Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>Cl.C(O)(C)C.C(OCC)(=O)C>[CH2:23]([C@H:22]1[NH:25][C:26](=[O:32])[N:19]([C:16]2[CH:15]=[N:14][C:13]([O:12][C:7]3[C:6]4[C:2]([CH3:33])([CH3:1])[CH2:3][O:4][C:5]=4[C:10]([CH3:11])=[CH:9][CH:8]=3)=[N:18][CH:17]=2)[C:20]1=[O:21])[CH3:24]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC[C@H]1NC(=O)N(c2cnc(Oc3ccc(C)c4c3C(C)(C)CO4)nc2)C1=O
Temperature: 35 °C
Yield: 89.6 %

Procedure:
1,1-dimethylethyl {(1R)-1-[({2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate (Intermediate 34, 213 mg, 0.47 mmol) was dissolved in HCl 5-6 N in isopropanol (1 mL) and the resulting solution was heated to 35° C. for 30 minutes. The reaction mixture was then concentrated under vacuum, the residue diluted with ethyl acetate (50 mL) and an aqueous 5% solution of K2CO3 (30 mL). Two phases were separated and the organic layer was washed with an aqueous saturated solution of ammonium chloride (30 mL), dried over Na2SO4 and concentrated under vacuum. The resulting crude was dissolved in ethyl acetate (10 mL) and triethylamine was added (0.23 mL, 1.64 mmol). The reaction mixture was cooled to 0-5° C. and a solution of triphosgene (55 mg, 0.185 mmol) in ethyl acetate (5 mL) was added drop wise in 10 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine dried over Na2SO4 and concentrated under vacuum. The residue was purified purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 50:50 as eluent affording the title compound (161 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=5)(=[O:27])=[O:26])=[CH:19][CH:20]=4)[C:15](=O)[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:38][OH:39]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=5)(=[O:26])=[O:27])=[CH:19][CH:20]=4)[C:15](=[N:38][OH:39])[C:14]=3[CH:13]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=O)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=NO)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
The product from Example 7A (134 mg, 0.257 mmol) in pyridine (3 mL) was treated with hydroxylamine hydrochloride (20 mg, 0.283 mmol) and stirred at ambient temperature. After 3 hours, the mixture was partitioned between ethyl acetate and 1N HCl. The separated organic phase was washed with 1N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was dissolved in a minimum amount of ethyl acetate and CH2Cl2 was added to effect precipitation. The solid was collected by filtration and dried under reduced pressure to provide the title compound as a white solid (123 mg, 89% yield). 1H NMR (300 MHz, DMSO-d6) δ 13.43 (bs, 1H), 10.17-10.35 (m, 1H), 9.96-10.13 (m, 1H), 9.46 (d, 1H), 8.76 (d, 1H), 8.02-8.18 (m, 3H), 7.8-7.93 (m, 2H), 6.98 (m, 1H), 6.81 (m, 1H), 6.5-6.6 (m, 2H), 6.32-6.44 (m, 2H), 6.16-6.28 (m, 2H), 5.1 (bs, 2H); MS (ESI) 535 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:18][N:19]([CH2:21][CH2:22]Cl)[CH3:20]>O1CCOCC1.O>[CH3:18][N:19]([CH3:20])[CH2:21][CH2:22][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1ccccc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCOc1ccccc1C(N)=O
Temperature: 85 °C
Yield: 60.7 %

Procedure:
A solution of 2-hydroxy-benzamide (10 g) and potassium carbonate (35.4 g) in dioxane (50 ml) and water (4.5 ml) was added with N,N-dimethyl-2-chlorethylamine hydrochloride (6.5 g). The mixture was heated at 85° C. for 3 hours. The solvent was evaporated off, the resulting residue was poured into 5% HCI and extracted with diethyl ether. The aqueous phase was adjusted to pH with sodium bicarbonate, then extracted with ethyl acetate. The organic layer was dried and evaporated to dryness to give the title compound as a white solid (5.7 g).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].N12CC3CC(CC(C3)C1)C2.O.[C:27]([O-])([O-])=[O:28].[K+].[K+]>C(O)(C(F)(F)F)=O>[C:10]1([C:2]([C:4]2[CH:9]=[CH:8][C:7]([CH:27]=[O:28])=[CH:6][CH:5]=2)([CH3:1])[CH3:3])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(c1ccccc1)c1ccccc1
Agent: C1C2CC3CC1CN(C2)C3
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(c1ccccc1)c1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
A suspension of propane-2,2-diyldibenzene (3.93 g, 20 mmol) and 1-aza-tricyclo[3.3.1.1*3,7*]decane (2.80 g, 20 mmol) in TFA (35 mL) was heated at 100° C. for 16 h. The reaction mixture was allowed to cool to RT, poured onto cold water and made alkaline (pH=9) with solid K2CO3. The aqueous solution was extracted with Et2O (3×250 mL) and the separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether:EtOAc 95:5) affording the title compound (3.47 g, 15.46 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1)([O-])=O.[C:13]1(=O)[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12.Cl.[OH-].[NH4+]>C1(C)C=CC=CC=1.O>[C:13]1(=[O:18])[N:10]([CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(CCN2C(=O)[C@H]3CC=CC[C@H]3C2=O)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
16.6 g of p-nitrophenethylamine and 15.1 g of cis-1,2,3,6-tetrahydrophthalic anhydride are heated under reflux in 300 ml of toluene, with stirring and a water trap, for 16 hours. This mixture is cooled and take to dryness by warming under reduced pressure. The residue is transferred to a flask containing 500 ml of water, 270 g ferrous sulfate heptahydrate and 1.3 ml concentrated hydrochloric acid. Steam is delivered to the mixture. When the temperature reaches 90° C., 75 ml of concentrated ammonium hydroxide is added in one portion, and at two-minute intervals three 25 ml portions of ammonium hydroxide are added. Continue stirring and heating during the additions. The total reaction time is 8-10 minutes. Immediately pour the mixture onto 1 kg of cracked ice. The solid is collected by filtration and washed with water. Recrystallize from water ethanol to obtain -4-(cis-1,2,3,6-tetrahydrophthalimidoethyl) aniline (1f).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:22]#[CH:23])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[H][H]>N1C=CC=CC=1.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([CH:22]=[CH2:23])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Product: C=C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Shake 13β-ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one (0.5 g.) in pyridine (20 cc.) containing a 2% palladium-calcium carbonate catalyst (150 mg.) with hydrogen at atmospheric pressure until one molecular equivalent of hydrogen has been absorbed. Recrystallise the product twice from ether-hexane and dry for 4 hours at 65°/.005 mm. to yield the title compound, m.p. 108°-111°; ultraviolet absorption peak at 240 (ε15,200); infrared absorption peak at 10.9μ.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=O.Cl.[NH2:15][OH:16].[OH-].[K+]>CO.O>[Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[N:15][OH:16]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(Cl)c(C=NO)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of Step 1 intermediate (56 g, 262.37 mmol) and hydroxylamine hydrochloride (22.8 g, 327.97 mmol) in methanol (525 ml) was added drop-wise a solution of KOH (18.3 g, 327.97 mmol) in water (32 ml) over a period of 1 h, while reaction mixture was maintained below 10° C. The mixture was stirred at room temperature for 1 h, and the resulting oxime precipitate was collected by filtration, washed with water (2×250 ml), methanol (2×150 ml) and dried to give 46.3 g of the product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 3.19 (s, 3H), 3.51 (s, 3H), 7.94 (s, 1H), 11.40 (br s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C([Si](C)(C)[O:13][C@@H:14]1[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][N:25]([CH2:38][CH:39](OC)OC)[C:26](=[O:37])[CH2:27][NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:19][CH2:18][C:15]21[CH2:17][CH2:16]2)(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:36][C:31]1[CH:30]=[C:29]([N:28]2[CH2:39][CH2:38][N:25]([CH2:24][CH2:23][CH2:22][N:20]3[CH2:19][CH2:18][C:15]4([CH2:17][CH2:16]4)[C@H:14]([OH:13])[CH2:21]3)[C:26](=[O:37])[CH2:27]2)[CH:34]=[CH:33][C:32]=1[Cl:35]
Reactant: COC(CN(CCCN1CCC2(CC2)[C@H](O[Si](C)(C)C(C)(C)C)C1)C(=O)CNc1ccc(Cl)c(Cl)c1)OC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(c2ccc(Cl)c(Cl)c2)CCN1CCCN1CCC2(CC2)[C@H](O)C1
Temperature: 60 °C
Yield: 17.2 %

Procedure:
Trifluoroacetic acid (1.51 g, 13.3 mmol) was added to a solution of N-{3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propyl}-2-(3,4-dichloro-phenylamino)-N-(2,2-dimethoxy-ethyl)-acetamide (142 mg, 0.24 mmol) in CH2Cl2 (1 mL) at RT, then after 3 h triethylsilane (140 mg, 1.21 mmol) was added. The solution was heated at 60° C. over 72 h, then partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc/MeOH 19:1) afforded the title compound (17 mg, 17%). Yellow gum, MS: 412.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[F:23][CH:24]([F:32])[O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:23][CH:24]([F:32])[O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: FC(F)OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[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: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC(F)F)CC1
Reaction time: 2 h

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 4-(difluoromethoxy)piperidine (18) (0.101 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and the reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.45 (1H, m), 1.65-1.56 (1H, m), 1.83-1.74 (1H, m), 1.98-1.92 (1H, m), 3.15-3.09 (1H, m), 3.40-3.26 (2H, m), 4.01-3.91 (1H, m), 4.33 (2H, s), 4.41-4.35 (1H, m), 6.75 (1H, t), 7.22 (1H, t), 7.38-7.36 (1H, m), 7.44-7.40 (1H, m), 7.83 (1H, t), 7.88 (1H, t), 7.97 (1H, d), 8.27 (1H, d), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 432).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH:4]=[N:3][CH:2]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].[I-].[K+]>CN(C)C=O.O>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[CH:4]=[N:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCCCCc1cncnc1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCc1cncnc1
Yield: 71.1 %

Procedure:
A solution of 22.3 g of 6-(5-pyrimidinyl)hexyl chloride, 41.6 g of potassium phthalimide, and 1.8 g of potassium iodide in 180 ml of dimethylformamide was heated to a bath temperature of 130° C. for 1 hour. The mixture was diluted with water and was extracted with dichloromethane. The combined organic layers were washed with water and were dried over potassium carbonate. The residue obtained after evaporation was crystallized from ethyl acetate-hexane to give 24.7 g (71%) of 2-[6-(5-pyrimidinyl)hexyl]-1H-isoindole-1,3-(2H)-dione, mp 124°-126.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.[C:20]([C:24]1[CH:29]=[C:28](C)[CH:27]=[C:26](C(C)(C)C)[C:25]=1O)(C)(C)[CH3:21].C([Sn](CCCC)(CCCC)C#CC1C=CC=CC=1)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=[C:4]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=1
Reactant: Cc1cc(Br)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C#Cc2ccccc2)nc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 43 %

Procedure:
To a solution of 2-bromo-4-methyl-6-(1-methyl-3-trifluoromethyl-pyrazol-5-yloxy)pyridine (3.0 g, 7.1 mmol), tetrakistriphenyl-phosphine palladium (0.2 g, 1.8 mmol) and 2,6-di-tert-butyl-4-methylphenol (3 crystals) in toluene (40 ml) under a nitrogen atmosphere is added dropwise tributyl-phenylethynyl-stannane (2.9 ml, 7.8 mmol) and the resulting mixture is heated at reflux for 2 hours. After cooling, the reaction mixture is diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and dried. 43% of the product (1.1 g, mp. 56° C.) is obtained by flash chromatography.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16](=O)[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1.Cl.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][NH:35][NH2:36])=[CH:32][CH:31]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Cl:26][C:11]1[N:10]=[C:9]([NH2:8])[N:14]=[C:13]2[N:35]([CH2:34][C:33]3[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:36]=[C:16]([CH2:17][CH:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)[C:12]=12
Reactant: COc1ccc(CNN)cc1
Reactant: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N)nc32)cc1
Reaction time: 17 h
Yield: 91.4 %

Procedure:
Triethylamine (83.68 ml) was added to a mixture composed of the above 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-one (61.23 g), (4-methoxybenzyl)-hydrazine hydrochloride (41.50 g) produced by the method described in U.S. Patent No. US2003/18197, and dichloromethane (600 ml) over 30 minutes under cooling in an ice bath. Thereafter, while the temperature of the reaction solution was gradually raised, it was stirred for 17 hours. Thereafter, a 10% citric acid aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure. A 5% citric acid aqueous solution was added to the resulting residue, and the precipitate was then collected by filtration. The resultant was washed with water, so as to obtain the title compound (73.84 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].Cl.Cl.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:1].[ClH:32].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:10]([NH:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[O:11])[CH2:24][CH2:23]2)=[CH:27][CH:28]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1c(Cl)cccc1Cl
Yield: 104 %

Procedure:
The procedure described in Example 29 was followed, using 2,6-dichlorophenyl isocyanate (1.88 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (50 ml) and triethylamine (4.3 ml; 31 mmole). Recrystallization from methanol provided the title compound (2.75 g; 52% yield) as colorless crystals, m.p. 246°-248° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:30][O:31][NH:32][CH3:33]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[N:32]([O:31][CH3:30])[CH3:33])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of 2(S)-tert-butoxycarbonylamino-3,3-dimethyl-butyric acid (30 g, 0.13 mol) in dichloromethane (400 mL) was added portionwise 1,1′-carbonyidiimidazole (63.3 g, 0.39 mol). After addition was complete the reaction was allowed to stir for 15 minutes before N-methoxy-N-methylamine hydrochloride (38 g, 0.39 mol) was added and the reaction allowed to stir for 16 hours. The solvents were removed in vacuo and the residue partitioned between ethyl acetate (250 mL) and 1M HCl (150 mL). The organic phase was washed with 1M HCl solution (2×100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL). The organic phase was dried over MgSO4, filtered and the solvents removed in vacuo to give a crude yellow oil. Purification by column chromatography (SiO2, 30% ethyl acetate in hexanes) afforded the title product as a pale yellow oil (26.5 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]3[C@H:10]([O:11][CH2:12][C:13](=[O:18])[NH:14]3)[CH2:9]2)=[CH:6][C:5]([C:19]#[N:20])=[CH:4][C:3]=1[NH:21]C1N=C(N(CC)CC2C=CC(OC)=CC=2)C2=NC=C(C#N)N2N=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.[Cl:60]CCCl>>[NH2:21][C:3]1[C:2]([Cl:1])=[C:7]([N:8]2[CH2:17][CH2:16][C@@H:15]([NH:14][C:13](=[O:18])[CH2:12][Cl:60])[C@H:10]([OH:11])[CH2:9]2)[CH:6]=[C:5]([C:19]#[N:20])[CH:4]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@H]4NC(=O)CO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Reactant: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1cc(N)c(Cl)c(N2CC[C@@H](NC(=O)CCl)[C@H](O)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was taken up in DCE (0.8 mL), anisole (0.043 mL, 0.391 mmol) and TFA (0.5 mL, 6.49 mmol). The mixture stirred 2 h at 25° C. and solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)-2-chloroacetamide (2.2 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[CH2:13][C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH3:9].IC.[Cl-].[NH4+]>O1CCCC1>[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[C@H:13]([CH3:1])[C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH3:9]
Reactant: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(OC)c1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@H]1[C@@H](O)[C@H](C)C(=O)N1c1ccc(C#N)c(OC)c1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of diisopropylamine (0.291 mL) in tetrahydrofuran (8 mL) was added dropwise n-butyllithium-hexane solution (1.24 mL, 1.6 mol/L) at −78° C., the mixture was stirred for 1 hr, and a solution of 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-methoxybenzonitrile (206.5 mg) in tetrahydrofuran (6 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min, iodomethane (0.247 mL) was added dropwise at −78C, and the mixture was stirred at 0° C. for 1 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/4) to give the title compound as a colorless solid (yield: 108.8 mg, 50%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]#[N:18])=[C:13]([NH2:16])[O:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:19]([O:22][CH:23](OCC)OCC)(=O)[CH3:20]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:17]#[N:18])=[C:13]([N:16]=[CH:23][O:22][CH2:19][CH3:20])[O:14][CH:15]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2coc(N)c2C#N)cc1
Reactant: CCOC(OCC)OC(C)=O
Solvent: CC(=O)O
Product: CCOC=Nc1occ(-c2ccc(NC(C)=O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
At room temperature, to the mixture of 4-(4-acetamidophenyl)-2-amino-3-cyanofurane 5 (6.0 g, 25 mmol) in acetic acid (60 mL), diethoxymethyl acetate (41 mL, 25 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min and then concentrated (below 40° C. in water bath). The residual paste was dried up with a pump. The dried solid material was triturated with ether then filtrated to afford 6 (3.93 g) as a solid. MS(ES) m/e 298 [M+H].