Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:20]([CH3:22])[CH:21]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1[N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[N:20]([CH3:22])[CH:21]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([F:10])=[C:12]([C:29]([F:32])([F:30])[F:31])[CH:13]=3)[N:18]=2)[CH2:24][CH2:25]1
Reactant: Nc1ncnc(Cl)c1Br
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 5-bromo-6-chloropyrimidin-4-amine (357.2 mg; 1.71 mmol; 1.02 eq.), 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine (550.00 mg; 1.68 mmol; 1.0 eq.), potassium carbonate (464.4 mg; 3.36 mmol; 2.0 eq.) in DMSO (6.0 ml) was stirred at 60° C. overnight. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound in 86% yield. LC-MS: (M+1=499, obsd.=499).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([OH:6])[CH2:12][C:11]#[N:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: CC#N
Product: N#CCC(O)c1cccc(Br)c1F

Procedure:
Reaction of 3-bromo-2-fluorobenzaldehyde with acetonitrile gave 3-(3-bromo-2-fluorophenyl)-3-hydroxypropanenitrile as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.54 (t, J=7.2 Hz, 2H), 7.11 (td, J=7.6, 0.4 Hz, 1H), 5.37 (dd, J=6.8, 4.4 Hz, 1H), 2.73-2.91 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CNS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-amino-1-(4-chlorophenyl)ethylcarbamate (Intermediate 73) (220 mg, 0.81 mmol) and N-ethyldiisopropylamine (0.281 mL, 1.63 mmol) in THF (5 mL) was treated with methanesulfonyl chloride (0.075 mL, 0.98 mmol). The resulting solution was stirred at ambient temperature for 2 hours. The mixture was partitioned between DCM and sodium bicarbonate solution. The organic layer was concentrated and the residue was purified by flash column chromatography on silica using gradient elution (10% ethyl acetate/DCM to 30% ethyl acetate/DCM). The desired product, tert-butyl 1-(4-chlorophenyl)-2-(methylsulfonamido)ethylcarbamate, was thus isolated as a colourless solid (154 mg, 54.3%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]2)[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]=[C:39]([C:43]4([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]4)[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)C1(c2cc(Br)ccn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccnc(C3(S(C)(=O)=O)CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 84 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-2-(1-methanesulfonyl-cyclopropyl)-pyridine following a procedure analogous to that described in Example 1. Yield: 84% of theory; LC (method 1): tR=1.86 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC1C=CC(S(O[C@H:22]([CH2:34][CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:23][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:25]#[N:26])(=O)=O)=CC=1.O>CN(C=O)C>[Cl:33][C:29]1[CH:28]=[C:27]([C@@:24]2([C:25]#[N:26])[CH2:23][C@@H:22]2[CH2:34][CH2:35][O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](CCOCc2ccccc2)CC(C#N)c2cccc(Cl)c2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: N#C[C@]1(c2cccc(Cl)c2)C[C@@H]1CCOCc1ccccc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
3.2 mL 1M LHMDS in hexanes (3.2 mmol) was added to 15 mL of DMF and cooled to −40° C. To this was added a solution of (1S)-3-(3-chlorophenyl)-3-cyano-1-(2-[(phenylmethyl)oxy]ethyl}propyl 4-methylbenzenesulfonate (1.00 g, 2.12 mmol) in 5 mL of DMF over 10 minutes and stirred for 40 minutes After warming to room temperature the reaction was stirred until no starting material remained by TLC. The reaction mixture was poured into 100 mL water, extracted with 50 mL EtOAc, the organic phase isolated, washed with brine and dried over MgSO4. The resulting residue was purified by silica gel chromatography with 25% EtOAc in hexanes to give the title compound (436 mg, 65% yield). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.4 (dd, J=7.5, 5.6 Hz, 1H) 1.5 (m, 1H) 1.7 (m, 1H) 2.0 (m, 2H) 3.6 (m, 2H) 4.5 (d, J=2.2 Hz, 2H) 7.1 (m, 1H) 7.2 (m, 3H) 7.3 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13](=O)[CH3:14])[CH2:8][CH2:7][CH2:6]2.[CH2:16]([NH2:18])[CH3:17].Cl.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH:13]([NH:18][CH2:16][CH3:17])[CH3:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2C(C)=O
Reactant: CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC(C)C1CCCc2cc(OC)ccc21

Procedure:
The product of Example 93 (2 g) was dissolved in anhydrous MeOH (20 ml) and EtNH2 (3 ml) and the pH adjusted to ca. 8 with methanolic HCl. Sodium cyanoborohydride (500 mg) was added and an additional 2 ml methanolic HCl dropwise. The reaction was stirred under N2 for 48h then 6 N HCl added to pH<2. The methanol was removed under vacuum and the aqueous layer extracted with CH2Cl2 (2×100 ml). The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated giving 0.18 g of an oil. The neutral CH2Cl2 extract was dried (MgSO4), filtered and evaporated then partitioned between 2 N HCl and a mixture of ether/hexane. The organic layer was separated and discarded. The acidic layer was basified and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and evaporated giving an additional 1.12 g of product.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3[C:26]([CH2:41][O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[C:27]([C:38](O)=[O:39])[CH:28]=[C:29]4[C:37]=3[C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=[CH:30]4)=[CH:24][C:19]=2[O:18][CH2:17]1.[CH2:50]([O:57][CH2:58][CH2:59][CH2:60][NH2:61])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:50]([O:57][CH2:58][CH2:59][CH2:60][NH:61][C:38]([C:27]1[CH:28]=[C:29]2[C:37](=[C:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)[C:26]=1[CH2:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:33]1[O:34][CH2:35][O:36][C:32]=1[CH:31]=[CH:30]2)=[O:39])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: NCCCOCc1ccccc1
Reactant: O=C(O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCCCOCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A 60% sodium hydride dispersion in mineral oil (4 g, 0.1 mol) in a small portion at room temperature was added to a stirred solution of 3-amino-1-propanol (7.51 g, 0.1 mol) in THF (150 mL). The mixture was stirred for 30 min under nitrogen, and benzyl bromide (11.9 mL, 0.1 mol) was added. The mixture was stirred for 10 h at room temperature, and concentrated in vacuo. The residue was partitioned between 1 N aqueous HCl solution and CH2Cl2. The aqueous layer was adjusted to pH 10 with 10% aqueous NaOH solution, and extracted with CH2Cl2 (3×100 mL). The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2/MeOH (3:1 to 2:1, v/v) to give 3-(benzyloxy)propylamine (1.37 g, 8.3%) as a yellow oil. 1,3-Dicyclohexylcarbodiimide (14.4 mg, 0.07 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise to a mixture of 5 (32 mg, 0.07 mmol) and 3-(benzyloxy)propylamine (11.6 mg, 0.07 mmol), and 1-hydroxybenzotriazole hydrate (9.5 mg, 0.07 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 18 h at room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography using CH2Cl2/MeOH (30:1, v/v) to afford 8 (36 mg, 85%) as a pale yellow liquid. 1H NMR (CDCl3) δ 8.05 (s, 1H, H4), 7.44 (d, 1H, H5, J=8.7 Hz), 7.19-7.28 (m, 11H, H6+2×OCH2Ph), 6.78-6.82 (m, 3H, H2′+H5′+H6′), 6.06 (AB, 2H, 3′,4′-OCH2O—, Δδ=6.9 Hz, J=1.5 Hz), 5.84 (AB, 2H, 7,8-OCH2O—, Δδ=4.2 Hz, J=1.5 Hz), 4.45 (s, 4H, 2×OCH2Pb), 4.38 (s, 2H, 2-CH2OBn), 3.55 (m, 4H, 3-CONHCH2CH2CH2OBn), 1.87 (quintet, 2H, 3-CONHCH2CH2CH2OBn. J=6.3 Hz); MS (FAB, positive) m/z 604 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])O[C:3]1=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:3]1=[O:4]
Reactant: Nc1ccncc1
Reactant: CC1CC(=O)OC1=O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1CC(=O)N(c2ccncc2)C1=O
Reaction time: 3.5 h

Procedure:
The starting material is prepared as follows: The mixture of 28.5 g of 2-methylsuccinic anhydride, 23.5 g of 4-aminopyridine and 350 ml of xylene is refluxed on a water separator while stirring for 3.5 hours. The hot solution is decanted from some gummy residue, cooled, filtered, the residue suspended in 100 ml of boiling isopropanol and filtered off again, to yield the 3-methyl-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 119°-120°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44](O)=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH3:60][C:61]1([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:63][CH2:62]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:67][S:64]([C:61]4([CH3:60])[CH2:63][CH2:62]4)(=[O:66])=[O:65])=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3(C)CC3)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Compound 2d (130 mg, 0.198 mmol) was dissolved in DCM (10 ml). EDAC (46 mg, 0.238 mmol) was added and the reaction mixture was stirred at RT for 2.5 h. Methyl cyclopropanesulfonic amide (30 mg, 0.3218 mmol) and DBU (63 μl, 0.416 mmol) were added and the mixture was stirred at RT over night. 5% Citric acid was added and the organic layer was washed with brine, dried, filtered and evaporated. The material was used directly in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4](C=O)=[CH:5][CH:6]=1.[NH2:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15]>>[Cl:1][C:2]1[O:3][C:4](=[N:9][N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:5][CH:6]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: NN1CCNC1=O
Product: O=C1NCCN1N=C1CC=C(Cl)O1

Procedure:
2-Chlorofuran-5-aldehyde is reacted with 1-amino-2-oxo-imidazolidine as in Example 1.1. 1-(5-Chlorofurylideneamino)- 2-oxo-imidazolidine of melting point 173°-175° C. is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:10]2)[N:3]=1.[CH3:24][Al](C)C>O1CCCC1.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>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][C@H:11]1[CH2:12][CH2:13][N:9]([C:4]2[N:3]=[C:2]([CH3:24])[C:7]([F:8])=[CH:6][N:5]=2)[CH2:10]1
Reactant: C[Al](C)C
Reactant: Fc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)ncc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
Dissolve (S)-[1-(4-chloro-5-fluoropyrimidin-2-yl)-pyrrolidin-3-yl]-(2,4-dichlorobenzyl)-amine (318 mg, 0.84 mmol) in dry tetrahydrofuran (7.5 mL) and add trimethylaluminium (510 μL, 1.01 mmol, 2 M in hexanes) and tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol). Stir at 70° C. overnight. Quench by addition of water and extract with chloroform. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter and chromatograph on silica gel. Dissolve the residue in methanol (2 mL) and deposit onto SCX cartridge, eluting with methanol, then 2 M ammonia in methanol. Concentrate the ammonia washing to give the title compound (180 mg, 60%). 1H NMR (400 MHz, MeOH-d4) δ 7.88 (1H, d, J=6.4 Hz), 7.43-7.54 (2H, m), 7.27-7.37 (1H, m), 3.84-3.96 (4H, m), 3.67-3.78 (1H, m), 3.55-3.64 (1H, m), 3.43-3.53 (1H, m), 2.41 (3H, s), 2.14-2.26 (1H, m), 1.89-2.00 (1H, m); MS (ES): m/z=355 [M+].
Reaction SMILES: N([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:7]=1[C:8](N)=[O:9]>O.OS(O)(=O)=O>[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:7]=1[C:8]([OH:2])=[O:9]
Reactant: O=N[O-]
Reactant: NC(=O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
A solution of NaNO2 (9.59 g, 139 mmol) in water (95 mL) was added slowly to a solution of commercially available (Oakwood) 2,6-dichloro-4-(trifluoromethyl)nicotinamide (20.0 g, 77 mmol) in conc. H2SO4 resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60° C. for 18 h. The solution was cooled to 0° C. and then water (15 mL) was added. The resulting mixture was extracted with Et2O (3×) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated with hexanes and vacuum-filtered to afford 2,6-dichloro-4-(trifluoromethyl)nicotinic acid (19 g, 95%) as an off-white solid: Rf=0.30 (9:1 CH2Cl2:MeOH), 1H-NMR (d6-DMSO, 300 MHz) δ 8.18 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.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>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:25][CH:21]3[CH2:24][CH2:23][CH2:22]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1CCC1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NC4CCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (90 mg, 0.34 mmol) was reacted with cyclobutanamine (CAS-2516-34-9) (48 mg, 0.68 mmol), HATU (146 mg, 0.38 mmol) and DIPEA (0.3 mL, 1.7 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-cyclobutylbenzamide 19. LC/MS (ESI+): m/z 320 (M+H). 1H NMR (400 MHz, DMSO) δ 8.76 (d, J=7.4 Hz, 1H), 8.70 (s, 1H), 8.59 (t, J=12.2 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.06 (d, J=33.2 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 4.48 (dq, J=16.3, 8.2 Hz, 1H), 2.37-2.22 (m, 2H), 2.22-1.99 (m, 2H), 1.79-1.60 (m, 2H).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[Li+].CC([N-]C(C)C)C.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>C1COCC1>[CH:18]1([CH2:17][C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CC(C)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)CC1CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of isobutyronitrile (29 mmol) in THF (60 mL) is added LDA (2 M in THF, 35 mmol) at −78° C. After stirring at −78° C. for 2 h, to this solution is added bromomethyl cyclopropane (32 mmol) at −78° C. The mixture is stirred at room temperature for 13 h, and then the reaction is quenched by the addition of aq. NH4Cl. The mixture is extracted with ether, and the combined organic extracts are washed with H2O and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give 3-cyclopropyl-2,2-dimethylpropionitrile, which is directly used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][C:3]=1[CH3:10].[C:11](=[O:13])=[O:12]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc([Mg]Br)ccc1F
Reactant: O=C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 4-fluoro-3-methylphenylmagnesium bromide in THF (1.0 M, 250 mL, 250 mmol) was added in a stream over 5 min to a mixture of Dry Ice (10 g) in dry THF (250 mL), and the reaction was allowed to warm to RT and concentrated. The residue was partitioned between water (500 mL) and ether (250 mL), and the layers were separated. The aqueous layer was washed with ether (2×250 mL) and acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was cooled in an ice bath and filtered. The solid was washed with water and dried to afford the title compound (25.92 g, 67%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.90-8.02 (m, 2H), 7.09 (t, J=8.9 Hz, 1H), 2.34 (d, J=1.7 Hz, 3H); IR (chloroform) 3400-2300 (broad), 1694 cm-1 ; MS(ES) m/e 155 [M+H+ ; m/e 153 [M-H]-.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH2:13][CH2:12]1>C(O)=O>[CH:5]([NH:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH2:13][CH2:12]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: NCCN1CCn2nccc21
Solvent: O=CO
Product: O=CNCCN1CCn2nccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of acetic anhydride (4.96 ml) and formic acid (2.51 ml) was stirred for 45 minutes at room temperature. The mixture was cooled to 5° C., and 1-(2-aminoethyl]-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (4.0 g) was added to the mixture. The mixture was stirred for an hour under ice-cooling. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. Fractions containing the object compound were combined and evaporated to give 1-(2-formamidoethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (2.6 g) as crystals.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH:24]=[O:25])=[CH:18][CH:17]=1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][OH:25])=[CH:18][CH:17]=1
Reactant: O=C/C=C/c1ccc(-c2ncccn2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: OC/C=C/c1ccc(-c2ncccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
DIBAL (1.0 M in THF, 18.0 mL) was added over 10 min to a −78° C. suspension of (2E)-3-[4-(2-pyrimidinyl)phenyl]-2-propenal (2.50 g, 11.89 mmol, prepared as described in Reference Example 29) in dichloromethane (100 mL). The resulting suspension was stirred for 30 min at −78° C., methanol (2 mL) was added cautiously, and stirring was continued for 5 min at −78° C. The mixture was poured into a mixture of 10% aq. citric acid (300 mL) and dichloromethane (200 mL) and allowed to stir for 1 h. The organic layer was separated, washed with sat. aq. NaHCO3 (200 mL) and brine (200 mL), dried (MgSO4), filtered through Celite, and concentrated. The resulting material was triturated with ether and dried in vacuo to provide 2.08 g (82%) of the title compound. MS 213 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH3:20])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([OH:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][CH2:30]Br.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH3:20])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:21][CH2:28][O:29][CH3:30])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1O
Reactant: COCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1OCOC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
To a solution of ethyl 4-(benzyloxy)-2-hydroxy-6-methylbenzoate (15.0 g, 52.4 mmol) in DMF (100 mL) were added potassium carbonate (14.5 g, 105 mmol) and bromomethyl methyl ether (6.40 mL, 78.5 mmol), and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 4:1) to give the title compound (14.9 g, yield 86%) as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH:13](O)=[O:14]>CCOCC>[CH:13]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[CH2:1])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:14]
Reactant: C=C(CCCCO)CC(C)(C)C
Reactant: O=CO
Solvent: CCOCC
Product: C=C(CCCCOC=O)CC(C)(C)C
Reaction time: 24 h

Procedure:
20 mM of 5-methylene-7,7-dimethyloctanol were esterified with 6 ml of concentrated formic acid. The reaction took place at room temperature, under nitrogen and by mixing the ingredients under stirring for 24 h. The mixture was taken up with ether, washed with 2N NaOH, then with water until neutrality. The desired product was obtained after drying, concentration and bulb distillation under reduced pressure.