Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]([NH2:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].[OH-]>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:18][C:11]([CH3:17])([CH3:10])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)CC(C)(C)N
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(Cl)n1
Temperature: 9 °C

Procedure:
Into a flask, 20 grams of water, 52.3 grams (0.284 mole) of cyanuric chloride and 130 grams of mixed xylenes having a boiling point of 138-141° C. were charged, and 37.5 grams (0.290 mole) of 1,1,3,3-tetramethylbutylamine was slowly and dropwise added into the mixture while maintaining the temperature at 8-10° C. Then, 57.9 grams of 20% aqueous hydroxide solution was slowly and dropwise added into the mixture while keeping the temperature at 8-10° C. After the reaction was complete, the oil (organic) and water phases were separated and the water phase was removed to obtain a xylene solution of 2,4-dichloro-6-(1,1,3,3-tetramethylbutylamino)-1,3,5-triazine,
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH3:27])[CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:32]1[CH:33]=[N:28][CH:29]=[N:30][CH:31]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1ccc(C2(c3ccc(F)c(Br)c3)N=C(N)c3ccccc32)cc1C
Product: COc1ccc(C2(c3ccc(F)c(-c4cncnc4)c3)N=C(N)c3ccccc32)cc1C
Yield: 41 %

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-(4-methoxy-3-methylphenyl)-1H-isoindol-3-amine (Example 126) as described in Example 67 Scheme #10, D in 41% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.07 (s, 1 H), 8.78 (d, J=1.26 Hz, 2 H), 7.76-7.61 (m, 2 H), 7.43-7.24 (m, 4 H), 7.22-7.11 (m, 1 H), 7.01-6.90 (m, 2 H), 6.88-6.54 (m, 3 H), 3.58 (s, 3 H), 1.92 (s, 3 H); MS (ESI) m/z 425 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[O:35]1[CH2:39][CH2:38][C@@H:37]([NH2:40])[CH2:36]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:40][C@@H:37]4[CH2:38][CH2:39][O:35][CH2:36]4)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: N[C@@H]1CCOC1
Product: O=C(N[C@@H]1CCOC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (3R)-tetrahydro-3-furanamine using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54-1.65 (m, 4 H), 1.88 (d, J=8.42 Hz, 1 H), 2.04 (t, J=5.69 Hz, 2 H), 2.23-2.32 (m, 1 H), 3.25-3.30 (m, 2 H), 3.45-3.54 (m, 2 H), 3.65 (dd, J=9.16, 2.84 Hz, 1 H), 3.72-3.88 (m, 3 H), 4.17 (s, 2 H), 4.39 (t, J=7.16 Hz, 2 H), 4.55 (s, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.43 (m, 2 H), 8.23 (s, 1 H), 8.58 (d, J=1.47 Hz, 1 H), 10.50 (d, J=7.16 Hz, 1 H), 16.83 (s, 1 H); ES+ MS: 509 (M+H+).
Reaction SMILES: CS[C:3]1[O:4][CH2:5][CH2:6][CH2:7][N:8]=1.[N+:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10]>[Cl-].[Zn+2].[Cl-]>[N+:9]([C:12](=[C:3]1[NH:8][CH2:7][CH2:6][CH2:5][O:4]1)[C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: CSC1=NCCCO1
Agent: [Cl-]
Agent: [Zn+2]
Product: COC(=O)C(=C1NCCCO1)[N+](=O)[O-]

Procedure:
A mixture of 25 g of 5,6-dihydro-2-(methylthio)-4H-1,3-oxazine (Clapp, et al., J. Heterocyclic Chemistry, 5, 107 (1968)), 25 g of methyl nitroacetate and a catalytic amount of zinc chloride was heated to 90° over one hour and maintained at that temperature for an additional hour. The mixture then was cooled and triturated with ether to effect crystallization. The solid was recrystallized from ethanol to give methyl nitro(tetrahydro-2H-1,3-oxazin-2-ylidene)acetate (1A), as a yellow solid, m.p.: 132°-3°.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:17]=1[OH:24].C(OC(C)C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH2:12]([NH:13][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([OH:24])[CH:18]=1)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCN
Reactant: COc1ccc(C=O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CCCCCCCCCCCCNCc1ccc(OC)c(O)c1
Yield: 80.9 %

Procedure:
In a 100-ml round-bottomed flask were placed n-laurylamine (11.1 g (60 mmol)) and isovaniline (1.52 g (10 mmol)) under nitrogen. While stirring, diisopropylether (17.5 ml) and glacial acetic acid (5 ml) were sequentially added dropwise. After completion of addition, the mixture was stirred for approximately 2 hours at room temperature, followed by the addition of a borane-pyridine complex (1.2 ml (10 mmol), product of Aldrich) over 10 minutes. The mixture was stirred for a further 2 hours. Subsequently, 5N-HCl (12 ml) was added dropwise and the resultant mixture was stirred for 10 minutes. The pH of the mixture was turned to basic using an aqueous 5N--NaOH solution. The product formed was extracted using diisopropyl ether, concentrated, and purified via silica gel column chromatography n-hexane:ethyl acetate=2:1), thereby obtaining 2.6 g of N-lauryl-3-hydroxy-4-methoxybenzylamine as mud yellow crystals (yield: 82%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[C:20]([C:35]([F:36])([F:37])[F:38])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1ccccc1CCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1CCCOc1ccc(CCC(N)(CO)CO)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 14-3 (750 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (510 mg) as a white powder.
Reaction SMILES: [C:1]([Si:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:6][CH2:7][C@@H:8]([CH3:13])[C:9]([O:11]C)=[O:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1CO>[C:1]([Si:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:6][CH2:7][C@@H:8]([CH3:13])[C:9]([OH:11])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O

Procedure:
Methyl (R)-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propionate (2.42 g, 7.05 mmol) was dissolved in 3:1 tetrahydrofuran-methanol (24 mL) and saponified with aqueous sodium hydroxide (1.0 N, 7.9 mL, 7.90 mmol) at 40° C. for 3 hours and then overnight at ambient temperature. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and then acidified with 1.0 N aqueous hydrochloric acid (˜8 mL). The organic phase was washed with brine (3×), dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (Biotage 40L, 20:80 ethyl acetate-hexanes) gave (R)-3-(tert-butyl-diphenyl-silanyloxy)-2-methylpropionic acid as an oil that solidified to a tacky white solid. (Yield 1.60 g, 67.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=N)[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.[NH:26]1CCCCC1>>[NH2:26][CH2:1][CH2:2][CH2:6][CH2:5][NH:4][CH:8]=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: C1CCNCC1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=CNCCCCN)cc1

Procedure:
The compound of Example 12 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of piperidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 281.37; found mol. wt. (M+H) 282.2; 562.9 (Dimer)
Reaction SMILES: [CH2:1]1[C:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:3](=[O:17])[CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:22](Cl)([CH3:24])=[O:23]>C(Cl)Cl>[C:22]([C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH:6]=[CH:5][C:4]4[C:3](=[O:17])[CH2:2][CH2:1][C:16]=4[C:15]=3[C:14]=2[CH:13]=1)(=[O:23])[CH3:24]
Reactant: CC(=O)Cl
Reactant: O=C1CCc2c1ccc1[nH]c3ccccc3c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2[nH]c3ccc4c(c3c2c1)CCC4=O
Temperature: 0 °C
Yield: 56.1 %

Procedure:
1,2-dihydro-6H-cyclopenta[c]carbazole-3-one 90 (6 g, 27.1 mmol) was suspended in dry CH2Cl2 (100 mL). Anhydrous AlCl3 (6 g, 45 mmol) was added with stirring on ice bath, followed by the dropwise addition of AcCl (2.4 mL, 33.2 mmol). The reaction mixture was stirred at about 5° C. for 24 h, and poured into ice water. The precipitated grey solid was filtered off, washed with water (2×100 mL), acetone (3×50 mL), diethyl ether (3×50 mL) to give 4 g (56.3%) of 9-acetyl-1,2-dihydro-6H-cyclopenta[c]carbazole-3-one 91.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][N:4]=1.C(O[CH:18](OCC)[N:19]([CH3:21])[CH3:20])C>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccnc(OC)c1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1ccnc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combined ethyl 2-(2-methoxypyridin-4-yl)acetate (320 mg, 1.639 mmol) and 1,1-diethoxy-N,N-dimethylmethanamine (2079 μl, 12.13 mmol) and heated to 100° C. for 1 h then cooled to ambient temperature with stirring overnight. The reaction was concentrated in vacuo to afford a brown oil. The oil was partitioned between EtOAc and water (200 mL). The aqueous phase was back-extracted with EtOAc (2×20 mL) and the organic layers were combined, washed with brine (100 mL), dried over sodium sulfate, and concentrated to an oil in vacuo. The oil was purified by flash chromatography (100 g basic silica using a 5% to 50% EtOAc in heptanes gradient) to give the title compound as a light yellow oil. MS m/z [M+H]+ 251.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C.[N+](C1C=NC2C(C=1O)=CC=CC=2)([O-])=O>ClCCl.Cl.NCC1(O)CCCCC1>[N+:22]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[NH:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([O-:24])=[O:23]
Reactant: NCC1(O)CCCCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Agent: O=[N+]([O-])c1cnc2ccccc2c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 105.3 %

Procedure:
A suspension of 1-aminomethyl-1-cyclohexanol hydrochloride (20.0 g, 121 mmol) and 4-chloro-3-nitroquinoline (24.0 g, 115 mmol) in dichloromethane (550 mL) was cooled to 0° C., and triethylamine (40 mL, 290 mmol) was added dropwise over a period of 30 minutes. The reaction was allowed to warm to room temperature over two hours. An analysis by HPLC indicated that the 4-chloro-3-nitroquinoline starting material actually contained some 3-nitroquinolin-4-ol, and additional pure 4-chloro-3-nitroquinoline (12.0 g, 57.5 mmol) was added. The reaction was stirred for four hours, and additional 1-aminomethyl-1-cyclohexanol hydrochloride (2.0 g, 12 mmol) was added, and the resulting suspension was stirred for three days. The solvent was removed under reduced pressure, and the residue was triturated in water for one hour and isolated by filtration. The resulting solid was triturated with hot dichloromethane and isolated by filtration from the hot mixture to provide 36.5 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol as a bright yellow powder.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH2:11][N:5]1[CH2:6][CH2:7]2.Cl.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:15][CH2:2][CH2:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH2:11][N:5]1[CH2:6][CH2:7]2
Reactant: O=S(Cl)Cl
Reactant: OCCC1CC2CCN1CC2
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCCC1CC2CCN1CC2

Procedure:
A solution of 10 g of 2-hydroxyethyl-quinuclidine in 80 ml of anhydrous chloroform was cooled to 0° C and treated with anhydrous gaseous hydrogen chloride. 50 ml of thionyl chloride were then added to the solution and the reaction mixture was heated to reflux for 3 hours. The excess thionyl chloride and the chloroform were removed by evaporation under reduced pressure on a water bath at 50° C. The residue was purified by washing with anhydrous ether. The ethereal suspension was filtered and the crystals obtained were dried under reduced pressure at room temperature. 12 g of 2-chloroethyl-quinuclidine, m.p. 202° C, were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[ClH:12]>C(OCC)C>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([Cl:12])([CH3:11])[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: Cl
Solvent: CCOCC
Product: CC1=CCC(O)(C(C)(C)Cl)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 15.2 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 200 ml of diethyl ether held at -10° C. was added dropwise 32 ml of 3.8N ethereal hydrochloric acid. After one hour at 0°-5° C., the mixture was washed with three 50 ml portions of water, dried and distilled to give 14.5 g of the desired product, b.p. 70°-75° C. (0.4 mm).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[N:28]=[C:29](N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)[CH3:24].Cl.ClCC1C=NC=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:29]=[N:28][CH:27]=[CH:23][CH:24]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cl
Agent: ClCc1cccnc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccnc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)pyridine hydrochloride and isolated as colorless gum (2.2 mg, 14%). MS (m/e): 374.4 (MH+).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.C([O:16][C:17]([C@H:19]1[N:23]([C:24](=[O:42])[C@@H:25]([NH:27][C@H:28]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:26])[C@H:22]2[CH2:43][CH2:44][CH2:45][C@H:21]2[CH2:20]1)=[O:18])C1C=CC=CC=1.ClCCl>C(N(CC)CC)C>[CH3:41][CH2:40][O:39][C:37]([C@@H:28]([NH:27][C@H:25]([C:24]([N:23]1[C@H:19]([C:17]([OH:18])=[O:16])[CH2:20][C@H:21]2[C@@H:22]1[CH2:43][CH2:44][CH2:45]2)=[O:42])[CH3:26])[CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:38]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Temperature: 2.5 °C

Procedure:
A 1.0 g portion of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid benzyl ester maleic acid salt 1 was placed into 100 mL of dichloromethane, and was cooled to 0-5° C. Triethylamine (0.19 g) was added to the mixture. The resulting mixture was washed with water, and the organic phase was evaporated to give an oil. This oil was deprotected using hydrogenolysis, as per examples stated in EP 079022 to give Ramipril as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:13]Cl)=[C:5]([Cl:12])[C:6]([Cl:11])=[C:7]([Cl:10])[C:8]=1[Cl:9].ClC1[C:21](Cl)=[C:20](Cl)[C:19](Cl)=[C:18]([CH3:25])C=1C>>[CH:19]1([CH2:13][C:4]2[C:3]([CH2:2][CH:18]3[CH:19]=[CH:20][CH:21]=[CH:25]3)=[C:8]([Cl:9])[C:7]([Cl:10])=[C:6]([Cl:11])[C:5]=2[Cl:12])[CH:18]=[CH:25][CH:21]=[CH:20]1
Reactant: Cc1c(C)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: ClCc1c(Cl)c(Cl)c(Cl)c(Cl)c1CCl
Product: Clc1c(Cl)c(Cl)c(CC2C=CC=C2)c(CC2C=CC=C2)c1Cl

Procedure:
The α,α',3,4,5,6-hexachloro-orthoxylene used in this example is prepared as described in Example 1, except that 3,4,5,6-tetrachloro-orthoxylene instead of 2,3,5,6-tetrachloro-paraxylene is used.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][NH2:22]>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:22][CH2:21][CH2:20][CH2:19][O:18][CH3:17])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=1
Reactant: COCCCN
Reactant: CCc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Product: CCc1ccc(-c2nc(Cl)cc(NCCCOC)n2)cc1

Procedure:
In a similar manner, 4,6-dichloro-2-(p-ethylphenyl)pyrimidine is reacted with γ-methoxypropylamine to obtain 4-chloro-2-(4-ethylphenyl)-6-[3-(methoxy)propylamino]-pyrimidine which is then reacted with thiophenol to afford 2-(4-ethylphenyl)-6-(3-methoxypropylamino)-4-phenylthiopyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:30][C:29]#[CH:28])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=[N:11]1
Reactant: C#CCBr
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-n2ncc(C(F)(F)F)c(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Then, 3.2 g of 2-[2-fluoro-4-chloro-5-hydroxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one was dissolved in about 50 ml of DMF, to which 2.0 g of potassium carbonate was added at room temperature. Furthermore, 1.3 g of propargyl bromide was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was mixed with 100 m of water, and the precipitated crystals were collected by filtration and washed with hexane. The resulting crystals were recrystallized from isopropanol to give 3.4 g of 2-[2-fluoro-4-chloro-5-(2-propynyloxy)phenyl]-4-methyl-5-trifluoromethylpyridazin-3-one (hereinafter referred to as compound A) (m.p., 140.7° C.; decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:30]([O:34][C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:42][C:39]4[CH:38]=[CH:37][C:36]([C:35]([O:34][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:43])=[CH:41][CH:40]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.7 %

Procedure:
A mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (57 mg, 0.137 mmol), tert-butyl-4-aminobenzoate (34.4 mg, 0.178 mmol), HATU (67.6 mg, 0.178 mmol) and DIEA (53 mg, 0.411 mmol) in 10 mL of DMF was stirred at room temperature for 72 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, ethyl acetate:petroleum ether=1:1) to give tert-butyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)benzoate (75 mg, 92%) as a solid. LC-MS: 591.2 [M+H]+, tR=1.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([C:11]#[C:12][C:13]([F:16])([F:15])[F:14])[CH2:9][CH3:10])=[CH:4][CH:3]=1>CO.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:11][CH2:12][C:13]([F:14])([F:15])[F:16])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(C#CC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: O=[Pt]=O
Solvent: CO
Product: CCC(CCC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from Step B (63 mg, 0.108 mmol, enantiomer A) and PtO2 (2.4 mg, 0.0108 mmol) in MeOH (3 mL) was purged air three times and then backfilled with H2. The mixture was stirred at RT overnight. The suspension was filtered off and filtrate was concentrated to give the title compound which was used for next step without purification. LC/MS m/z=610.7 [M+Na]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[ClH:10].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([Cl:19])=[O:18].C(OCC)C>O1CCCC1>[ClH:19].[ClH:10].[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[O:18])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: COc1ccc(N)cn1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2ccccn2)cn1
Yield: 73.8 %

Procedure:
5-Amino-2-methoxypyridine (4.40 g, 35.4 mmol), dissolved in a small amount of tetrahydrofuran, was added slowly to a stirred solution of pyridine-2-carbonyl chloride hydrochloride (7.12 g, 40.0 mmol) in tetrahydrofuran (75 mL). After stirring overnight at room temperature diethyl ether was added. The solids were isolated by suction, washed with diethyl ether and dried in a vacuum oven at 45° C., yielding the title compound (7.89 g, 75%).