Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[CH:3][N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: CCC(COC)n1cc(I)c2c(OC)nccc21
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COC)n1cc(-c2ccc(S(N)(=O)=O)cc2)c2c(OC)nccc21
Temperature: 130 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridine (70.8 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (60.0 mg), tetrakis(triphenylphosphine)palladium(0) (19.2 mg) and potassium carbonate (46.0 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (24.2 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=12.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:28][C:2]2[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:7]=23)=[CH:25][CH:24]=1
Reactant: Cc1c(C)n(CC=Cc2ccccc2)c2c(Cl)nncc12
Reactant: OCc1ccc(F)cc1
Product: Cc1c(C)n(CC=Cc2ccccc2)c2c(OCc3ccc(F)cc3)nncc12
Yield: 47.7 %

Procedure:
The title compound (trans) was prepared as pale yellow crystals in 47.7% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(3-phenyl-2-propenyl)pyrrolo[2,3-d]pyridazine (trans) and 4-fluorobenzyl alcohol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][C:18]2([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Cl[CH2:32][C:33]1[N:34]=[C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]2[CH:41]=1.[I-].[Na+]>CC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][C:18]2([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[O:23][C:22](=[O:24])[CH:21]([CH2:32][C:33]3[N:34]=[C:35]4[N:40]=[CH:39][CH:38]=[CH:37][N:36]4[CH:41]=3)[C:20](=[O:25])[CH2:19]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: ClCc1cn2cccnc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3cn4cccnc4n3)C(=O)O2)cc1Cl
Yield: 21.5 %

Procedure:
Potassium carbonate (35.4 mg, 0.256 mmol) was added to a solution of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (30 mg, 0.085 mmol), 2-(chloromethyl)imidazo[1,2-a]pyrimidine (17.2 mg, 0.103 mmol) and sodium iodide (5 crystals) in acetone (40 ml). The reaction mixture was stirred at reflux for 24 hrs, after which time the mixture was acidified to pH=3 and the product was extracted with ethyl acetate (3×25 ml). The combined organics were washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by prep HPLC to afford the title compound as a white solid (8.8 mg).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6](O)[CH3:7].[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([C:26]([OH:28])=[O:27])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11]>O>[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([C:26]([O:28][CH2:6][CH3:7])=[O:27])[CH2:24][CH2:25]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C(=O)OCC)CC2)CC1
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (5.0 mL) was added to an ethanol suspension (150 mL) of trans-4-(2-(trans-4-propylcyclohexyl)ethyl)cyclohexanecarboxylic acid (50.0 g), and the resultant was thereafter heated and refluxed for six hours. It was cooled to room temperature to halt the reaction by the addition of water. An organic layer was extracted by using ethyl acetate. The thus collected organic layer was washed by using a saturated sodium bicarbonate aqueous solution and brine in that order, and dried with anhydrous sodium sulphate. Solvents were removed by distillation to obtain a slightly yellow solid of 55.1 g.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C1CCCCC1>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(C2CC2)nn1-c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: O=C(Nc1cc(C2CC2)nn1-c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
To a stirred solution of 3-cyclopropyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 5.03 mmol) and triethylamine (0.66 g, 6.53 mmol) at rt, was added phenyl chloroformate (0.94 g, 6.01 mmol). The reaction mixture was stirred at rt for 15 h. The reaction mixture was partitioned between a mixture of dichloromethane (20 mL) and water (20 mL) and the organic layer was washed thrice with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give yellow oil. Trituration with cyclohexane afforded phenyl 3-cyclopropyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.01 g, 63%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 6.71-7.55 (m, 10H), 6.18 (s, 1H), 1.92 (m, 1H), 0.91 (m, 2H), 0.73 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:14]([CH3:15])[CH2:13][O:12][C@H:11]([CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH2:8].[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH:32]=O)=[N:28][NH:29]2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([C:32]3[NH:8][C:7]4[CH:6]=[CH:5][C:4]([N:9]5[C@@H:14]([CH3:15])[CH2:13][O:12][C@H:11]([CH2:16][N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH2:10]5)=[CH:3][C:2]=4[N:1]=3)=[N:28][NH:29]2)=[CH:25][CH:24]=1
Reactant: O=Cc1n[nH]c2cc(F)ccc12
Reactant: CCN(CC)C[C@@H]1CN(c2ccc(N)c(N)c2)[C@@H](C)CO1
Product: CCN(CC)C[C@@H]1CN(c2ccc3[nH]c(-c4n[nH]c5cc(F)ccc45)nc3c2)[C@@H](C)CO1

Procedure:
The title compund is synthesized according to the general procedure described in Example 4 with {[(2R,5S)-4-(3,4-diaminophenyl)-5-methylmorpholin-2-yl]methyl}diethylamine and 6-fluoro-1H-indazole-3-carbaldehyde.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]Br.[Mg].C(Br)CBr.[Cl-:17].[Zn+2:18].[Cl-].CC(CCCC(C)C)CC[Mg]Br>O1CCCC1>[Cl-:17].[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][Zn+:18]
Reactant: [Zn+2]
Reactant: CC(C)CCCC(C)CCBr
Agent: CC(C)CCCC(C)CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC[Zn+]
Reaction time: 1 h

Procedure:
A Grignard reagent was prepared from 3.63 g (0.016 mol) of 3,7-dimethyloctyl bromide, 0.363 g (0.015 mol) of metallic magnesium, 40 ml of tetrahydrofuran and 3 droplets of ethylene dibromide as a reaction initiator. 2.09 g (0.015 mol) of anhydrous zinc chloride was added to the tetrahydrofuran solution of 3,7-dimethyloctylmagnesium bromide, while keeping the solution at 20° C. The obtained mixture was stirred at that temperature for one hour to give a cloudy tetrahydrofuran solution of 3,7-dimethyloctylzinc chloride. 0.3 g (0.0007 mol) of CuI·(C6H5)3P was added to this solution, followed by stirring for 5 minutes. 20 ml of a solution of 1.0 g (0.0024 mol) of 2,5,7,8-tetramethyl-2-(3'-chloro-4'-methylenepentyl)-6-yl benzyl ether having a purity of 98% in tetrahydrofuran was dropped into the obtained mixture at 20° C. over a period of 5 minutes. After the completion of the dropping, the obtained mixture was stirred at that temperature for 2 hours and subjected to TLC and HPLC to confirm the disappearance of the chlorine-containing raw material. The ratio of the γ-adduct to the α-adduct (γ:α) was 98:2 (conversion: 95%).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18]>C(O)(=O)C>[Br:1][C:21]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([NH:14][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:4]=2[CH3:3])=[CH:23][CH:22]=1
Reactant: Cc1c(Nc2ccccc2C(=O)O)cccc1C(F)(F)F
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1c(Nc2ccc(Br)cc2C(=O)O)cccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
Over a 30 minute period and with constant stirring, add 16 g. of bromine dissolved in 50 ml. of glacial acetic acid to a mixture of 37 g. of N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid in 350 ml. of glacial acetic acid. Pour the resulting mixture into 1500 ml. of water, filter and dry the precipitate. Recrystallize the product from acetonitrile to obtain 5-bromo-N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid, m.p. 223°-225° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22]([CH:23]=CC)=[CH:21][C:20]([F:26])=[CH:19][C:18]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2C2C=CC=CC=2)[CH:14]=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:40][CH2:41]Cl>C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:14]=[CH:23][C:22]3[C:17](=[C:18]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[C:41]4[CH:40]=[CH:4][CH:3]=[CH:2][CH:1]=4)[CH:19]=[C:20]([F:26])[CH:21]=3)[O:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(C=CC)cc(F)cc1-c1ccccc1-c1ccccc1
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4ccccc4-c4ccccc4)c3O2)cc1
Yield: 82 %

Procedure:
Treatment of (2R)-2-(5-fluoro-2′-phenyl-3-(prop-1-enyl)biphenyl-2-yloxy)but-3-enyl 4-methylbenzenesulfonate (1.8 g, 3.40 mmol) with benzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (1.0 g, 1.22 mmol) in 1,2-dichloroethane (100 mL) according to the procedure described for Example 69, Step 7 provided 1.36 g (82%) of ((2R)-8-(biphenyl-2-yl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a brown solid. MS (ESI) m/z 504.1 ([M+NH4]+).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][NH:61][CH2:60][CH:59]5[CH:64]([CH3:66])[CH3:65])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:53].[ClH:1].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][N:58]5[CH2:63][CH2:62][N:61]([CH3:4])[CH2:60][CH:59]5[CH:64]([CH3:66])[CH3:65])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:33][CH2:34]1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Reactant: CC(C)C1CNCCN1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Agent: Cl
Product: CC(C)C1CN(C)CCN1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from racemic 2-{5-chloro-2-[3-(2-isopropyl-piperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 527 (35Cl) and 529 (37Cl) [M(free base)+H].
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.C=O.Cl.[CH2:27](Cl)[Cl:28]>[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:27][Cl:28])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccccc2)CC1
Agent: C=O
Agent: Cl
Agent: [Cl-]
Product: CN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
33.8 g of trans-N-(4-chlorobenzoyl)-N-methyl-4-phenylcyclohexylamine, 24.3 g of paraformaldehyde and 24.3 g of zinc chloride are suspended in 1300 ml of methylene chloride at ambient temperature and over a period of 2.5 hours hydrogen chloride is introduced, whilst the temperature rises to 29° C. The solution obtained is stirred overnight, poured into 1500 ml of ice water and then stirred until phase separation is obtained. The organic phase is washed with water, dried and concentrated by evaporation and the residue is recrystallised from ethyl acetate. 30.1 g of the title compound, melting point 174°-176° C., are obtained.
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3CCOCC3)=O)C)=CN=2)=CC=1.[NH2:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29].[C:45]1([CH:51]([CH3:55])[C:52](O)=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:33]2[N:34]=[N:35][C:30]([CH:28]([NH:27][C:52](=[O:53])[CH:51]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH3:55])[CH3:29])=[CH:31][N:32]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Reactant: CC(C(=O)O)c1ccccc1
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)C(C)c3ccccc3)nn2)cc1
Reaction time: 15 h
Yield: 86.6 %

Procedure:
In a similar manner as described for Intermediate 50, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 2-phenylpropionic acid (0.061 mL, 0.45 mmol), except the reaction was stirred for 15 h, to give N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-phenylpropanamide (134 mg) as: a yellow solid. MS m/z 376 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[N:20]=[C:12]3[C:13]([Br:19])=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>O1CCOCC1.O>[Br:19][C:13]1[C:12]2[N:11]([N:10]=[C:9]([C:6]3([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[N:20]=2)[C:16]([O:17][CH3:18])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(c2nc3c(Br)ccc(OC)n3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Br)c2nc(C3(C(=O)O)CC3)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(8-Bromo-5-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropanecarboxylic acid ethyl ester (0.22 g, 0.64 mmol) was dissolved in 1,4-dioxan (15 mL). LiOH (0.085 g, 1.9 mmol) in H2O (3 mL) was added. The mixture was stirred at RT overnight. The solvent was evaporated. H2O (50 mL) was added and the aqueous phase was adjusted to pH 1 with 2 N HCl. The aqueous phase was extracted (×3) with EtOH/DCM 1/10. The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].[N:16]#[C:17]Br>>[CH2:13]([N:6]([CH2:5][C:2]1([CH3:15])[CH2:3][O:4][C:17]([NH2:16])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: N#CBr
Reactant: CCN(CC(C)(N)CO)c1ccccc1
Product: CCN(CC1(C)COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1.d (RS)-2-amino-3-(ethyl-phenyl-amino)-2-methyl-propan-1-ol was reacted with cyanogen bromide to give (RS)-4-[(ethyl-phenyl-amino)-methyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine as a colourless gum. MS (ISP): 234.0 ([M+H]+).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:3](=[O:5])[CH2:2][C:1]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Product: O=C(CC(=O)Nc1ccc(Cl)cc1Cl)Nc1ccc(Cl)cc1Cl
Temperature: 200 °C

Procedure:
A mixture of diethyl malonate (24 g, 0.15 mol) and 2,4-dichloro aniline (60.8 g, 2.5 eq) was heated at 200° C. upon passing nitrogen gas stream to distil out ethanol. Six hours later, the reactants were cooled to room temperature with adding diethylether. The solids produced were filtered and washed with diethylether (yield: 48 g, 82%): 1H NMR (CDCl3) δ10.04 (s, 2H) 8.04 (d, J=9 Hz, 2H) 7.42 (m, 2H) 7.26, (dd, J=2.4, 9 Hz, 2H) 3.74 (s, 2H)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.CCCCCC>ClCCl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:1](=[O:3])[CH3:2])=[CH:12][CH:11]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Acetic anhydride (10.21 g, 9.4 mL, 100 mmol) was added dropwise over 1 hour to a stirred solution of p-anisidine (12.32 g, 100 mmol) in dichloromethane (40 mL) at 25-30° C. The mixture was stirred for an additional 1 hour at the same temperature. Hexane (120 mL) was added dropwise to the mixture at 25-30° C. The obtained suspension was stirred for 1 hour at the same temperature. The precipitated crystals were separated by filtration and dried under reduced pressure to give 15.31 g (92.7%) of N-(4-methoxyphenyl)acetamide [3a] as off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH2:32][C:33](=[O:37])[NH:34]2)=[CH:29][C:28]=1[F:38]>>[F:38][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:27]=1[NH:26][C:15]1[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[N:17]3[N:16]=1)[NH:34][C:33](=[O:37])[CH2:32][CH2:31]2
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: Nc1cc2c(cc1F)CCC(=O)N2
Product: COc1ccccc1-c1ccc2cnc(Nc3cc4c(cc3F)CCC(=O)N4)nn12

Procedure:
Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.080 g, 0.21 mmol) and 7-Amino-6-fluoro-3,4-dihydro-1H-quinolin-2-one (0.045 g, 0.25 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h. The product was triturated and washed with acetone. LC/MS: 403.9 (M+H)HPLC: 2.966 min, 99% purity. MP: 300-305° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.57 (s, 1H), 7.91 (d, J=7.6 Hz, 1H) 7.62-7.53 (m, 2 h), 7.44 (s, 1H), 7.24-7.23 (m, 1H), 7.19-7.01 (m, 6H), 7.17-7.10 (m, 3H), 7.08 (s, 1H), 8.89 (s, 3H), 2.94 (t, 2H), 2.66, (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH3:19])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:15]C)=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.Br>>[Cl:1][C:2]1[C:3]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH3:19])=[N:4][C:5]([NH:8][C:9]2[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1ncccc1Nc1ncc(Cl)c(N[C@@H](C)c2ccc(F)cn2)n1
Agent: Br
Product: C[C@H](Nc1nc(Nc2ccc[nH]c2=O)ncc1Cl)c1ccc(F)cn1
Temperature: 100 °C
Yield: 87.1 %

Procedure:
A mixture of (S)-5-chloro-N4-(1-(5-fluoropyridin-2-yl)ethyl)-N2-(2-methoxypyridin-3-yl) pyrimidine-2,4-diamine (Preparation 3b, 0.184 g, 0.49 mmol) and 48% aqueous hydrogen bromide solution (1.6 mL) was heated to 100° C. for 3 hours. The solvent was evaporated under reduced pressure and the residue was treated with a saturated aqueous solution of potassium carbonate and then extracted with ethyl acetate (×3). The combined organic extracts were dried (Na2SO4) and the solvent evaporated to yield the title compound (0.154 g, 91%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][SH:7].[H-].[Na+].CCCCCC.[CH3:21][O:22][C:23]([C:25]1[C:30]([N+]([O-])=O)=[CH:29][C:28]([C:34]([O:36][CH3:37])=[O:35])=[CH:27][N:26]=1)=[O:24]>CN(C)C=O.O.C(O)(=O)C>[CH3:21][O:22][C:23]([C:25]1[C:30]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)=[CH:29][C:28]([C:34]([O:36][CH3:37])=[O:35])=[CH:27][N:26]=1)=[O:24]
Reactant: FC(F)(F)c1cccc(CS)c1
Reactant: COC(=O)c1cnc(C(=O)OC)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1cnc(C(=O)OC)c(SCc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C

Procedure:
The solution of 4.6 g of m-trifluoromethylbenzylmercaptan in 30 ml of dimethylformamide is added to the slurry of 1.08 g of 50% sodium hydride in mineral oil (washed 2 times with hexane), under nitrogen while stirring at room temperature. After several minutes, a clear yellow solution is obtained, which is combined with that of 5.0 g of 3-nitro-2,5-pyridinedicarboxylic acid dimethyl ester in 50 ml of dimethylformamide. The mixture is warmed on the steam bath for 30 minutes at 90° and stirred at room temperature overnight. It is acidified with 2 ml of acetic acid and diluted to 400 ml with a mixture of ice and water. The precipitate formed is collected and recrystallized from methanol-diethyl ether (1:1), to yield the 3-(m-trifluoromethylbenzylmercapto)-2,5-pyridine-dicarboxylic acid dimethyl ester melting at 102°-106°.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20]C)=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([OH:20])=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A mixture of methyl 3-(4-(4-chlorophenoxy)piperidine-1-carbonyl)benzoate (301 mg, 0.81 mmol, Step-1), 2M sodium hydroxide aqueous solution (2 mL), tetrahydrofuran (2 mL), and methanol (2 mL) was stirred at 60° C. for 2 hours. The mixture was acidified by 2M aqueous hydrochloric acid solution and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 270 mg (93% yield) of the title compound as a white solid.