Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][N:18]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>O1CCOCC1.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]1=[O:16])#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Oc1ccnc(O)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(O)cc2=O)[C@@H]1O
Yield: 18.3 %

Procedure:
3 g of 6-cyano-2,2-dimethyl-3,4-epoxychromane are refluxed for 20 hours with 1.8 g of 2,4-dihydroxypyridine in 30 ml of dioxane and 20 ml of dimethylformamide, in the presence of 0.6 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide. The solvents are evaporated off under vacuum and the residue is then crystallized by the addition of isopropyl ether. The crystals obtained are taken up with water, filtered off and then washed with acetone to give 850 mg of the expected product.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].[CH2:13]1COCC1.C[Mg]Br>O.CCOC(C)=O>[C:4]([CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)(=[O:5])[CH3:13]
Reactant: CON(C)C(=O)C1CCOCC1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C1CCOCC1
Reaction time: 6 h
Yield: 81 %

Procedure:
A flask was charged with N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2 (11.7 g, 67.5 mmol) and THF (350 mL). The resulting mixture was immersed in a cooling bath at −60° C., and methylmagnesium bromide (3.0 M in ether, 33.8 mL, 101.4 mmol) was added via syringe over ˜8 min. The temperature of the bath was allowed to rise to 0° C. over 6 h. At that time, the reaction was diluted with water and EtOAc and stirred vigorously for 10 min. The phases were separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120 g silica, 80 mL/min, 0% to 100% EtOAc/hexanes) to give 4-acetyltetrahydro-4H-pyran 3 (7.05 g, 55.0 mmol, 81%). 1H NMR (400 MHz, CDCl3) for 3: δ 3.95 (ddd, J=11.6, 4.4, 2.8 Hz, 2 H), 3.38 (dt, Jd=2.8 Hz, Jt=11.6 Hz, 2 H), 2.50 (m, 1 H), 2.12 (s, 3 H), 1.75 (m, 2 H), 1.65 (m, 2 H). LCMS for 3 (conditions D): tR=0.83 min, m/e=129.4 (M+H, base).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.[Cl:10][C:11]1[C:19]([Cl:20])=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([F:21])[CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Br>CN(C=O)C.O>[Cl:10][C:11]1[C:19]([Cl:20])=[CH:18][C:14]([C:15]([NH:9][C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=2)=[O:16])=[C:13]([F:21])[CH:12]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1F
Reactant: COc1cc(N)ccn1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(Cl)c(Cl)cc1F
Temperature: 95 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
A solution of 2-methoxypyridin-4-amine (186.2 mg, 1.5 mmol), 4,5-dichloro-2-fluoro-benzoic acid (285.1 mg, 1.36 mmol), HATU (622.4 mg, 1.64 mmol) and N-methylmorpholine (299.9 μL, 2.73 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with water (3×), brine and dried over Na2SO4, filtered through a short plug of silica and evaporated to dryness. The material was taken up in HBr (in acetic acid) (6.689 mL of 33% w/v, 27.28 mmol) and stirred at 95° C. for 16 h. The solution was cooled to room temperature, filtered and solid product washed with water (2×) and then ether (2×) and dried under vacuum to give 4,5-dichloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (250 mg, 61%) as an off white solid. ESI-MS m/z calc. 299.99, found 301.3 (M+1)+; Retention time: 1.16 minutes (3 minutes run).
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH2:20])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](Cl)(=[O:25])[CH3:24]>>[CH2:2]([C:9]1[CH2:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][NH:20][C:23](=[O:25])[CH3:24])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(CCN)=C(Cc1ccccc1)C2
Agent: Cl
Product: COc1ccc2c(c1)C(CCNC(C)=O)=C(Cc1ccccc1)C2

Procedure:
Starting with 2-(2-benzyl-5-methoxy-1H-inden-3-yl) ethylamine hydrochloride and acetyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 94%).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Si:39]([O:46][C:47]1[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])=[C:53]([CH3:63])[CH:52]=[CH:51][C:48]=1[CH:49]=O)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>O1CCCC1.CCCCCC.[Cl-].[Na+].O>[CH3:63][C:53]1[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])=[C:47]([O:46][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[C:48](/[CH:49]=[CH:7]\[C:6]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:4]([O:3][CH3:2])[CH:5]=2)=[CH:51][CH:52]=1
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Reactant: Cc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1cc(/C=C\c2ccc(C)c(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.7 %

Procedure:
A suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (1.77 g, 3.4 mmol) in tetrahydrofuran (40 mL) was cooled to 0° C. and butyllithium (2.1 mL of a 1.6 N solution in hexane, 3.39 mmol) was added dropwise. The brick red solution was stirred at 0° C. for 20 min, then cooled to −78° C. and a solution of 16 (0.86 g, 2.26 mmol) in tetrahydrofuran (15 mL) was added dropwise. The temperature was allowed to rise to room temperature overnight, than the reaction was poured into brine (100 mL, containing 5 mL of 1 n HCl) and extracted twice with tert-butylmethyl ether (ca 100+50 mL). The combined organic extracts were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure to give a crude which was purified by column (cyclohexane:AcOEt 9:1) to give 0.6 g of 17:
Reaction SMILES: [C:1](=[O:22])([O:20][CH3:21])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1[C:16]([CH3:19])([CH3:18])[CH3:17]>[Pd].CO>[C:1](=[O:22])([O:20][CH3:21])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:5][C:4]=1[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Oc1cc(N)c(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C

Procedure:
2,4-Di-tert-butyl-5-nitrophenyl methyl carbonate (1.00 eq) was charged to a suitable hydrogenation reactor, followed by 5% Pd/C (2.50 wt % dry basis, Johnson-Matthey Type 37). MeOH (15.0 vol) was charged to the reactor, and the system was closed. The system was purged with N2 (g), and was then pressurized to 2.0 Bar with H2 (g). The reaction was performed at a reaction temperature of 25° C.+/−5° C. When complete, the reaction was filtered, and the reactor/cake was washed with MeOH (4.00 vol). The resulting filtrate was distilled under vacuum at no more than 50° C. to 8.00 vol. Water (2.00 vol) was added at 45° C.+/−5° C. The resultant slurry was cooled to 0° C.+/−5. The slurry was held at 0° C.+/−5° C. for no less than 1 hour, and filtered. The cake was washed once with 0° C.+/−5° C. MeOH/H2O (8:2) (2.00 vol). The cake was dried under vacuum (−0.90 bar and −0.86 bar) at 35° C.-40° C. to give compound 32. 1H NMR (400 MHz, DMSO-d6) δ 7.05 (s, 1H), 6.39 (s, 1H), 4.80 (s, 2H), 3.82 (s, 3H), 1.33 (s, 9H), 1.23 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6]/[C:5](=[N:8]\O)/[CH2:4][C:3]1([CH3:11])[CH3:10].C(Cl)Cl>CO.[Ni]>[NH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[C:3]([CH3:11])([CH3:10])[CH2:4]1
Reactant: CC1(C)C/C(=N/O)CCC1O
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC(N)CCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (E)-4-hydroxy-3,3-dimethylcyclohexanone oxime (1.0 equiv.) in MeOH (0.8 M) was added Raney-Ni (10 equiv.). The reaction mixture was stirred at room temperature under hydrogen atmosphere overnight. TLC (DCM:MeOH=10:1) showed that the reaction was completed. The mixture was filtered and the filtrate was concentrated in vacuo to give 4-amino-2,2-dimethylcyclohexanol (92% yield), which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([N:11]1[CH2:15][C@@H:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[C@H:12]1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[F:38])=[O:10])C.[Li+].[OH-]>C1COCC1.O>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([C@@H:12]2[C@:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[C@H:14]([CH2:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:15][N:11]2[C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:39])=[O:3])=[O:10])[CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCCNC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCCCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a mixture rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-butyric acid ethyl ester (98.6 mg, 0.170 mmol, Example C10) in THF (6 mL) was added a solution of LiOH (Aldrich, 47.1 mg, 1.12 mmol) in water (4 mL) and the reaction mixture was stirred at rt for 6 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 4-5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-butyric acid (93.9 mg, 100%). HRMS (ES+) m/z Calcd for C27H29Cl2F2N3O3+H [(M+H)+]: 552.1627; Found: 552.1628.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=O)[O:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.CO.[CH3:22][NH2:23]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:11])[N:23]([CH3:22])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1
Reactant: CN
Reactant: O=c1oc(C(F)(F)F)ccc1-c1ccc(F)cc1F
Solvent: CO
Solvent: CCO
Product: Cn1c(C(F)(F)F)ccc(-c2ccc(F)cc2F)c1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
13.8 g (50 mmol) of 3-(2,4-difluorophenyl)-6-trifluoromethyl-2H-pyran-2-one was dissolved in 150 ml of ethanol, and 5.5 g (70 mmol) of a 40% methylamine methanol solution was added, followed by stirring for 6 hours under heating and refluxing. The reaction solution was poured into ice water and extracted with ethyl acetate. After washing with 1N hydrochloric acid and water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 3.8 g (yield: 26%) of the desired product. Melting point: 123-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH2:60]([N:67]1[CH2:71][CH2:70][CH:69]([CH2:72][NH2:73])[O:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>C(#N)C.C(N(CC)CC)C>[CH2:60]([N:67]1[CH2:71][CH2:70][CH:69]([CH2:72][NH:73][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)([C:24]([F:27])([F:25])[F:26])[O:13][N:12]=3)=[CH:15][C:16]=2[CH3:23])[O:68]1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NCC1CCN(Cc2ccccc2)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC1CCN(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (1.75 g) (prepared according to WO 2009/080250) in acetonitrile (35 ml) and triethylamine (2.04 ml) were added under nitrogen atmosphere TBTU (1.61 g), AZA.HOBT (0.68 g) and C-(2-Benzyl-isoxazolidin-5-yl)-methylamine (Step B, 1.61 g) were added. The resulting solution was stirred at room temperature for 4 hours, then quenched by addition of aqueous saturated ammonium chloride solution. The mixture was then extracted with ethyl acetate, dried over sodium sulfate, filtered then concentrated in vacuo. The residue purified by column chromatography (ethyl acetate/cyclohexane 1:1) to afford the title compound as a white solid (60 mg, (mixture of diasteroisomers). LCMS (Method F) 2.20 min, M+H 636/638.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:28])=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.723 mmol) in DCM (6.0 mL) was added tert-butyl {[2-(aminooxy)ethyl]sulfamoyl}carbamate 78 (0.276 g, 1.085 mmol), 1-hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 79 (0.35 g, 93%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=[C:14]([Br:24])[CH:13]=1)=[O:11].C(Cl)Cl.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1>[Br:24][C:14]1[CH:13]=[C:12]([C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:29](=[O:30])[O:31][CH3:32])=[O:11])[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=1
Reactant: COC(=O)Cl
Reactant: Cc1cccc(N)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1cccc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 0 °C
Yield: 31.6 %

Procedure:
N-(2-amino-6-methylphenyl)-3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide prepared in Step 2 (1.18 g, 2.91 mmol), CH2Cl2 (2 M, 1.46 mL) and pyridine (1 M, 2.91 mL) were introduced to a 50 mL round flask. The mixture thus obtained was cooled down to 0° C., added with methyl chloroformate (2.25 mL, 29.1 mmol, 10.0 eq), and refluxed at 80° C. for 15 hours. Upon completion of the reaction, the solvent was removed under reduced pressure. The residue was extracted with 1 M HCl (20 mL) and ethyl acetate (20 mL x 2), washed with brine (20 mL). The organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EA:Hex=2:3→EA:Hex=1:1) to obtain the title compound (426.7 mg, yield: 32%).
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.CS([O-])(=O)=O.[O:19]=[C:20]1[C@@H:25]2[CH2:26][C@@H:22]([CH2:23][NH2+:24]2)[O:21]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O.CN(C)C=O>[CH3:1][C:2]1([C:5]([N:24]2[CH2:23][C@@H:22]3[CH2:26][C@H:25]2[C:20](=[O:19])[O:21]3)=[O:7])[CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CC1
Reactant: O=C1O[C@@H]2C[NH2+][C@H]1C2
Agent: CS(=O)(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C(=O)N2C[C@@H]3C[C@H]2C(=O)O3)CC1
Temperature: 2 °C
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
Methyl-cyclopropanecarboxylic acid (56.4 g, 552 mmol) was dissolved in dichloromethane (365 mL) and dimethylformamide (405 μl, 5.2 mmol) was added. The mixture was cooled to 2° C. and oxalyl chloride (70.8 g, 547 mmol) was added dropwise. It was allowed to warm and stirred for 90 min at room temperature. After that, it was added to a suspension of (1S,4S)-3-oxo-2-oxa-5-azonia-bicyclo[2.2.1]heptane methanesulfonate (110 g, 526 mmol) in dichloromethane (400 mL). The resulting suspension was cooled to 2° C. and triethylamine (256 mL, 1.84 mol) was added slowly (exothermic). After stirring for 70 min at room temperature, a solution of citric acid (81.0 g, 421 mmol) in water (550 mL) was added at 2° C. After separation of the phases, the aqueous phase was extracted with dichloromethane (300 mL). The combined organic extracts were washed with water (400 mL) and concentrated in vacuo to a volume of ca. 500 mL. Ethyl acetate (330 mL) was added and the residual dichloromethane was distilled off in vacuo (internal temperature 40° C.). Further ethyl acetate (50 mL) was added, internal temperature was increased to 50° C. and heptane (800 mL) was added slowly. Crystallization started after addition of ca. 300 mL heptane. The suspension was stirred for 12 h at room temperature and filtered. The crystals were washed with cold heptane (400 mL) and dried in vacuo at 40° C. to afford the title compound as colorless crystals (88.45 g, 86%). mp. 101-102° C. MS (ESI & APCI): m/z=196.1 [M+H]+. 1H NMR (CDCl3, 600 MHz); δ 0.60-0.67 (m, 2H), 0.87-0.91 (m, 1H), 1.13-1.17 (m, 1H), 1.39 (s, 3H), 2.04 (dd, J=1.2 Hz, 10.9 Hz, 1H), 2.32 (d, J=10.8 Hz, 1H), 3.59 and 3.69 (AB, JAB=11.5 Hz, each 1H), 4.97 (s, 1H), 5.18 (s, 1H).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[C:10]([CH3:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1>O>[Cl:16][C:17]1[CH:22]=[C:21]([O:8][C:9]2[C:10]([CH3:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Cc1ncccc1O
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1ccnc(Cl)c1
Reaction time: 1 h
Yield: 90 %

Procedure:
Sodium hydride (1.07 g, 42.3 mmol) was added to DMF (25 mL). 3-Hydroxy-2-methylpyridine (4.40 g, 40.3 mmol) was slowly added to the mixture and the reaction was stirred for 1 hour. 2-Chloro-4-nitropyridine (6.71 g, 42.3 mmol) was added and the reaction was stirred overnight at ambient temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give the title compound (8.0 g, 90% yield) as a yellow oil, which solidified upon standing at ambient temperature.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[CH:21]=[N:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].[Cl:26][C:27]1[CH:45]=[CH:44][C:30]([CH:31]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:28]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:38]2[CH2:39][CH2:40][N:41]([CH2:2][C:3]([N:5]3[CH2:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=4)[N:7]4[CH:21]=[N:22][C:23]([C:24]#[N:25])=[C:6]34)=[O:4])[CH2:42][CH2:43]2)=[CH:44][CH:45]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: N#Cc1ncn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ncn2c1N(C(=O)CN1CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC1)CC=C2c1cccc(C(F)(F)F)c1
Yield: 77.7 %

Procedure:
A mixture of 1.53 g of 1-(chloroacetyl)-1,2-dihydro-4-[3-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrimidine-8-carbonitrile, 1.32 g of N-(p-chlorobenzhydryl)piperazine and 990 mg of [1,8-bis(dimethylamino)naphthalene, N,N,N',N'-tetramethyl-1,8-naphthalenediamine] in 60 ml of toluene was stirred and heated at reflux for 17 hours. The reaction mixture was filtered hot. The filtrate was cooled, then shaken with 50.0 ml of 1N sodium hydroxide and worked up by the procedure of Example 7 to obtain a viscous oil. The oil in ethyl acetate was passed through a silica column to give a solid upon evaporation of the solvent. The solid was dissolved in 40% ethyl acetate/hexane and again passed through a short silica column. Evaporation of the solvent in vacuo gave 2.00 g of the desired product as a yellow solid, mp 105°-107° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)=O.[CH3:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]1[CH2:51][C@@:49]2([CH3:50])[C@@H:45]([CH2:46][CH2:47][C@@H:48]2[OH:52])[C@@:44]2([CH:53]=[CH2:54])[C@H:35]1[C:36]1[CH:37]=[CH:38][C:39]([OH:55])=[CH:40][C:41]=1[CH2:42][CH2:43]2>>[CH3:26][N:27]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:17])([F:18])[C:13]([F:14])([F:15])[F:16])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]1[CH2:51][C@@:49]2([CH3:50])[C@@H:45]([CH2:46][CH2:47][C@@H:48]2[OH:52])[C@@:44]2([CH:53]=[CH2:54])[C@H:35]1[C:36]1[CH:37]=[CH:38][C:39]([OH:55])=[CH:40][C:41]=1[CH2:42][CH2:43]2
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCC(F)(F)C(F)(F)F)cc1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCNC)C[C@@]1(C)[C@H]2CC[C@@H]1O
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN(C)CCCCCCCC(F)(F)C(F)(F)F)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with 8,8,9,9,9-pentafluorononyl tosylate analogously to instructions 22.1, 39 mg of amine 31b yields 22 mg of amine 36b as a colorless foam (GC-MS: m/z theor.: 627, pract.: 627).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]>C(O)(C)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=[C:6]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)CN
Solvent: CC(C)O
Product: CC(C)(C)CNc1cc(Cl)nc(NCC(C)(C)C)n1

Procedure:
After dropwise adding 5.00 g (27.26 moles) of 2,4,6-trichloropyrimidine to the solution of 11.88 g (136.3 mmoles) of 1-amino-2,2-dimethylpropane in 50 ml of isopropanol while cooling and stirring, the reaction mixture is boiled under reflux for 20 hours, then evaporated. The evaporation residue is distributed between 80 ml of chloroform and 25 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. The evaporation residue is subjected to chromatography by using a mixture of hexane and ethyl acetate as eluent on a silica gel column. By carrying out the elution with a 99:1 mixture, 6-chloro-2,4-bis(2,2-dimethylpropylamino)pyrimidine is obtained which is recrystallized from hexane to give a yield of 5.74 g (73.9%), m.p.: 95°-97° C.