Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[F:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[C:29]([F:28])=[CH:35][CH:34]=[CH:33][C:32]=1[F:36])([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(CNc1c(F)cccc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.6 %

Procedure:
17.0 g of sodium triacetoxyborohydride (80.0 mmol) was added to a solution of 15.0 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (80.0 mmol), 5.16 g of 2,6-difluoroaniline (40.0 mmol) and 2.09 ml of acetic acid (40.0 mmol) in methylene chloride (400 ml) under ice-cooling, and the mixture was stirred at room temperature for 19 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=20/1-10/1) to obtain 3.68 g of the title compound (yield: 31%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=[O:8].[Br:9]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:9][C:5]1[N:4]=[C:3]([CH:7]=[O:8])[N:2]([CH3:1])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccnc1C=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Br)nc1C=O
Temperature: 25 °C
Reaction time: 144 h
Yield: 43.1 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-carbaldehyde (10 g, 90 mmol) in deoxygenated DMF (300 mL) was treated with N-bromosuccinimide (17.8 g, 100 mmol) and the resulting solution stirred at RT for 6 days. Water (750 mL) was added and the resulting mixture was extracted with EtOAc (4×200 mL) the combined extracts were dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel (n-heptane/EtOAc=4/1) to yield the title compound (7.33 g, 40%) as a white solid. LC-MS: m/z=191.2 (MH+), tR=0.48 minutes, method A. 1H NMR (600 MHz, DMSO-d6): δ 9.62 (s, 1H), 7.80 (s, 1H), 3.92 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[N:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1.O>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:30])([F:29])[F:19])[CH:26]=1
Reactant: CN1CCC(N=Cc2nc3ccccc3[nH]2)CC1
Reactant: FC(F)(F)c1cccc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(NC(c2cccc(C(F)(F)F)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of (1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine (70 mg) in tetrahydrofurane (3 mL) is added a 1.5M solution of 3-trifluoromethylphenylmagnesium bromide in tetrahydrofurane (0.77 mL) at room temperature. The mixture is then stirred at 40° C. for 1 h, hydrolyzed with water and extracted with ethyl acetate. The pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5) to give [(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine as a yellow solid melting at 90° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][C:4]1[S:3][C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1sc(Br)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1ccccc1
Yield: 18.1 %

Procedure:
A solution of 2-bromo-5-methyl-4-phenyl-1,3-thiazole (9.56 g, 37.6 mmol), tert-butyl piperazine-1-carboxylate (14.8 g, 75.2 mmol) and potassium carbonate (5.20 g, 37.6 mmol) in dimethylformamide (125 ml) was stirred at 120° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.45 g (18.1%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH2:23]([C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:2]1([NH:1][C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:32][CH:33]=2)=[O:39])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3]1)[CH3:22]
Reactant: CCCCCCCCc1ccc(N=C=O)cc1
Reactant: CCOC(=O)CC1(N)CCN(C(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C(=O)OCc3ccccc3)C2)cc1
Yield: 30.6 %

Procedure:
To a solution of benzyl 3-amino-3-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (260 mg, 0.85 mmol) and p-octylphenylisocyanate (215 mg, 0.93 mmol) in CH2Cl2 (3 mL) was added triethylamine (0.35 mL, 2.55 mmol) to give the title compound as a brown solid (140 mg, 31%). MS ESI 538.2 [M+H]+, calcd for [C31H43N3O5+H] 538.32.
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].[NH3:12]>C1(C)C=CC=CC=1>[NH2:12][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11]
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: N
Solvent: Cc1ccccc1
Product: CCCC1CC(=O)N(CN)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (41.34 g, 0.235 mol) in toluene (350 ml) is added dropwise at −78° C. to liquid ammonia (300 ml). At the end of the addition, the temperature is raised slowly to room temperature, and ammonia of the crude mixture is allowed to distille at room temperature overnight. Filtration of the reaction mixture and subsequent evaporation lead to 55 g of the crude 1-(aminomethyl)-4-propylpyrrolidin-2-one x76 which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1/[CH:4]=[N:13]/[OH:14]
Reactant: NO
Reactant: O=Cc1c(O)ccc(O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C/c1c(O)ccc(O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.9 %

Procedure:
A mixture of 7A (25.0 g, 144.87 mmol), hydroxylamine hydrochloride (12.08 g, 173.84 mmol, 1.2 eq) and NaOH (8.69 g, 217.3 mmol, 1.5 eq) in EtOH (200 mL) and H2O (100 mL) was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the mixture was extracted with ethyl acetate and concentrated to give a yellow solid 7B (34.2 g, 100% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]#[N:25]>C(O)C.N1CCCCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[CH:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1)[C:24]#[N:25]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Reactant: N#CCc1ccccn1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(C=C(C#N)c2ccccn2)cc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (9.17 mmole) 3,5-di-tertbutylbenzaldehyde in 75 ml absolute ethanol are added 1.19 g (10.1 mmole) 2-pyridylacetonitrile and 12 drops piperidine. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction is stirred and heated. After refluxing for 8 hours, the reaction is allowed to cool to room temperature and stirred overnight for 16 hours. The solvent is removed by rotary evaporation, and the residue purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 98:2. The colorless solid is washed with cold ether-hexane to give 2-(2-pyridyl)-3-(3,5-di-tert-butylphenyl)-2-propenenitrile, m.p. 90°-93° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([O:27]C)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+].Cl>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: COC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 124.6 %

Procedure:
A mixture of methyl 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylate (560 mg, 1.48 mmol) and lithium hydroxide monohydrate (125 mg, 2.97 mmol) in methanol (10 ml) and water (3 ml) is stirred for 18 hours at 50° C. The methanol is evaporated and the resulting suspension treated with 2N aqueous hydrochloric acid (1.485 ml, 2.97 mmol) The solvent is evaporated affording 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid containing 2 equivalents lithium chloride (670 mg, 101%). mp.: >250° C. MS: m/z=362.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[F:13][C:14]([F:21])([F:20])[CH2:15][O:16][CH2:17][CH2:18][OH:19].[H-].[Na+]>>[F:13][C:14]([F:21])([F:20])[CH2:15][O:16][CH2:17][CH2:18][O:19][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCCOCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(OCCOCC(F)(F)F)nc1
Reaction time: 0.05 h
Yield: 71 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 71% yield starting from ethyl 6-chloronicotinate and 2-(2,2,2-trifluoroethoxy)ethanol. The reaction between sodium hydride and 2-(2,2,2-trifluoroethoxy)ethanol was performed at 0° C. for 3 min, then ambient temperature for 15 min and then cooled to 0° C. before ethyl 6-s chloronicotinate was added; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, 1 H), 8.15 (dd, 1 H), 6.93 (d, 1 H), 4.42-4.52 (m, 2 H), 4.14 (q, 2 H), 3.92-3.97 (m, 2 H); MS (APPI/APCI) m/z 266[M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[C:6]([NH2:13])=[N:5]2.[C:14](OC(=O)CC)(=O)[CH2:15][CH3:16]>C(O)(=O)CC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:14]([CH2:15][CH3:16])=[N:13][C:6]1=[N:5]2
Reactant: Nc1nc2ccc(Cl)cc2nc1N
Reactant: CCC(=O)OC(=O)CC
Solvent: CCC(=O)O
Product: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1
Yield: 88.1 %

Procedure:
78 G (0.4 mole) of 6-chloro-2,3-diamino-quinoxaline were dissolved in 500 ml of anhydrous propionic acid and 105 g (0.8 mole) of propionic anhydride were added thereto. The reaction mixture was heated to the boil under reflux for 5 hours. After cooling, the solvent was distilled off in vacuo, the residue was taken up in dilute sodium hydroxide solution, the mixture was filtered, the filtrate was acidified with dilute hydrochloric acid and the resulting precipitate was filtered off. It was well washed with water and dried in vacuo at 110°C. 82 g (representing 88% of theory) of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline of melting point 190°C (decomposition) were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:19]([CH3:35])[C:20]([C:33]#[N:34])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:19]([CH3:35])[C:20]([C:33]#[N:34])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccccc3O)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3ccccc3O)nc2c1C#N
Temperature: 120 °C
Yield: 24.7 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (100 μl, 0.79 mmol) and triethylamine (220 μl) were added to a dimethyl sulfoxide (5 ml) solution of 7-fluoro-2-(2-hydroxyphenyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-212) (204 mg, 0.59 mmol). The system was purged with nitrogen, then sealed up, and heated at 120° C. for 30 minutes. After cooling, the solvent was evaporated away under reduced pressure, then the resulting residue was dissolved in chloroform, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Elution with a mixed solvent of chloroform/methanol (97:3, v/v) gave a main product. This was washed with a mixed solvent of isopropyl ether and ethanol, and the solid was collected by filtration to obtain the entitled compound (64 mg, 24%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2.C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39]Cl>C(Cl)Cl>[CH3:22][O:21][C:9]1[C:8]([CH3:23])=[C:7]2[C:3]([C:4](=[O:24])[O:5][CH2:6]2)=[C:2]([O:1][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[C:10]=1[CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COCCOCCl
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1c(C/C=C(\C)CCC(=O)OC)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (61.0 g) in methylene chloride (1000 ml) at 0° C. was added diisopropylethylamine (30.4 g) and methoxyethoxymethyl chloride (29.2 g). After 31/2 hours the solution was washed with dilute hydrochloric acid, dried and evaporated to give methyl (E)-6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate as an oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([CH:12]([NH2:16])[CH2:13][CH2:14]Br)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[C:5]([CH:12]([NH2:16])[CH2:13][CH2:14][N:1]=[N+:2]=[N-:3])([O:7][C:8]([CH3:10])([CH3:11])[CH3:9])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(N)CCN=[N+]=[N-]
Temperature: 25 °C
Yield: 85.1 %

Procedure:
An aqueous solution (5 mL) of NaN3 (1.4 g; 21.5 mmol) and 2-3 drops of Aliquat 336 are added to a stirred solution of 3-BOC-amino-propyl bromide (5 g; 21.5 mmol) in toluene (10 mL); the mixture is heated at the reflux temperature for 4 hrs. After cooling at r.t., the organic phase is separated, dried over Na2SO4, and evaporated to dryness in vacuum to give 3-BOC-amino-propyl azide (3.75 g; 18.3 mmol) as a transparent oil (yield 85%).
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:44])[C@@H:18]([NH:28][C:29]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:32]=2)=[O:30])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:12]1)=[O:10])[CH3:7]>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:44])[C@@H:18]([NH:28][C:29]([C:31]2[CH:36]=[C:35]([CH:1]([CH3:3])[CH3:2])[N:34]=[C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:32]=2)=[O:30])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CC(C)[Mg]Br
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(C)C)nc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Isopropylmagnesium bromide (29.5 mg) was added to an orange solution of 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (56 mg) and iron(III) acetylacetonate (1.8 mg) in anhydrous THF (1 ml) under argon. After stirring at RT for 30 min, it was quenched with a 1M HCl solution and extracted with EA. The org. phases were dried (Na2SO4) and evaporated off to give 50 mg of the desired compound.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1>C(N(CC)CC)C.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>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:3]#[C:2][CH2:1][OH:4])[N:7]=1
Reactant: C#CCO
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cccc(C#CCO)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 134.8 %

Procedure:
Pd(Ph3P)4 (99 mg, 2%), CuBrSMe2 (38 mg) and propargyl alcohol (1.3 ml, 21 mmol) are added successively to a solution of 2,6-dibromopyridine (5.0 g, 21.1 mmol) in triethylamine (120 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 2 h. After cooling, the reaction mixture is filtered off through kieselguhr, and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (7:3)] on a silica gel column. This gives the title compound (2.65 g) as a colorless solid. TLC, silica gel (glass plates) [toluene/acetone (7:3)], Rf=0.15.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.C(#N)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:36][NH:37][S:38]([CH3:41])(=[O:40])=[O:39]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:37]([CH3:36])[S:38]([CH3:41])(=[O:40])=[O:39])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
In a 1000 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 50.0 g (172 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 20.8 g (189 mmol.) of sodium t-pentoxide, and 344 mL of acetonitrile, and the resulting mixture was stirred at 0-10° C. for 30 minutes. To the mixture was slowly added 36.1 g (189 mmol.) of p-toluenesulfonyl chloride, and the reaction was carried out at for 5 hours at room temperature. Subsequently, the reaction mixture was cooled to a temperature of 0-10° C. To the cooled reaction mixture were added 28.2 g (258 mmol.) of N-methylmethanesulfonamide and 26.5 g (241 mmol.) of sodium t-pentoxide. The mixture was kept at 0-10° C. for one hour and then heated to 75-82° C. for 2 hours under refluxing, to carry out a reaction. After the reaction was complete, the mixture was cooled to room temperature. To the cooled mixture was added 344 mL of water. The aqueous mixture was cooled to 0-10° C. and stirred for one hour, precipitating a crystalline product. The crystalline product was collected by filtration and dried, to obtain 45.3 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesul-fonylamino)pyrimidine as a pale yellow crystalline product. The yield was 68% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:11])[O:12][CH2:13][CH3:14])[CH2:8][CH2:9]2)[CH:6]=1
Reactant: CC[O-]
Reactant: N#CC1(n2cc(Cl)cn2)CC1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbonitrile (17.3 g, 103 mmol) in ethanol (50 mL) was added sodium ethoxide (prepared from 3.2 g, 139 mmol of sodium metal dissolved in 150 mL of ethanol). The reaction mixture was stirred at 70° C. for 2 h to afford ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate which was used for the next step without further purification. An aliquot of the solution was concentrated for analysis: 1H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H), 1.46 (q, 2H), 1.73 (q, 2H), 4.15 (q, 2H), 7.51 (s, 1H), 7.52 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1nccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (10 g, 33.4 mmol, 1 eq) in 1,4-dioxane (160 mL) add a 4 M solution of hydrochloric acid in 1,4-dioxane (80 mL, 0.3 mol, 10 eq) and stir under nitrogen at room temperature overnight. Dilute with DCM (600 mL) then basify with 50% aqueous sodium hydroxide. Add water (100 mL), separate the layers and extract the aqueous twice with DCM (200 mL). Combine the organic extracts, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter, and concentrate to give 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a viscous oil which solidifies on standing (6.39 g, 96%). MS (ES): m/z=199.1, 201.1 [M+H]+.