Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH:4]=[CH2:5].[Mg].[CH2:10]([O:17][CH2:18][CH2:19][C:20]([CH3:34])([CH3:33])[CH2:21][C@H:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][CH2:18][CH2:19][C:20]([CH3:34])([CH3:33])[CH2:21][C@H:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:23]([OH:24])[CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH:4]=[CH2:5])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=CC(CBr)C(C)C
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [Mg]
Product: C=CC(C[C@H](O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C

Procedure:
88.5 g of 1-bromo-2(R,S)-isopropyl-3-butene, 13 g of magnesium powder and 41.9 g of 6-benzyloxy-2(S)-tert-butoxycarbonylamino-4,4-dimethyl-hexanal are reacted in a manner analogous to that described in Example 37f). Purification is carried out by FC over 1 kg of silica gel (mobile phases G and E): Rf (3:1 mixture of toluene and ethyl acetate)=0.47; Rt (I)=33.8/34.2 min; FAB-MS: (M+H)+ =520.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O)=[CH:6]N(C)C)[CH3:2].[N+]([O-])(O)=O.[NH2:22][C:23]([NH2:25])=[NH:24].C([O-])(=O)C.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:24][C:23]([NH2:25])=[N:22][CH:6]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccco1
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N)nc1-c1ccco1
Temperature: 90 °C
Yield: 27.8 %

Procedure:
Following the method of Sansebastiano et al. (Il Farmaco 1993, 48, 335), to a stirred solution of 2.44 g (10.3 mmol) 3-dimethylamino-2-(furan-2-carbonyl)-acrylic acid ethyl ester and 2.26 g (18.5 mmol) guanidine nitrate in 20 ml DMF was added 1.51 g (18.5 mmol) sodium acetate and the mixture heated at 90° C. for 36 h. The reaction mixture was then partitioned between ether and water. The phases were separated and the aqueous phase extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was recrystallised from ether/ethyl acetate/hexane to afford 669 mg (28%) 2-amino-4-furan-2-yl-pyrimidine-5-carboxylic acid ethyl ester as a white crystalline solid. Chromatography (ethyl acetate/hexane 2/1) of the mother liquor afforded a further 150 mg (6%) product. ES-MS m/e (%): 234 (M+H+, 100), 206 ([M—C2H4]+, 35), 188 ([M+H-EtOH]+, 42).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1)=[S:40]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:40][C:39]([N:41]3[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]3)=[N:38][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[C:12]=2[F:29])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Agent: O=C1CCC(=O)N1Br
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 38 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (2.00 g, 4.53 mmol), NBS (0.85 g, 4.75 mmol) and 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperazinecarboxylate (2.22 g, 9.05 mmol) the title compound of Step A was obtained (1.16 g, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.30 (d, J=5.49 Hz, 1H), 7.62-7.76 (m, 1H), 7.46 (td, J=7.46, 1.28 Hz, 1H), 7.38 (t, J=6.09 Hz, 1H), 7.32 (t, J=7.78 Hz, 1H), 7.25 (t, J=9.11 Hz, 2H), 6.46 (d, J=5.40 Hz, 1H), 3.56 (br. s., 4H), 3.47 (br. s., 4H), 1.42 (s, 9H). m/z (ES+): 668 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[F-].[K+]>C1(C)C=CC=CC=1>[CH2:14]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH:13]=[CH2:12]
Reactant: Brc1cccc2ncccc12
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCc1cccc2ncccc12
Reaction time: 3 h
Yield: 95.9 %

Procedure:
5-Bromo-quinoline (5.6 g, 27 mmol) was dissolved in 40 mL toluene. BHT (50 mg) was added, along with allyl tributyl stannane (9.3 mL, 30 mmol), and tetrakis(triphenyl)phospine palladium (600 mg, 0.52 mmol). The reaction was refluxed overnight, then cooled. Potassium fluoride solution (1.0 g, in 18 mL H2O) was added. The reaction was stirred for 3 hours, then filtered. The reaction mixture was concentrated in vacuo. It was chromatographed in 3:1 hexane/ethyl acetate to yield 4.38 g (95%) of 5-allyl-quinoline as a yellow oil. MS (APCI) m/z 170.1 (M+1).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]([F:11])([F:10])[F:9])=[N:4][N:3]=1.[Cl:12][C:13](Cl)=[C:14]([Cl:17])[C:15]#[N:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][N:6]1[C:5]([C:8]([F:9])([F:11])[F:10])=[N:4][N:3]=[C:2]1[S:1][C:13]([Cl:12])=[C:14]([Cl:17])[C:15]#[N:16]
Reactant: Cn1c(S)nnc1C(F)(F)F
Reactant: N#CC(Cl)=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(SC(Cl)=C(Cl)C#N)nnc1C(F)(F)F
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a stirred mixture of 3.5 g (0.0192 mole) 3-mercapto-4-methyl-5-trifluoromethyl-1,2,4-triazole (the product of Example 6) and 3.0 g (0.0192 mole) trichloro-acrylonitrile in methylene chloride, 1.94 g (0.0192 mole) triethylamine in methylene chloride were added dropwise. The reaction mixture was stirred at room temperature for several days. The reaction mixture was washed with water and then dried over magnesium sulfate. The organic phase was passed through a short silica gel (SiO2) column and stripped to give a thick oil which soon crystallized. The material was recrystallized from methylene chloride/hexane to give 1.5 g of the above-identified product as a light yellow solid, melting point 90°-94° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:13]>CCO.[Pd]>[ClH:13].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH2:10])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCc1ccc(CN)cc1
Yield: 86 %

Procedure:
A solution of 4-butylbenzonitrile (30.09 g) in EtOH (380 mL) and HCl (4N in dioxane, 50 mL, 200 mmol) was hydrogenated at 50 psi on a Parr shaker in the presence of 10% palladium on carbon (6.09 g). The catalyst was removed via filtration through Celite® and the solution was concentrated in vacuo. The residue was suspended in Et2O and filtered to provide 4-butylbenzylamine hydrochloride as an off-white solid (32.47 g). 1H NMR (400 MHz, CD3OD) δ 7.33 (d, 2H), 7.22 (d, 2H), 4.04 (s, 2H), 2.60 (t, 2H), 1.56 (m, 2H), 1.31 (m, 2H), 0.89 (t, 3H).
Reaction SMILES: Cl[C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5].[OH-].[NH4+:12].O>C(O)C>[NH2:12][C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: [NH4+]
Reactant: CC(C)C(Cl)=C(C#N)C#N
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(N)=C(C#N)C#N
Temperature: 0 °C
Reaction time: 3.75 h

Procedure:
A solution of 530.5 g of 3-chloro-2-cyano-4-methyl-2-pentenenitrile in 515 ml of ethanol was added dropwise during one hour to a stirred solution of 2,400 ml of concentrated ammonium hydroxide in 1,560 ml of ethanol while maintaining the reaction mixture at 35°-40° with an ice-water bath. The reaction mixture was stirred for 3.5-4 hours and was poured into 6.5 liters of ice and water. The mixture was stirred until all the ice had melted (approximately thirty minutes). The precipitate was collected by filtration. The filter cake was washed with two 1500-ml portions of water and air-dried on the filter. After the drying the 400 g of 3-amino-2-cyano-4-methyl-2-pentenenitrile, mp 182°-184°, was used in the next synthesis step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1>>[CH3:23][O:22][C:20](=[O:21])[C:19]1[C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: COC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)cc1C(F)(F)F

Procedure:
As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (3.47 g, 18.4 mmol) was converted using methyl 6-chloro-4-(trifluoromethyl)nicotinate instead of 6-chloronicotinonitrile to the title compound which was used directly in the next transformation without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:4]=[CH:5][N:6]=1.[CH3:16][O:17][CH:18]([O:22][CH3:23])N(C)C>>[CH3:16][O:17][CH:18]([O:22][CH3:23])[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH2:15][CH2:14]1
Reactant: COC(OC)N(C)C
Reactant: Cc1nccn1CCCC1CCNCC1
Product: COC(OC)N1CCC(CCCn2ccnc2C)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[3-(2-methyl-1H-imidazol-1-yl)propyl]piperidine (2.3 g, 0.0105 M) and dimethylformamide dimethylacetal (20 ml) was heated at 100° C. for 6 hrs. Removal of the excess of dimethylformamide dimethylacetal gave 4-[3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde dimethylacetal. A solution of this piperidine carboxaldehyde dimethylacetal in methylene chloride (10 ml) was added to a mixture of 6-aminopenicillanic acid (2.16, 0.01 M) and diisopropyl ethylamine (1.15 ml) in methylene chloride (50 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr and room temperature for 3 hrs. The solvent was removed and water (50 ml) was added. After being washed with ether, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-3,3-dimethyl-6-[[[4-[ 3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.15 molar hydrochloride 1.75 molar hydrate (1.76 g, 33% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.CN1CCOCC1>CO>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: COc1ccc(CNS(=O)(=O)c2ccc3nc(-c4c(C)n[nH]c4N)sc3c2)cc1
Yield: 11.6 %

Procedure:
the title compound (15 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 4-methoxybenzylamine (79 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 430.5 (M+1, 100%). Yield=11%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:1][CH2:2][CH2:3][CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])[CH:21]=[CH:22][CH:23]=1)[CH:12]([F:13])[F:14]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: NCCC(O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: OC(CCNCc1cccc(OC(F)(F)C(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.8 %

Procedure:
The 4amino-2-hydroxy-1,1,1-trifluorobutane (1.0 g, 7.0 mmol) from EX-611A and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (1.5 g, 7.0 mmol) were dissolved in 20 mL of dichloroethane and acetic acid (0.40 mL, 7.7 mmol), then solid NaBH(OAc)3 (1.8 g, 8.4 mmol) was added. The mixture was stirred at room temperature for 3 d, then quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4, and evaporated to give 1.6 g of crude product, which was purified by reverse phase HPLC to give 0.90 g (37%) of the desired 4-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-butanol product as a yellow oil. HRMS calcd. for C13H14F7NO2: 350.0991 [M+H]+, found: 350.0971.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:21])=[C:9]([O:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:26]=1[NH2:27].Cl.N1C=CC=CC=1>>[Cl:24][C:25]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:26]=1[NH:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:21])=[C:9]([O:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: N#Cc1cnc2cc(F)c(OCCN3CCOCC3)cc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc(F)c(OCCN4CCOCC4)cc23)c(Cl)cc1Cl

Procedure:
Following the procedure of Reference Example 8, a mixture of 4-chloro-7-fluoro-6-(2-morpholin-4-ylethoxy)-3-quinolinecarbonitrile (136 mg, 0.41 mmol), 2,4-dichloro-5-methoxyaniline (90.5 mg, 0.47 mmol) and pyridine hydrochloride (95 mg, 0.82 mmol) provides, after preparative thin layer chromatography eluting with 7% methanol in dichloromethane, 58 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-(2-morpholin-4-ylethoxy)-3-quinolinecarbonitrile, mp 166-168° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH3:5][O:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O>CO>[C:10]1([C:8](=[N:4][CH2:3][CH2:1][OH:2])[CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:6][CH3:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Product: COC(C(=NCCO)c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Ethanolamine, 8.34 g (0.137 mole) and 4.52 g (0.020 mole) of 2-methoxy-1,2-diphenylethanone were mixed together and heated at 120° C. under a gentle stream of nitrogen for 2 hr. Mass spec analysis indicated none of the 2-methoxy-1,2-diphenylethanone remained. The mixture stood at ambient temperature for 16 hr, after which it was dissolved in 20 ml of methanol. The solution was poured into 100 ml of water. A yellow oil separated which became semisolid after 1 hr. The semisolid was extracted twice with 50 ml portions of methylene chloride. The extract was dried over magnesium sulfate, filtered, and concentrated to give 5.04 g of yellow oil (94%) which began to solidify on standing. Trituration with petroleum ether gave 2.19 g of off-white solid after filtration. The filtrate was concentrated to give an additional 2.25 g of yellow oil which was identical to the white solid and which crystallized on standing.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([NH:26][C:27](=O)[O:28]CC)=[C:18]([F:32])[CH:17]=1.C(O)(=O)C>CN(C)C=O>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:19]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:27]2=[O:28])=[C:18]([F:32])[CH:17]=1
Reactant: CCOC(=O)Nc1cc(OC(C)C)c(Cl)cc1F
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.5 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 25 ml of absolute dimethylformamide is added dropwise while stirring at 0° C. during 5 minutes to a suspension of 2.5 g of a 55% sodium hydride dispersion in 25 ml of absolute dimethylformamide. The temperature rises to 20° C. and the mixture is subsequently stirred at this temperature for 30 minutes. Thereafter, 14.4 g of ethyl N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-carbamate are added, and the mixture is stirred at room temperature for 30 minutes and heated at 150° C. (bath temperature) for 2.5 hours. The reaction mixture is cooled to 50° C., neutralized with 3.5 ml of concentrated acetic acid and largely concentrated at 60° C. under reduced pressure. The residue is poured into a solution of 200 ml of water and 30 ml of 2N hydrochloric acid and the aqueous mixture is extracted twice with 150 ml of diethyl ether each time, and the organic phases are washed twice with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether-n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 195°-197° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH:9]([O:12][CH2:13][CH3:14])=[CH:10][CH3:11]>Cl>[CH2:13]([O:12][CH:9]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH3:11])[CH3:14]
Reactant: CC=COCC
Reactant: CCOC(=O)C(C)O
Agent: Cl
Product: CCOC(=O)C(C)OC(CC)OCC
Temperature: 75 °C
Yield: 82.6 %

Procedure:
To a 250 mL flask containing 37.0 g (0.31 mole) ethyl lactate and four drops 32% hydrochloric acid at 30° C. is added 71 g (0.82 mole) ethyl propenyl ether. The mixture is heated to 75° C. for thirty minutes, cooled to 25° C., then quenched with 100 g 5% sodium bicarbonate solution. The organic material was flash distilled yielding 52.3 g (90%) ethyl 2-[(1'-ethoxy)propoxy]propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[Cl:13].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1>N1C=CC=CC=1>[C:31]1([C:28]2[CH:29]=[N:30][C:25]([N:22]3[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]4[C:6](=[O:8])[C:5]5[C:4](=[CH:3][C:2]([Cl:1])=[C:12]([Cl:13])[CH:11]=5)[C:9]4=[O:10])[CH2:24][CH2:23]3)=[N:26][CH:27]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: NCCCCN1CCN(c2ncc(-c3ccccc3)cn2)CC1
Solvent: c1ccncc1
Product: O=C1c2cc(Cl)c(Cl)cc2C(=O)N1CCCCN1CCN(c2ncc(-c3ccccc3)cn2)CC1

Procedure:
0.005 mol of 4,5-dichlorophthalic anhydride and 0.005 mol of 1-(4-aminobutyl)-4-(5-phenyl-2-pyrimidinyl)-piperazine in 20 ml of absolute pyridine are boiled under reflux, under an atmosphere of N2, for several hours. After cooling, the product which has crystallised out is filtered off and washed with isopropyl ether.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.[N:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39][CH:38]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:43][C:40]4[CH:41]=[CH:42][N:37]=[CH:38][N:39]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccncn3)ccc21
Temperature: 0 °C
Yield: 100 %

Procedure:
A flask was charged with perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.256 g, 0.419 mmol) and pyrimidin-4-amine (0.048 g, 0.503 mmol). A septum was attached and THF (2.096 ml) was added under N2 flow. The mixture was cooled to 0° C. A THF solution of lithium bis(trimethylsilyl)amide (0.880 ml, 0.880 mmol, 1 M) was added dropwise to give a brown solution with a tan precipitate. The solution was maintained at 0° C. for 20 min, and allowed to warm to rt and maintained for 2 h. The reaction mixture was partitioned between 1 N HCl (10 mL) and EtOAc (20 mL), the layers were separated and the aqueous layer was extracted with 1:1 MeOH:EtOAc (1×20 mL). The combined organic layers which were dried (Na2SO4) and concentrated to provide 1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamide (0.219 g, 0.419 mmol), which was of sufficient purity for the subsequent step. m/z (ESI) 521.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](Br)[N:7]=1.[CH3:11][S:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:20]=2)[N:7]=1
Reactant: Cn1cc(Br)nc(N)c1=O
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)nc(N)c1=O
Yield: 17.9 %

Procedure:
A solution of 3-amino-5-bromo-1-methylpyrazin-2-one (81.0 mg, 0.4 mmol), (3-methylsulfonylphenyl)boronic acid (120.0 mg, 0.6 mmol), Cs2CO3 (391.0 mg, 1.2 mmol), Pd(PPh3)4 (20.0 mg, 0.017 mmol) in dioxane (20.0 mL) and water (2.0 mL) was stirred at 95° C. for 12 h under N2. The mixture was concentrated and purified by silica gel chromatography (PE: EA=3:2) to give the title compound (20.0 mg, 18%). 1H NMR (DMSO-d6 400 MHz): δ 8.35 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J=8.0 Hz, 1H), 6.93 (brs, 2H), 3.50 (s, 3H), 3.24 (s, 3H). LCMS (M+H)+ 280.
Reaction SMILES: [CH:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1)#[N:25]>>[C:24]([C:26]1([C:29]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:18][CH:19]=2)=[O:30])[CH2:28][CH2:27]1)#[N:25]
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1ccc(CCCCCCCCOCC2CCCCC2)cc1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCCOCC3CCCCC3)cc2)CC1
Yield: 98 %

Procedure:
General procedure E was used to convert 2.05 mmol of 13c and 3.08 mmol of 1-cyanocyclopropanecarboxylic acid to 2.01 mmol (98%) of the title compound.