Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O-:2][CH2:3][CH3:4].[Na+].[CH2:6]([C:11]1[CH:12]=[C:13]([OH:23])[CH:14]=[C:15](O)[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:7][CH2:8][CH:9]=[CH2:10].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:3]([O:2][C:15]1[C:16](=[C:11]([CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[CH:12]=[C:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]1[CH:16]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: CC[O-]
Reactant: ClCc1ccccc1
Reactant: C=CCCCc1cc(O)cc(O)c1C(=O)OCC
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: C=CCCCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)OCC

Procedure:
The first step in the sequence in the pyrolysis of 3-hydroxy-1,5-hexadiene to prepare 5-hexenal which is reacted with malonic acid to form 2,7-octadienoic acid. The foregoing acid is esterified by treatment with diazomethane and the resulting methyl ester is reacted with the sodium salt of ethyl acetoacetate under the influence of sodium methoxide in a methanol menstruum to yield the sodium salt of methyl 6-(4pentenyl)-β-dihydroresorcylate. The dihydroresorcylate sodium salt is then brominated at low temperature to form methyl 3 -bromo-6-(4 -pentenyl)-β-dihydroresorcylate which is de-hydrobrominated by treatment with sodium ethoxide in an anhydrous ethanol menstruum to prepare ethyl 6-(4-pentenyl)-β-resorcylate. The foregoing resorcylate is reacted with benzyl chloride to yield ethyl 6-(4-pentenyl)-β-resorcylate dibenzyl ether which is treated with the sodium alcoholate of 4-penten-2 -ol to produce 4 -penten-2-yl 6-(4-pentenyl)-β -resorcylate dibenzyl ether. The foregoing compound is treated successively with 2,3-dimethyl-2-butylborane, carbon monoxide, sodium acetate solution, and hydrogen peroxide to form zearalanone dibenzyl ether. On Hydrogenation zearalanone dibenzyl ether is converted to (R,S)-zearalanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:29][C:30](Br)=[O:31].[CH:33]1([NH2:43])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:29][C:30]([NH:43][CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1)=[O:31]
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)NCC2
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)N(CC(=O)NC1CCCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])=[C:3]([C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:4]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2ccc(Cl)cc21
Reactant: CCC(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(NC(=O)CC)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)indole (step 1 of Example 30) and propionyl chloride.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23].[OH2:24]>CS(C)=O>[OH:23][CH2:22][CH2:21][CH2:20][NH:19][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:19][CH2:20][CH2:21][CH2:22][OH:24])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: NCCCO
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Solvent: CS(C)=O
Product: O=C1c2cccc(NCCCO)c2C(=O)c2cccc(NCCCO)c21
Temperature: 130 °C

Procedure:
1,5-Dichloroanthraquinone (2.8 g; 10 mmol) is mixed with 3-amino-1-propanol (10 mL) in DMSO (50 mL) and heated to 130° C. for 4 hours. The mixture is cooled to ˜80° and added water (150 mL). When the mixture has reached RT the formed precipitate is isolated by filtration, washed with water (2×50 mL), boiled in toluene (200 mL) and the un-dissolved product is isolated by filtration and dried. Yield: 3.2 g (90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and aniline (2.23 g) was treated in the same manner as described in Preparation Example 37 to give white needles of the title compound.
Reaction SMILES: [C:1]1(C2C=CNN=2)C=CC=CC=1.[C:12]([CH:15]([NH:28]C(CC(C)C)C(O)=O)[CH2:16][C:17]1[CH:21]=[CH:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1)([OH:14])=[O:13].C1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:1][O:14][C:12](=[O:13])[CH:15]([NH2:28])[CH2:16][C:17]1[CH:21]=[CH:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1
Reactant: CC(C)CC(NC(Cc1ccn(-c2ccccc2)n1)C(=O)O)C(=O)O
Reactant: c1ccc(-c2cc[nH]n2)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(N)Cc1ccn(-c2ccccc2)n1
Reaction time: 2 h
Yield: 100 %

Procedure:
2-[1-carboxy-2-(1phenyl-1H-pyrazol-3-yl)-ethylamino]-4-methyl-pentanoic acid Phenyl pyrazole 54-3 was prepared as described by R. M. Adlington et al. from 54-1 (J. Chem. Soc. Perkin Trans I 2000, 2311–2316). This reaction with phenyl hydrazine provided a single isomer whose structure was confirmed with 2D NMR methods (NOESY, HMBC, and HMQC). Phenyl pyrazole 54-3 (380 mg, 0.98 mmol) was dissolved in dichloromethane (4 mL) and a solution of HCl (2.45 mL, 9.80 mmol, 4 N in dioxane) was added dropwise. The resulting mixture was stirred for 2 hours at room temperature, and a precipitate formed. The reaction mixture was concentrated to give a brown oil (290 mg, 100% yield). 1H NMR was consistent with the desired amino acid (with some tert-butyl ester). This oil was dissolved in methanol (5 mL) and toluene (5 mL) and a solution of trimethylsilyldiazomethane (2 mL, 3.92 mmol, 2 M in hexane) was added (gas evolution and precipitate formation). After 2 hours, the reaction mixture was concentrated to a brown oil. This oil was redissolved in ethyl acetate and the solution was extracted with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated to give 2-amino-3-(1-phenyl-1H-pyrazol-3-yl)-propionic acid methyl ester (54-4) as a brown oil (262 mg, >100% yield, contaminated with some tert-butyl ester). This ester was alkylated with triflate 54-5 as described above. The resulting diester was hydrolyzed to 2-[1-carboxy-2-(1phenyl-1H-pyrazol-3-yl)-ethylamino]-4-methyl-pentanoic acid 54-6 (Compound OD) as described above. 1H NMR (300 MHz, CD3OD) δ 8.17 (d, 1H, J=2.4 Hz); 7.76 (d, 2H, J=7.7 Hz); 7.46 (dd, 2H, J1=7.7 Hz, J2=8.1 Hz); 7.30 (t, 1H, J=7.3 Hz); 6.45 (d, 1H, J=2.4 Hz); 4.08 (dd, 1H, J1=4.5 Hz, J2=7.3 Hz); 3.97 (dd, 1H, J1=J2=6.9 Hz); 3.43 (dd, 1H, J1=4.7 Hz, J2=16.1 Hz); 3.34 (dd, 1H, J1=7.3 Hz, J2=16.3 Hz); 1.90–1.98 (m, 1H); 1.78–1.84 (m, 2H); 1.01 (d, 3H, J=5.3 Hz); 0.99 (d, 3H, J=5.7 Hz). Anal. Calc'd. for C18H23N3O4.H2O: % C, 59.49; % H 6.93; % N, 11.56. Found: % C, 59.85; % H, 6.96; and % N, 11.46.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(OCC)C>[C:8]1([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[N:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[CH2:22][CH2:21]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC1CCN([C@@H]2CCCC[C@@H]2c2ccccc2)CC1
Reactant: Brc1cncnc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1ccc([C@H]2CCCC[C@H]2N2CCC(Nc3cncnc3)CC2)cc1
Temperature: 70 °C
Yield: 20.6 %

Procedure:
The title compound, MS (ISP): m/e=446.4 (M+H+), was prepared as for example 209, steps (A) to (C). Step (B) was performed using 5-bromo-pyrimidine as follows: A suspension of (+/−)-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-amine (1.46 g, 5.65 mmol) in toluene (35 ml) was degassed with a flow of argon for 10 minutes. Tris-(dibenzylideneacetone)dipalladium chloroform complex (179 mg, 0.17 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP, 108.0 mg, 0.17 mmol), sodium tert-butoxide (0.660 g, 6.87 mmol) and 5-bromopyrimidine (0.720 g, 4.53 mmol) were added under argon. The flask was sealed and warmed to 70° C. for 3 hours. The mixture was diluted with ethyl acetate (30 ml) and diethyl ether (30 ml) and washed three times with saturated sodium chloride solution. The organic phase was dried with sodium sulphate and evaporated, yielding a red oil. Purification was achieved by flash chromatography (dichloromethane/methanol/25% NH3 90:10:1). (+/−)-[cis-1-(2-Phenyl-cyclohexyl)-piperidin-4-yl]-pyrimidin-5-yl-amine (0.392 g, 20.6%) was obtained as an orange foam, MS (ISP): m/e=337.3 (M+H+). This was reacted with 5-methyl-isoxazole-3-carbonyl chloride in step (C).
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.NCCC[C:24]1[NH:25][CH:26]=[CH:27][N:28]=1>>[N:25]1([CH2:10][CH2:6][CH2:7][NH:8][CH:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[CH2:7]2)[CH:26]=[CH:27][N:28]=[CH:24]1
Reactant: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: NCCCc1ncc[nH]1
Product: O=[N+]([O-])c1ccc(N2CCC(NCCCn3ccnc3)C2)cc1
Yield: 48.2 %

Procedure:
30 g (0.105 mol) of 1-(4-nitrophenyl)pyrrolid-3-yl methylsulphonate (2) were heated at 90° C. for 18 hours with 120 g of aminopropylimidazole (0.958 mol). This mixture was poured into ice-cold water and the product was extracted with dichloromethane. The yellow powder obtained was chromatographed, eluting with dichloromethane/methanol (98/2), and 15.2 g of derivative (7) were recovered (48.2% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH3:19][NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>>[CH3:19][N:20]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:15](=[O:16])[CH2:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:1])([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Reactant: CNc1ccc(C(=O)OC)cc1
Product: COC(=O)c1ccc(N(C)C(=O)Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 53.4 %

Procedure:
In a manner similar to Example 4(c), by reaction of 2.46 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthylacetic acid with 1.65 g (10 mmol) of methyl 4-methylaminobenzoate, 2.1 g (54%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>ClCCl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=2)=[O:30])=[N:3][CH:4]=[N:5]3)=[CH:14][CH:15]=1
Reactant: COc1ccc(Oc2cccc3ncnc(N)c23)cc1
Reactant: O=C=Nc1cccc(Br)c1
Solvent: ClCCl
Product: COc1ccc(Oc2cccc3ncnc(NC(=O)Nc4cccc(Br)c4)c23)cc1
Yield: 82.7 %

Procedure:
4-Amino-5-(4-methoxyphenoxy)quinazoline (0.35 g, 1.3 mmol) and 3-bromophenyl isocyanate (0.31 g, 1.6 mmol) were reacted in 20 ml of dichloromethane according to procedure E to give 1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea (0.5 g, 83.3%, m.p. 249-251° C.).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C(N(C(C)C)CC)(C)C.O[C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=C(O)[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=O)[CH:33]=2)[N:17]=1.Cl[CH2:42][Cl:43]>>[Cl:3][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:42]([Cl:43])[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:40])[CH:33]=2)[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCCl
Reactant: COc1ccccc1Oc1c(O)nc(-c2ccnc(C(N)=O)c2)nc1O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1Cl
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Within 20 min. 61 ml (633 mmol) of POCl3 were added dropwise to 34 ml (200 mmol) of diisopropyl ethylamine at 5° C. to 10° C. followed by stirring at 5° C. to 10° C. for 15 min. Then 23.5 g (66 mmol) of 4-[4,6-dihydroxy-5-(2-methoxy-phenoxy)-pyrimidine-2-yl]-pyridine-2-carboxylic acid amide were added in four portions under cooling followed by stirring at 90° C. for 25 hr. The reaction mixture was cooled down to 20° C. and transferred to a new flask together with 50 ml of dichloromethane. Volatile components (i.e. excess of POCl3) was removed by evaporation from 20° C. to 70° C. followed by re-distillation with 100 ml of toluene. After adding 250 ml of dichloromethane to the residue (88 g of a black oil) the solution was heated to 35° C. to 40° C. and 80 ml of de-ionized water were added dropwise within 30 min. whereby the pH was kept constant by the subsequent addition of 28% NaOH solution (60 ml) within 5 to 6 hr. The mixture was stirred at 35° C. to 40° C. for 30 min. followed by removal of dichloromethane by distillation. The resulting suspension was allowed to cool down to 20° C. and was stirred for additional 2 hr. The solid was filtered off under suction, washed with 500 ml of water and dried at 70° C., 2000 Pa for 16 hr. There were obtained 21.3 g (86% of theory) of 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidine-2-yl]-pyridine-2-carbonitrile with a HPLC purity of 94.3% (w/w).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[CH2:51]>CN(C)C=O>[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[CH:51][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: C=Cc1ccccc1Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C1Nc2cccc(/C=C/c3ccccc3Cl)c2/C1=C/c1ccc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(C=Cc3ccccc3Cl)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (39 mg, 0.116 mmol) (from Example 71 above), triethylamine (65 μL, 0.464 mmol), tri-o-tolylphosphine (7 mg, 0.023 mmol) (Aldrich), palladium(ll) acetate (2 mg, 0.009 mmol) (Aldrich), and 2-chlorostyrene (24 mg, 0.173 mmol) (Aldrich) in 3 mL of dry N,N-dimethylformamide was heated at 85° C. under a nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 5% ethyl acetate-benzene elution) to yield pure 4-[(E)-2-(2-chlorophenyl)-ethenyl]-1,3-dihydro-(Z)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow solid. (Yield 27 mg, 67%; mp=257-258° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:13]([NH:20][CH3:21])[CH2:12]1.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]([NH:20][CH3:21])[CH2:12]1
Reactant: CN[C@@H]1C[C@H](c2c[nH]c3c(F)cccc23)c2ccccc21
Agent: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Product: CN[C@H]1C[C@@H](c2c[nH]c3c(F)cccc23)c2ccccc21
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of the racemate cis-3-(7-Fluoro-1H-indol-3-yl)-indan-1-yl-methyl-amine (409 mg/2ml EtOH) was added a solution of Di-p-toluoyl-D-tartaric acid (1 eq; 564 mg/2 ml Acetone). The mixture was heated to 50° C. and stirred for 15min. Evaporated the solvent and triturated with acetone (2 ml). The white solid (84% ee) was collected and stirred with 10 ml hot EtOH for 30 min. The remaining white solid was collected and converted to free base to give [(1S,3R)-3-(7-Fluoro-1H-indol-3-yl)-indan-1-yl]-methyl-amine (93% ee).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])(O)(O)=O.[K+]>CS(C)=O.C(OCC)(=O)C.[Cu]>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of ethyl bromodifluoroacetate (1.1 equiv.) and 2-bromopyridine (1 equiv.) in DMSO was added copper bronze (2.2 equiv.) and the mixture was heated to 50° C. with stirring for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. A solution of potassium dihydrogen phosphate was added and the mixture stirred for 30 minutes before filtering. The copper salts were washed with ethyl acetate and the organic layer was washed with water. Solvent evaporation and purification by flash column chromatography on silica gel (diethyl ether-hexane) gave the title compound as a colorless oil in 82% yield.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][N:10]1[CH:14]=[N:13][N:12]=[C:11]1[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CN(C=O)C>[Cl:8][C:20]1[CH:21]=[C:15]([C:11]2[N:10]([CH3:9])[CH:14]=[N:13][N:12]=2)[CH:16]=[CH:17][C:18]=1[NH2:19]
Reactant: Cn1cnnc1-c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cn1cnnc1-c1ccc(N)c(Cl)c1
Temperature: 90 °C
Yield: 81 %

Procedure:
NCS (0.077 g, 0.574 mmol) was added to a solution of 4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (0.1 g, 0.574 mmol) in DMF (1.1 mL). The reaction mixture was heated at 90° C. for 1 hour and was then concentrated under vacuum. The residue was purified via Biotage silica gel column chromatography elutin with (DCM/EtOH 99/1 to 90/10) to afford the title product as a white solid (97 mg, 81%). 1H NMR (500 MHz, CD3OD) δ 3.78 (s, 3H), 6.95 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.4, 2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 8.48 (s, 1H). LC (Method B)-MS (ESI, m/z) tR 1.25 min, 209 [(M+H+), 100%].
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.C(OC(=O)C)(=[O:13])C>CC(O)=O>[CH:1]([C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)=[O:13]
Reactant: Cc1nc2cnccc2s1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=Cc1nc2cnccc2s1
Yield: 35.5 %

Procedure:
A mixture of 2-methylthiazolo[4,5-c]pyridine [prepared according to the procedure of T. Takahashi et al., Pharm. Bull. (Japan) 2, 196 (1954)] (635 mg, 4.2 mmoles), 2.55 g of SeO2, 10 ml of CH3COOH and 10 ml of acetic anhydride was heated at 90 100° C. for 2.5 hours, and the reaction mixture then was filtered to remove insolubles. The filtrate was evaporated in vacuo, and purified by a column of SiO2 (50 ml) to give 248 mg (35.5%) of the title compound. Mp. 96.5°~98° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30].O>C(Cl)Cl>[C:28]([O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:4]2[C:5]3[S:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH:15]=1)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)Cl
Reactant: Oc1cccc(-c2cccc3c2sc2ccccc23)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1cccc(-c2cccc3c2sc2ccccc23)c1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
1.03 g of the thus obtained 3-(4-dibenzothiophenyl)phenol is placed in a round bottom flask and suspended in 15 mL of methylene chloride; after ice cooling the flask, 0.45 g of triethylamine is added; 0.40 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and ethyl acetate, respectively and then gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=80/20 (volume ratio)) to concentrate a component having an Rf of 0.50, thereby obtaining 0.90 g (yield: 73%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 6.03 (dd=1.2 & 10.4 Hz, 1H), 6.36 (dd=10.4 & 17.2 Hz, 1H), 6.64 (dd=1.2 &17.2 Hz, 1H), 7.20 to 7.24 (m, 1H), 7.44 to 7.55 (m, 6H), 7.62 to 7.65 (m, 1H), 7.82 to 7.85 (m, 1H), 8.14 to 8.19 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.C1COCC1.[CH3:25][NH2:26]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:26][CH3:25])=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CN
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNCc1sc2c(N3CCOCC3)nc(Cl)nc2c1C
Reaction time: 24 h
Yield: 70 %

Procedure:
2-Chloro-7-methyl-4-morpholinothieno-[3,2-d]pyrimidine-6-carbaldehyde 36 was dissolved in 20 mL toluene and 20 mL THF followed by the addition of 15 mL 40% methylamine in H2O and the reaction was stirred for 24 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in 30 mL methanol and 30 mL THF followed by the addition of NaBH4. The reaction was stirred at room temp for at least 24 hours and product formation was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography to give 2.53 g (2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 37 (70% yield) MS (Q1) 314 (M)+