Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCCCO)CC4)n3)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
120 mg (0.34 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine were suspended in 3 ml of DMF with 100 μl (0.68 mmol) of 4-bromobutyl acetate and 56 mg (0.41 mmol) of potassium carbonate and stirred at 60° C. overnight. The reaction mixture was taken up in dichloromethane, washed once each with a concentrated sodium hydrogencarbonate solution and a 1N hydrochloric acid solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The protecting group is cleaved off by means of a 1N NaOH solution in methanol: The reaction mixture was stirred at room temperature and subsequently evaporated. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].NC(N)=N>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C1C[C@H](c2ccc(Cl)cc2)CN1
Agent: N=C(N)N
Agent: O=S(=O)(O)O
Product: O=C1C[C@H](c2ccc(Cl)c([N+](=O)[O-])c2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
(4R)-4-(4-Chlorophenyl)pyrrolidin-2-one (44 g, 225.6 mmol) was treated with conc. sulfuric acid (220 mL). This solution was cooled in ice. Guanidine nitrate (27.5 g, 225.6 mmol) was added in portions. The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was then poured into ice. The product crashed out as a pale yellow solid and was filtered, washed with hexane, and dried to give the title compound (51 g, 95% yield). 1H-NMR (400 MHz, CD3OD): δ7.12 d, J=8.4 Hz, 1H), 6.73-6.74 (d, J=4.0 Hz, 1H), 6.52-6.55 (m, 1H), 3.70-3.74 (m, 1H), 3.54-3.62 (m, 1H), 3.32-3.46 (m, 1H), 2.63-2.69 (dd, J=16.4, 8.8 Hz, 1H), 2.37-2.43 (dd, J=16.8, 8.8 Hz, 1H); MS (ESI) m/z 241.05 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:23][C:22]4[CH:21]=[C:20]([O:31][Si](C(C)(C)C)(C)C)[CH:19]=[CH:18][C:17]=4[C:12]=3[CH2:13][O:14][C:15]=2[CH:16]=1)(C)(C)C.C([Si](C)(C)OC1C=CC2C3C(C4C=CC(OCCN5CCCCC5)=CC=4)OC4C=C(O[Si](C(C)(C)C)(C)C)C=CC=4C=3COC=2C=1)(C)(C)C>>[C:25]1([CH:24]2[C:11]3[C:10]4[CH:9]=[CH:8][C:7]([OH:6])=[CH:16][C:15]=4[O:14][CH2:13][C:12]=3[C:17]3[CH:18]=[CH:19][C:20]([OH:31])=[CH:21][C:22]=3[O:23]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(c1ccccc1)C1=C2COc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)C1=C2COc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Product: Oc1ccc2c(c1)OC(c1ccccc1)C1=C2COc2cc(O)ccc21

Procedure:
The title product was prepared according to the procedure described in Example 44 with substitution of 2,8-Bis-(tert-butyl-dimethyl-silyloxy)-5-phenyl-5,11-dihydro-chromeno[4,3-c]-chromene, prepared as in Example 41, for 1-(2-{4-[2,8-Bis-(tert-butyl-dimethyl-silyloxy)-5,11-dihydro-chromeno[4,3-c]-chromen-5-yl]-phenoxy}-ethyl)-piperidine.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:32])[NH:41][CH2:40][CH2:39][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 61.4 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 2-phenylethylamine (available from Aldrich Chemical Company, Inc.; 75 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-phenethylcarbamoyl-biphenyl-2-carboxylic acid (74 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 8.62 (t, J=5.4 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.18-7.35 (m, 5H), 3.52 (q, J=6.7 Hz, 2H), 2.88 (t, J=7.4 Hz, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](/[C:7](=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)/[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:37])=[C:26]([CH:28]=[N:29][C:30]([O:32][Si](C)(C)C)=[CH2:31])[CH:27]=1>C1(C)C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([CH:13]2[CH2:31][C:30](=[O:32])[NH:29][CH:28]([C:26]3[CH:27]=[C:22]([F:21])[CH:23]=[CH:24][C:25]=3[CH3:37])[C:7]32[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]3=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: COc1ccc2c(c1)NC(=O)/C2=C\c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)NC(=O)C21C(c2cccc(Cl)c2)CC(=O)NC1c1cc(F)ccc1C
Yield: 10 %

Procedure:
In a manner similar to the method described in example 1c, E/Z-6-methoxy-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 168b was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a, in toluene to give racemic (2′R,3R,4′S)-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-6-methoxy spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.05 g, 10%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([OH:40])[CH:36]=[CH:37][C:38]=1[F:39].C(OC([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[F:39])[O:40][CH:51]1[CH2:52][CH2:53][NH:48][CH2:49][CH2:50]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(F)c(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Fc1ccc(OC2CCNCC2)cc1Cl
Reaction time: 8 h
Yield: 105.2 %

Procedure:
DEAD (0.43 ml) was added to a solution of triphenylphosphine (0.72 g), 3-chloro4-fluorophenol (0.403 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g) in THP at room temperature (RT). The resulting mixture was stirred overnight, HCl in dioxan (2 ml of 4M) was added and the mixture stirred at RT overnight. The mrixture was then evaporated to dryness and triethylamine (5 ml) was added. The mixture was evaporated and the residue was dissolved in methanol (10 ml), placed onto a SCX cartridge (Varian, 10 g, SCX cartridge available from International Sorbent Technology Isolute® Flash SCX-2) and eluted: first with methanol then with 10% NH3 in methanol. The basic fractions were combined and evaporated to give the product as an oil (0.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:21][C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)=[CH:4][CH:3]=1.Cl[CH2:23][CH:24]1[CH2:26][CH2:25]1.[I-].[K+].C(=O)(O)[O-].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([OH:39])=[O:38]>CN(C)C=O.O.C(Cl)Cl>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([OH:39])=[O:38].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:21][C:15]3([CH2:16][CH2:17][N:18]([CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH2:19][CH2:20]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2SC3(CCNCC3)c3ccccc32)cc1
Reactant: ClCC1CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ccc(C2SC3(CCN(CC4CC4)CC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2.0 g of 3-(4-chlorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine], Example 15, 0.7 g of chloromethylcyclopropane, 1.4 g of potassium iodide and 1.4 g of sodium bicarbonate in 20 ml of dimethylformamide is heated with stirring at 80°-85° C. for 17 hours. The reaction mixture is permitted to cool to ambient temperature before being diluted with 75 ml of water and 30 ml of methylene chloride. The aqueous phase is extracted twice with methylene chloride and all the methylene chloride solutions are combined. The combined solutions are washed, sequentially, with water and saturated sodium chloride solution and then dried effecting a clear oil. The oil is chromatographed on an alumina column with an ether eluant to obtain the oil with enhanced purity. This oil is converted to its maleic acid salt which is recrystallized from an acetone-ether mixture to obtain the salt, mp 217.5°-218° C. of 3-(4-chlorophenyl)-1'-cyclopropylmethyl-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine] maleate.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1.C(O)C(N)(CO)CO>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:13]=2)[S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(c1ccc(NCc2ccc(Cl)cc2)cc1)N1CCN(c2ccccc2)CC1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccccc2)cc1)N1CCN(c2ccccc2)CC1
Reaction time: 18 h
Yield: 125.6 %

Procedure:
To a stirred solution of [4-(4-chloro-benzylamino)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone (30 mg, 0.07 mmol) and phenylsulfonyl chloride (14.2 μl, 0.11 mmol) in anhydrous dichloromethane (1 ml) was added pyridine (7.2 μl, 0.09 mmol) and the reaction was stirred at ambient for 18 hours. PS-trisamine (32 mg, 0.13 mmol) was added and the mixture was agitated for 3 hours then filtered. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid (48 mg, 98% yield). HPLC retention time 7.7 min. Mass spectrum (ES+) m/z 547 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N+:14]([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[NH2:14]
Reactant: CCOCCSc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOCCSc1ccc(N)c(N)c1

Procedure:
6.4 G. of 1-amino-2-nitro-4-(2-ethoxyethylthio) benzene in 100 ml. of methanol and 50 ml. of water is treated with 16 ml. of sodium dithionite and 14 g. sodium carbonate at reflux under nitrogen. Heating is continued for one-half hour, then the methanol is evaporated from the mixture. The mixture is diluted with 100 ml. of water and is extracted with chloroform. The chloroform solution is dried over sodium sulfate and 1,2-diamino-4-(2-ethoxyethylthio) benzene is obtained by evaporation of the solution.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:34]([NH:38][S:39]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)(=[O:41])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([NH:38][S:39]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=4)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:47]=1)(=[O:41])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-(4-{4-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidin-2-yl}-pyridin-2-yl)-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.56) (0.16 g, 0.32 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.11 g, 0.41 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.21 g), which was subsequently deprotected.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[CH2:17](O)[CH:18]1[O:22][CH2:21][CH2:20][CH2:19]1>C1CCCCC1.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.C.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O:15][CH2:17][CH:18]2[O:22][CH2:21][CH2:20][CH2:19]2)=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Reactant: OCC1CCCO1
Agent: C
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Product: CC(C)=CCc1ccc(C(C)C(=O)OCC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of 21.8 g of 2-(p-prenylphenyl)propionic acid, 10.2 g of tetrahydrofurfuryl alcohol and 0.4 g of graphite bisulfate in 100 ml of cyclohexane was stirred at room temperature for 8 hours. The mixture was passed through a column of silica gel, and the solvent was evaporated to give 24.5 g of tetrahydrofurfuryl 2-(p-prenylphenyl)propionate. b.p. 135° C./0.08 mmHg, IR νmaxneat ; 1730 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[C:7]2[CH:31]=[CH:30][NH:29][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH:20]3[CH2:23][N:22]([CH2:24][CH2:25][F:26])[CH2:21]3)=[CH:15][C:14]=2[O:27][CH3:28])[N:11]=1.C(N(C(C)C)CC)(C)C.C(Cl)Cl.[C:47](Cl)(=[O:50])[CH:48]=[CH2:49]>C1COCC1>[F:26][CH2:25][CH2:24][N:22]1[CH2:23][CH:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]3[N:11]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:47](=[O:50])[CH:48]=[CH2:49])[CH:34]=[CH:33][CH:32]=4)[C:7]4[CH:31]=[CH:30][NH:29][C:8]=4[N:9]=3)=[C:14]([O:27][CH3:28])[CH:15]=2)[CH2:21]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(NC2CN(CCF)C2)ccc1Nc1nc(Oc2cccc(N)c2)c2cc[nH]c2n1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(NC4CN(CCF)C4)cc3OC)nc3[nH]ccc23)c1

Procedure:
A 50 mL-round-bottom flask with a magnetite was charged with N1-(4-(3-aminophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-N4-(1-(2-fluoroethyl)azetidin-3-yl)-2-methoxybenzene-1,4-diamine (125 mg, 0.27 mmol), diisopropylethylamine (43 mg, 0.33 mmol) and DCM (20 mL). The mixture was cooled with an ice bath until the temperature was below 0° C., and a solution of acryloyl chloride (33 mg, 0.33 mmol) in THF (2 mL) was added dropwise over 5 minutes. The title compound is isolated and purified by preparative HPLC or preparative LC/MS, or by other standard purification techniques.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:11]2[CH:10]=[CH:9][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Clc1cc(-c2ccc3ccccc3c2)ncn1
Yield: 48 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 5.0 g of 4,6-dichloropyrimidine, 11.7 g of 2-naphthaleneboronic acid, 7.2 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 2.9 g of 2-naphthaleneboronic acid, 1.8 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 5:1, so that a pyrimidine derivative 4-chloro-6-(naphthalen-2-yl)pyrimidine, which was the objective substance, was obtained (yellow white powder, yield of 48%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (h-1) of Step 1 is shown below.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14]([OH:17])(=O)[CH3:15].N([O-])=O.[Na+]>O>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([O:1][CH:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][OH:17])=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: OCC(Oc1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 80 °C

Procedure:
2.89 g. of 2-(biphenylyl-4-oxy)-2-phenyl-ethylamine (obtainable by reacting 4-hydroxy-biphenyl with 2-bromophenylacetenitile and subsequently reducing the resulting nitrile) are dissolved in 50 ml. of 15% aqueous acetic acid and a solution of 1 g. of NaNO2 in 5 ml. of water is added while cooling with ice. The mixture is heated at 80° C. for 1 hour, worked up in the usual manner and purified by chromatography on silica gel to give 2-(4-biphenylyloxy)-2-phenyl-ethanol, m.p. 126°-127° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].O1CCOCC1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH2:25]([O:24][C:22]([NH:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:7])[CH3:8])[C:3]([OH:5])=[O:4])=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: CC(C)SC(C)(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Reaction time: 6 h
Yield: 21 %

Procedure:
2-(R)-Amino-3-isopropylsulfanyl-3-methyl-butyric acid (approx. 27 mmol; crude material from the previous step) was dissolved in 40 mL of water and 40 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Ethyl chloroformate (3.3 mL) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 11) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times. Evaporation of the solvent in vacuo gave a yellow oil, which was purified by HPLC (RP-18; pH 2.3; H2O/CH3OH 3/7) to give 1.50 g (21%) of the title compound as a colorless oil. (+)-APCI-MS: 264 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[CH3:17][S:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>CC#N>[CH3:17][S:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][N:6]3[C:10](=[O:11])[C:9]4=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]4[C:7]3=[O:16])[CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C1c2ccccc2C(=O)N1OCCCBr
Reactant: CSc1cccc(N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSc1cccc(N2CCN(CCCON3C(=O)c4ccccc4C3=O)CC2)c1
Temperature: 25 °C
Reaction time: 84 h
Yield: 145 %

Procedure:
A solution prepared from N-(3-bromopropyloxy)phthalimide (5.00 g), 1-(3-methylthiophenyl)piperazine (3.85 g), diisopropylethylamine (4.55 g) and CH3CN (150 ml) was stirred at room temperature under N2 for 84 hr. The solution was concentrated in vacuo and dried under vacuum yielding 10.5 g of a foam. TLC analysis showed one major product. The foam was extracted with EtOAc (250 ml) yielding after concentration 7.1 g of an oil. The oil was chromatographed (2 silica gel columns) to provide 4.00 g of an oil. The oil was triturated with EtOAc/Et2O to give a solid which was recrystallized from EtOAc/Et2O yielding 3.08 g of crystals, mp 103°-106° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12](OCC)=[O:13])=[CH:4][C:3]=1[Cl:17].O.[NH2:19][NH2:20]>C(O)C>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:19][NH2:20])=[O:13])=[CH:4][C:3]=1[Cl:17]
Reactant: CCOC(=O)c1cc(Cl)c(N)c2c1OCCO2
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(Cl)c(N)c2c1OCCO2

Procedure:
38.4 g (0.149 mol) of ethyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylate suspended in 150 ml of ethanol are introduced into a 1 l reactor, 149 g (2.98 mol) of hydrazine hydrate are added, over 15 min, and the mixture is refluxed for 1 h.