Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([O:17][CH3:18])[C:9]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:9]2[C:10]([O:17][CH3:18])=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[F:7])[CH:6]=1
Reactant: Clc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])cc(F)c1-n1cnc(Cl)c1
Temperature: 80 °C
Yield: 22.1 %

Procedure:
Step M (5): A mixture of 4-chloro-1H-imidazole (102 mg, 1.00 mmol), 1,2-difluoro-3-methoxy-5-nitrobenzene (200 mg, 1.00 mmol), and cesium carbonate (325 mg, 1 mmol) in acetonitrile (6 mL) was heated at 80° C. for 12 h. The reaction mixture was quenched with 1 N HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (20% EtOAc/hexane) to afford 4-chloro-1-(2-fluoro-6-methoxy-4-nitrophenyl)-1H-imidazole (60 mg, 22% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:19]C=2C=1.C(Cl)CCl.CN>C(Cl)Cl>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([NH2:19])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)c(N)c(C(=O)O)c1
Agent: CN
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(C)c(N)c(C(N)=O)c1
Reaction time: 16 h
Yield: 209.6 %

Procedure:
A solution of 2-amino-3,5-dimethyl-benzoic acid (550 mg) in DCM (30 mL) was treated with HOBt (225 mg), EDC (1280 mg), and CH3NH2 (8.5 mL, 2N in THF). The reaction mixture was stirred for 16 hours in a sealed bottle, diluted with DCM (100 mL), and washed with brine three times. The organic layer was dried (sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography to provide 573 mg of 2-amino-3,5-dimethyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 7.9 (s, 1H), 7.8 (s, 1H), 6.1 (bs, 1H), 5.3 (bs, 2H), 2.9 (d, 3H), 2.2 (s, 3H), 2.1 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[C:14]([C:18]2[C:19]([C:24]([F:27])([F:26])[F:25])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:12]3)=[CH:5][C:3]=1[NH2:4].[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33].N1C=CC=CC=1>CC#N>[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:4][C:3]1[CH:5]=[C:6]([C:9]2[N:10]=[C:11]3[N:16]([CH:17]=2)[N:15]=[C:14]([C:18]2[C:19]([C:24]([F:25])([F:27])[F:26])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:12]3)[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:33]
Reactant: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1N
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1NC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A 20 mL vial is charged with 2-methyl-5-[6-[2-(trifluoromethyl)-3-pyridyl]imidazo[2,1-f]pyridazin-2-yl]aniline (0.444 g, 1.2 mmol), 3-bromobenzoyl chloride (0.378 mL, 1.8 mol), pyridine (0.292 mL, 3.6 mmol), MeCN (4 mL) and the mixture is stirred at room temperature for 18 hr. The reaction mixture is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in CH2Cl2) to give the title compound (530 mg). LCMS (m/z)=552.3 and 554.3 [M+H]+, tR=3.04 min.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3].[CH2:23](O)[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCC/C=C\CCO
Reactant: CCCOCCCCCc1ccc(-c2ccc(O)cn2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC/C=C\CCOc1ccc(-c2ccc(CCCCCOCCC)cc2)nc1
Yield: 59.6 %

Procedure:
1.0 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-hydroxypyridine, 0.42 g of (Z)-3-octen-1-ol, 0.58 g of diethyl azodicarboxylate, 0.88 g of triphenylphosphine and 100 ml of tetrahydrofuran are reacted in an analogous manner to Example 3 to give 0.8 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-([(Z)-3-octenyl]oxy)pyridine.
Reaction SMILES: [C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)(O)=[O:2].C[N:22]1CCOCC1.ClC(OCC(C)C)=O.N>C1COCC1.CN1C(=O)N(C)CCC1.O1CCOCC1>[NH2:22][C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)=[O:2]
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Alternative stage 10.1: A mixture of 2.165 g (7.5 mmol) of 6-carboxy-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine in 60 ml of THF and 10 ml of DMPU is heated under reflux for 30 min and then cooled to 0° C., whereupon a fine suspension is obtained. 824 μl (7.5 mmol) of N-methylmorpholine followed by 981 μl (7.5 mmol of isobutyl chloroformate in 10 ml of THF and, after 1 h at 0° C., 824 μl (7.5 mmol) of N-methylmorpholine followed by 981 μl (7.5 mmol) of isobutyl chloroformate again are added dropwise. The mixture is stirred for 1 h and then added dropwise to 70 ml of a saturated solution of ammonia in dioxane. After 3 h, the mixture is concentrated in vacuo. The residue is poured into water, and the precipitate is filtered off and washed with water and boiling isopropanol, whereupon 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine is obtained. Further product is obtained from the isopropanol filtrate.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc([N+](=O)[O-])cn4)cc3CC[C@@H]12
Yield: 72.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-bromo-5-nitropyridine (93 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 106 mg (73%) of the title compound as an amorphous foam. mp 188°-191°. FDMS: m/e=383. α[D]589 =+57.07 (c=0.68, chloroform).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[CH:23]1[C:27](=[O:28])[CH:26]=[CH:25][CH:24]1[OH:29].C(O)(C)C>CC(C)=O.C(OCC)(=O)C>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[CH:23]1[C:24](=[O:29])[CH:25]=[CH:26][C:27]1=[O:28]
Reactant: Cc1cc(C)c(C2C(=O)C=CC2O)c(C)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: Cc1cc(C)c(C2C(=O)C=CC2=O)c(C)c1
Reaction time: 1 h

Procedure:
Jones' reagent (138 ml of 1.67 M solution, 230 mmol) is added dropwise over 40 minutes to a cooled (ice-bath) solution of 5-(2,4,6-trimethylphenyl)-4-hydroxycyclopent-2-enone (49.66 g, 230 mmol) in acetone (600 ml). The mixture is stirred for 1 hour. Isopropanol (100 ml) is added and the mixture is stirred at room temperature for 2 hours. The mixture is diluted with ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 2-(2,4,6-trimethylphenyl)cyclopent-4-ene-1,3-dione.
Reaction SMILES: C([O:8][C:9](=[O:44])[CH2:10][C@@H:11]([C:25]1[CH:29]=[CH:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[CH:26]=1)[C:12]([NH:14][C@H:15]([C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])C1C=CC=CC=1>CCO.C1COCC1>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH:28]=[CH:29][C:25]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20]4[NH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH2:10][C:9]([OH:44])=[O:8])=[CH:26]3)=[CH:35][CH:34]=2)=[CH:37][CH:38]=1)#[N:43]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)c1ncc[nH]1
Yield: 54 %

Procedure:
According to the procedure described in Example 1(a), 3(S)-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid benzyl ester was hydrogenolyzed in EtOH/THF for 3 h to give a 54% yield of 3(S)-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid: mp 206-210° C. (dec); 1HNMR (DMSO-d6): δ 12.0 (bs, 1H), 8.31 (d, 1H, J=8.45 Hz), 7.93 (s, 4H), 7.86 (d, 2H, J=8.5 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.33-7.30 (m, 2H), 6.81 (s, 2H), 6.18 (s, 1H), 5.02 (dd, 1H, J=15.8, 8.8 Hz), 3.86 (dd, 1H, J=9.6, 4.8 Hz), 2.87 (dd, 1H, J=16.9, 10.3 Hz), 2.60 (dd, 1H, J=16.5, 4.8 Hz), 1.7-1.5 (m, 3H), 0.87 (d, 3H, J=6.6 Hz), 0.84 (d, 3H, J=5.9 Hz); HRFABMS Calculated for C29H29N5O3Cs (M+Cs): 628.1325 Found: 628.1335.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)C.O>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: NCCCCCCOc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[6-(N-tert-Butoxycarbonylamino)-1-hexyl-oxy]-quinoline (480 mg) was treated with a large excess of hydrogen chloride in dietyl ether with stirring for 1 hour at room temperature. The crystalline product was isolated by filtration and redissolved in water whereafter the solution was made strongly alkaline with sodium hydroxide and extracted twice with chloroform. The organic phase was dried over potassium carbonate, filtered and evaporated to yield the title compound as a colourless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH2:9]([NH2:11])[CH3:10]>CCOCC>[CH2:9]([NH:11][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH3:10]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCN
Solvent: CCOCC
Product: CCNS(=O)(=O)CCCCl
Yield: 100 %

Procedure:
To a solution of 3-chloropropylsulfonyl chloride (1) (6.1 g, 34.5 mmol) in ether (25 ml) was dropwise added ethylamine (2a) (a 70% aqueous solution, 4.4 g, 68.3 mmol) with stirring and ice-cooling over 15 minutes, and the resultant mixture was stirred for one hour at room temperature. The reaction mixture was concentrated in vacuo, Benzene (100 ml) was added to the residue, and the solvent was removed in vacuo. To the residue was added ether (150 ml) and filtered to remove the insoluble material. The filtrate was distilled in vacuo to remove ether and 6.96 g (yield, about 100%) of crude N-ethyl-3-chloro propylsulfonamide (intermediate 3a) was obtained as colorless crystals (m.p.=30-32° C.). To a solution of this intermediate (3a) (6.96 g, 34.5 mmol) in THF (50 ml) was slowly added sodium hydride (60% in oil, 1.52 g, 38.0 mmol) with stirring under ice-cooling over 15 minutes. To reaction mixture was stirred for another 30 minutes at room temperature. After the addition of the ether (50 ml), the mixture was filtered to remove insoluble material and solvent was distilled in vacuo to gi 4.93 g (96%) of the desired compound 4a as a pale yellow oil. IR (CH3Cl) cm−1: 3018, 2976, 2868, 1452, 1306, 1220, 1179, 1129, 1015; NMR (CDCl3)δ: 1.24 (3H, t, J=7.4 Hz), 2.28-2.42 (2H, m, CH2), 3.10 (2H, q, J=7.4 Hz, CH2), 3.15 (2H, t, J=7.6 Hz, CH2), 3.22-3.29 (2H, m, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH:10]=[CH:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]([CH:34]=O)[CH2:27]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]([CH2:34][N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][N:9]1[C:8](=[O:17])[CH2:7][C:6]3[CH:18]=[C:19]([O:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH:11]=[CH:10]1)[CH2:27]2
Reactant: COc1cc2c(cc1OC)C(C=O)C2
Reactant: CNCCCN1C=Cc2cc(OC)c(OC)cc2CC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CC1Cc3cc(OC)c(OC)cc31)C=C2
Temperature: 0 °C
Yield: 96.4 %

Procedure:
Dissolve 1.1 g (3.78 mmol) of 7,8-dimethoxy-3-[3-(methylamino)propyl]-1,3-dihydro-2H-3-benzazepin-2-one in 50 ml of THF and 7 ml of dichloromethane. Add 0.69 g (4.53 mmol, 1.2 equivalent) of 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde and 0.22 ml of acetic acid. Cool the reaction mixture to 0° C. and add 1.2 g (5.67 mmol, 1.5 equivalent) of sodium triacetoxyborohydride. The reaction is instantaneous. Evaporate to dryness. The residue is taken up in water, and the aqueous phase is adjusted to pH=8 by adding 20% sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water, dried over MgSO4, filtered and evaporated to dryness. 1.7 g of an oil is obtained, which is purified by flash chromatography on 100 g of silica (eluant=dichloromethane/ethanol/NH4OH:95/5/0.5) to yield 1.4 g of title product in the form of a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1N)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[K+]>O.C(OCC)(=O)C.[Cu](I)I>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:21])[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: [I-]
Agent: I[Cu]I
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)O)ccc1I
Reaction time: 2 h

Procedure:
20 g (0.132 mol) of 3-methyl-4-aminobenzoic acid and 175 ml of sulfuric acid (20%) were introduced into a three-necked flask. At -10° C., a solution of 11.9 g (0.172 mol) of sodium nitrite in 50 ml of water was added dropwise and the mixture was stirred for two hours. This solution was introduced dropwise via a dropping funnel cooled to -5° C. into a solution of 35 g (0.211 mol) of potassium iodide, 35.2 g (0.185 mol) of copper iodide and 175 ml of sulfuric acid (20%). The mixture was stirred for eight hours, and the reaction medium filtered. The solids obtained were dissolved in ethyl acetate, washed with water and then with a sodium sulfite solution, dried over magnesium sulfate and evaporated. 24.4 g (70%) of 3-methyl-4-iodobenzoic acid of melting point 205°-210° C. were recovered.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][O:79][CH2:78][CH2:77]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a mixture of 0.060 g (0.139 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0212 g (0.209 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0532 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(tetrahydro-pyran-4-yl)-benzamide (I-187) as a white solid.
Reaction SMILES: C(O[C:4](=O)[NH:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[O:9]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.[OH-].[Na+]>C1COCC1>[F:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([CH2:14][CH2:13][CH:10]2[O:9][CH:8]([CH2:7][CH2:6][NH:5][CH3:4])[CH2:12][CH2:11]2)[CH:20]=1
Reactant: CCOC(=O)NCCC1CCC(CCc2cc(F)ccc2OC)O1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCCC1CCC(CCc2cc(F)ccc2OC)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a flame dried round bottom flask, purged with Ar(g), was placed 23 (112 mg, 0.33 mmol, 1.0 eq) and anhydrous THF (1.6 mL). The flask was cooled with an ice bath and stirred for 15 min. LAH (1.0 M, 1.32 mL, 1.32 mmol, 4.0 eq) was then slowly added via syringe over a period of 5 min. The reaction was allowed to warm to rt and stirred an additional 4 hrs. The reaction was then stopped with ice cold MeOH and then stirred for an additional 15 min at rt. The resulting solution was acidified with 1N HCl(aq) and then transferred to a beaker and then made basic with 10 M NaOH(aq). The basic solution was then extracted with diethyl ether (3×20 mL) and then the organic layer was washed with brine. The diethyl ether extract was dried over Mg2SO4 for 15 min and then filtered and concentrated to oil under reduced pressure to afford the crude product. The oil was purified with preparative TLC (developed with MeOH/CH2Cl2, 5:95, v:v, Rf 0.05); 1H NMR (CDCl3, 500 MHz) 6.87-6.82 (m, 2 H), 6.74-6.71 (m, 1 H), 4.05-3.77 (m, 2 H), 3.78 (s, 3 H), 2.71-2.56 (m, 5 H), 2.08-1.51 (m, 10 H); HRMS (ESI) [M+H]+ calcd for C16H25FNO2 282.3784, found 282.3762; HPLC>97% pure (tR=30.23 min, 100(A):0.5(D); tR=26.05 min, 90(A):10(C):0.5(D)).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-].CO>ClCCl.CCOCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:16]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCC1CCCCC1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)COCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of cyclohexylmethanol (1.23 mL, 10.0 mmol) in dichloromethane (30 mL) is added rhodium (II) acetate dimer (11 mg) followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at RT for 30 min. To the reaction mixture is added MeOH, and the reaction mixture is rotary evaporated, and the residue dissolved in Et2O, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at to give 2.02 g of the product 419. 1H NMR (CDCl3) δ 4.22 (q, 2 H), 4.05 (s, 2 H), 3.33 (d, 2 H), 1.8-1.5 (m, 7 H), 1.4-1.1 (m, 5 H), 1.1-0.9 (m, 2 H); MS: m/z 200 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:24]1([C:4]2[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:8][C:9]3[CH:23]=[CH:22][C:12]([O:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([C:20]5[NH:32][N:31]=[N:30][N:21]=5)[CH:15]=4)=[CH:11][CH:10]=3)[CH:5]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1nc(Nc2ccc(Oc3ccnc(-c4nnn[nH]4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
A mixture of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile (0.20 g, 0.53 mmol, prepared in Example 8), sodium azide (0.051 g, 0.79 mmol), and triethylamine (0.11 g, 0.79 mmol) in toluene (15 mL) was heated at 100° C. for 2 days. The mixture was then treated with cold water. The solid was collected by filtration, washed with water and methanol to give pure product, 0.14 g (63%). 1H NMR (DMSO-d6) δ 9.51 (s, 1H), 8.62 (d, 1H), 7.94 (m, 4H), 7.55 (d, 1H), 7.48 (m, 3H), 7.19 (m, 3H), 6.48 (m, 3H); MS ES 424 (M+H)+ calc 424.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[CH2:23][N:24]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[NH2:24][CH2:23][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[N:5][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CN
Yield: 22.8 %

Procedure:
A suspension of 6-methyl-4-(3-nitrophenyl)-5-phthalimidomethyl-2-phenylpyrimidine (6.9 g) and hydrazine monohydrate (0.8 g) in ethanol (140 ml) was refluxed for 6 hours. After filtering off the insolubles, the filtrate was poured into a suspension of chloroform (200 ml) and water (300 ml) under stirring. The organic layer was separated, washed with aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo and the resulting crystals were recrystallized from ethanol to give 5-aminomethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.12 g).