: CCc1ncnc(Cl)c1C(=O)OC
Reactant: C[Si](C)(C)[C@H]1CC[C@@H](N)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1ncnc(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)c1C(=O)OC

Procedure:
12.4 g (62.0 mmol) of 4-chloro-6-ethyl-5-methoxycarbonylpyrimidine, 11.1 g (62.0 mmol) of cis-4-trimethylsilylcyclohexylamine and 12.55 g (124 mmol) of triethylamine were heated in 30 ml of toluene at 90° C. for 3 hours. After complete reaction, the mixture was partitioned between dichloromethane and water to give, after further extraction with dichloromethane and column chromatography on silica gel, 17.76 g (85.4% of theory) of the cyclohexylaminopyrimidine as a pale brown oil, nD21 =1.5230.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:32]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1ccc(F)cc1Cl
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1Cl
Yield: 96 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-chloro-4-fluorobenzene boronic acid (82 mg, 0.472 mmol), sodium carbonate (0.4 mL, 2M solution), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan (2 mL) were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and Brine. The Aqueous layer was extracted with EtOAc ×3. The combined extracts were dried and evaporated. The residue was purified on a 25+M column eluting with 0-50% EtOAc/Pet Et2O. Impurities still seen. Sent to MDAP for purification to afford the title compound in a 96% yield.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1)=[O:2].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([O:9][C:8]([C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[S:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: O=Cc1cc(C(=O)O)cs1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(C=O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g). 5-Formyl-3-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (1.58 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The extract was washed with 5 % potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl-3-thiophenecarboxylic acid ethyl ester (0.71 g). 5-Formyl-3-thiophenecarboxylic acid ethyl ester (1.47 g) synthesized in this manner in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.2 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml), and 1N aqueous sodium hydroxide (5 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:29][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: NC1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNC2CCCC2)c1
Yield: 42.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-((cyclopentylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), cyclopentanamine (0.043 g; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.024 g (42%) of the title compound as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7].NCC[CH2:13][OH:14]>>[OH:14][CH2:13][CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7]
Reactant: NCCCO
Reactant: NC(=O)C(=O)NCCO
Product: NC(=O)C(=O)NCCCO
Yield: 75 %

Procedure:
Prepared as in Intermediate 3, using 3-aminopropanol to give the title compound as a white powder (1.15 g, 75%); NMR [(CD3)2SO] 1.6 (2H, m), 3.18 (2H, m), 3.42 (2H, m), 4.47 (1H, t), 7.73 (1H, br s), 8.0 (1H, br s), and 8.63 (1H, t).