Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8](Cl)=[C:7]([Cl:13])[N:6]=1)=[O:4].[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:21]([O:23][CH2:24][CH3:25])=[CH2:22])CCC.[NH4+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:21]([O:23][CH2:24][CH3:25])=[CH2:22])=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=C(OCC)c1nc(N)c(C(=O)OC)nc1Cl
Temperature: 80 °C
Yield: 64.1 %

Procedure:
A mixture of 3-amino-5,6-dichloro-pyrazine-2-carboxylic acid methyl ester [1458-18-0] (600 mg, 2.62 mmol), lithium chloride (389 mg, 9.17 mmol), Pd(PPh3)2Cl2 (184 mg, 0.262 mmol) and tributyl-(1-ethoxy-vinyl)-stannane [97674-02-7] (1.6 ml, 4.50 mmol) in DMF (27 ml) under argon was heated at 80° C. bath temperature for 3 h and 50 min. Saturated aq. NH4Cl was added and the mixture was extracted with MTBE (3×). The combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 7:3) to provide the title compound as yellow solid (433 mg).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:6][C:7]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(COCc2ccccc2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(COCc3ccccc3)s2)c1Br
Yield: 31.2 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide was prepared as described in Example 10 from 2-chlorosulfonyl-5-(benzyloxymethyl)thiophene (520 mg, 1.72 mmol) and 5-amino-4-bromo-3-methyl isoxazole (319 mg, 1.8 mmol). Purification by column chromatography using 10% MeOH/CHCl3) gave 238 mg of pure N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide as a brown semisolid (31% yield, m.p. 92° C).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.[C:14]([Cu])#[N:15].C(OCC)(=O)C>CN(C=O)C>[F:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:12][CH3:13])[C:5]=1[N+:9]([O-:11])=[O:10])[C:14]#[N:15]
Reactant: N#C[Cu]
Reactant: COc1cc(Br)cc(F)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Temperature: 160 °C

Procedure:
A mixture of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (1.5 g, 6 mmol), and CuCN (698 mg, 7.8 mmol) in 10 mL of DMF was heated in a sealed tube at 160° C. overnight. It was then cooled down, diluted to ethyl acetate, washed by brine and water. The organic extract was dried and concentrated to a red solid (1 g, 85%) which was used for next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.01 (s, 3 H) 7.14 (s, 1 H) 7.17 (d, J=8 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:29]1([CH2:35][CH2:36][OH:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.O>[N:29]1([CH2:35][CH2:36][O:37][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:19]=[C:18]([NH2:28])[N:17]=4)=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccccc2)n1
Reactant: OCCN1CCOCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc(Nc2ccc(Oc3ccnc(OCCN4CCOCC4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
N4-[4-(2-chloro-pyridin-4-yloxy)-phenyl]-6-phenyl-pyrimidine-2,4-diamine (Example 48, 75 mg, 0.19 mmol) was dissolved in toluene (1.5 mL). 2-Morpholin-4-yl-ethanol (61 mg, 0.46 mmol), powdered KOH (22 mg, 0.38 mmol), and 18-crown-6 (20 mg, 0.08 mmol) were subsequently added. The mixture was stirred at 90° C. overnight, after which time it was diluted with water and extracted with both ethyl acetate and dichloromethane. The combined organic extracts were concentrated and the residue was purified by prep HPLC to give the title compound (14 mg, 15%). 1H NMR (DMSO-d6) δ 10.79 (br s, 1H), 9.99 (br s, 1H), 8.08 (d, J=5.8 Hz, 1H), 7.90 (m, 2H), 7.77 (dd, J=7.6, 2.0 Hz, 2H), 7.64 (m, 3H), 7.21 (d, J=8.9 Hz, 2H), 6.69 (dd, J=5.8, 2.1 Hz, 1H), 6.60 (s, 1H), 6.22 (d, J=2.2 Hz, 1H), 4.57 (t, J=5.1 Hz, 2H), 3.96 (m, 2H), 3.68 (m, 2H), 3.50 (m, 4H), 3.15 (m, 2H); MS ES: 485 (M+H)+, calcd 485, RT=1.96 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].I[CH2:25][CH2:26][CH3:27]>O.C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:25][CH2:26][CH3:27])[CH2:12][CH2:11]1
Reactant: Cc1cccc(C)c1NC1CCNCC1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCCN1CCC(Nc2c(C)cccc2C)CC1
Temperature: 40 °C
Reaction time: 40 h

Procedure:
To a warm (about 40° C.) and stirred mixture of 5 parts of N-(2,6-dimethylphenyl)-4-piperidinamine, 5 parts of sodium carbonate, a few crystals of potassium iodide in 120 parts of benzene is added dropwise a solution of 5.1 parts of 1-iodopropane in 80 parts of benzene. After the addition is complete, stirring is continued for 40 hours at reflux temperature. The reaction mixture is cooled and 50 parts of water are added. The organic layer is separated, dried and evaporated in vacuo. The oily residue is distilled, yielding 10.2 parts of N-(2,6-dimethylphenyl)-1-propyl-4-piperidinamine; bp. 135° C. at 0.2 mm. pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(C2OCCO2)nc1
Yield: 82.4 %

Procedure:
A mixture of 2-pyridinecarboxaldehyde (300 g), 300 mL of ethylene glycol, 3 L of toluene and 100 g of p-toluenesulfonic acid in a 5 L 3 neck-flask equipped with a Dean-Stark head was refluxed for 4 h, separating the water formed. The mixture was concentrated in vacuo to 1/2 of its volume, and poured into a 5 L flask containing a cold (5° C.) sodium bicarbonate solution. The aqueous layer was extracted with methylene chloride (3×500 mL), the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to yield a dark oil. The oil was distilled (1 mm/100°-110° C.) to afford 349.1 g (82.4%) of 2-(1,3-dioxolan-2-yl)pyridine.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].CC(C)([O-])C.[Na+].[CH3:13][C:14]([C:17]1[CH:22]=[C:21]([C:23]2[O:24][C:25](S(C)(=O)=O)=[N:26][N:27]=2)[CH:20]=[C:19]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:18]=1[OH:36])([CH3:16])[CH3:15]>C(O)(C)(C)C>[CH3:16][C:14]([C:17]1[CH:22]=[C:21]([C:23]2[O:24][C:25]([NH:5][C:4]([NH2:6])=[NH:3])=[N:26][N:27]=2)[CH:20]=[C:19]([C:32]([CH3:33])([CH3:34])[CH3:35])[C:18]=1[OH:36])([CH3:13])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)o2)cc(C(C)(C)C)c1O
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(-c2nnc(NC(=N)N)o2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
Sodium (0.68 g, 29.7 mmol) is dissolved in 40 ml of t-butanol under N2 atmosphere. Guanidine hydrochloride (3.31 g, 34.65 mmol) is added to the sodium t-butoxide solution and stirred at room temperature for 0.5 hour. 2,6-Bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-oxadiazole-2-yl]-phenol (3.50 g, 9.93 mmol) is added and the reaction is warmed at reflux overnight. The cool reaction mixture is concentrated in vacuo and is recrystallized from methanol-water. The solid is dissolved in diethyl ether and treated with ethereal HCl and the precipitate is collected and recrystallized from ethanol-ether to give 1.53 g (3.29 g theor., 46%) of N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazole-2-yl]-guanidine, monochloride as a white solid: mp 223°-224° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.C([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=O>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: BrCCOc1ccc(Br)cc1
Reactant: O=CN1CCNCC1
Solvent: CC(C)O
Product: Brc1ccc(OCCN2CCNCC2)cc1
Yield: 70.1 %

Procedure:
A mixture of 56.0 g (0.2 moles) of 2-bromoethyl p-bromophenyl ether and 45.6 g (0.4 moles) of 1-formylpiperazine in 500 ml of 2-propanol was heated at reflux for 18 hours. The mixture was cooled and filtered. The filter was washed with 2-propanol and the filtrate was evaporated to an oil in vacuo. Water was added and the oil was extracted three times with about 200 ml of chloroform. The extracts were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated to an oil to which 250 ml of 5N sodium hydroxide was added. The mixture was refluxed for 18 hours, cooled and extracted three times with about 200 ml of chloroform. The extracts were combined, dried over magnesium sulfate and evaporated to an oil. The oil was distilled, bp 125°-128° C./0.05 mm of mercury, and gave 40 g of 1-[2-(4-bromophenoxy)ethyl]-piperazine as a yellowing oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8](Cl)=[N:7][C:6]=2[C:5]([Cl:12])=[CH:4][CH:3]=1.[CH3:13][S-:14].[Na+].C(=O)(O)[O-].[Na+].[Cl-].[Li+]>CN(C)C=O>[NH2:1][C:2]1[C:10]2[S:9][C:8]([S:14][CH3:13])=[N:7][C:6]=2[C:5]([Cl:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)c2nc(Cl)sc12
Reactant: C[S-]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CSc1nc2c(Cl)ccc(N)c2s1
Temperature: 60 °C
Yield: 82.6 %

Procedure:
The reaction was repeated with 2.3 grams (10.5 mmole) of 7-amino-2,4-dichlorobenzothiazole, 1.2 grams (17 mmole) of sodium thiomethoxide, and 25 mL of N,N-dimethylformamide as reagents. After the reaction mixture had been heated for two hours at 60° C. the 0.8 grams from the previous reaction was added, and the reaction mixture was heated for an additional three hours. The reaction mixture was cooled and poured into 300 mL of cold aqueous sodium bicarbonate solution. To this was then added 10 grams of solid lithium chloride. The reaction mixture was extracted with three 100 mL portions of diethyl ether. The combined organic extracts were washed with an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 2.0 grams of 7-amino-2-methylthio-4-chlorobenzothiazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19]Cl)[CH:14]=1.[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH2:19][C:15]1[CH:14]=[C:13]([Br:12])[CH:18]=[CH:17][N:16]=1)[C:1]([O:8][CH3:9])=[O:7]
Reactant: ClCc1cc(Br)ccn1
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cc(Br)ccn1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of dimethyl malonate (3.83 g) in dry THF (10 mL) at 0° C. was added NaH (463 mg) and the reaction mixture was stirred at rt for 30 min. A solution of 4-bromo-2-chloromethyl-pyridine (1.99 g) in dry THF (10 mL) was added and the reaction mixture stirred at rt for 15 h. It was then diluted with DCM, treated with a sat. aq. NH4Cl solution and the org. layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The title compound was obtained, after purification by CC (Hept/EA 100:0 to 50:50), as a yellow oil (1.65 g; 57% yield).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:15][C:14]4[N:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][NH:37][CH:38]=[S:39])=[CH:35][C:30]=2[O:29][CH2:28]1.CO>ClCCl>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][NH:37][C:38]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[N:12]=[CH:11][N:10]=[C:9]5[C:8]=4[S:15][C:14]4[N:16]=[CH:17][CH:18]=[CH:19][C:13]5=4)[CH2:6][CH2:5]3)=[S:39])=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: S=CNCc1ccc2c(c1)OCO2
Reactant: c1cnc2sc3c(N4CCNCC4)ncnc3c2c1
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: S=C(NCc1ccc2c(c1)OCO2)N1CCN(c2ncnc3c2sc2ncccc23)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-piperazinopyrido[3′,2′;4,5]thieno[3,2-d]pyrimidine (200 mg, 0.74 mmol) and pyridine (0.5 mL, 7.9 mmol) in dichloromethane (20 mL) was added a solution of product 1c in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 110 mg (32%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[CH3:16][N:17]1[CH:21]=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[N:18]1>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][N:5]([CH3:6])[S:22]([C:20]1[CH:19]=[N:18][N:17]([CH3:16])[CH:21]=1)(=[O:24])=[O:23]
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CNCC(OC)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CN(C)S(=O)(=O)c1cnn(C)c1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cool a solution of methylaminoacetaldehyde dimethyl acetal (22.5 mL, 0.18 mol) and triethylamine (26.5 mL, 0.19 mol) to 0° C. in CH2Cl2, then add dropwise a solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (30 g, 0.17 mol). Stir the reaction mixture at room temperature overnight, dilute with CH2Cl2 (500 mL), and wash with water. Dry the combined organics over Na2SO4, filter and concentrate. The resulting oil is placed under high vacuum and within two hours a resulting off white solid is formed, which is used without further purification (38.22 g, 87%).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([CH:6]3[CH:11]([CH:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:4][C:3]=1[O:24][CH3:25].C[Li].[Li]C(C)(C)C.Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[CH3:37][O:36][C:34]([C:2]1[C:3]([O:24][CH3:25])=[CH:4][C:5]2[CH:6]3[CH:11]([CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:12]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:13][C:14]=2[CH:15]=1)=[O:35]
Reactant: COc1ccc(C2Cc3cc(Br)c(OC)cc3C3CCCCC23)cc1
Reactant: COC(=O)Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(cc1OC)C1CCCCC1C(c1ccc(OC)cc1)C2
Reaction time: 2 h
Yield: 110.4 %

Procedure:
At −78° C., combine 7-Bromo-6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (0.2 g, 0.5 mmol), tetrahydrofuran (4 ml), CH3Li (0.623 ml, 1.6M), then add t-BuLi (0.59 ml, 1.7M). After 30 minutes add methyl chloroformate (0.19 g, 2.0 mmol) and remove cooling. After 2 hours at r.t., add ammonium chloride solution solution and ethyl acetate. Wash organic layer with water, dry over anhydrous sodium sulfate, remove solvent in vacuo to yield the titled compound (0.21 g, 100%). MS m/z 381 (M−1).
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22](O)=[O:23])=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>O.CN(C)C=O>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[C:15]([C:22]([N:31]4[CH2:32][CH2:33][CH:28]([C:27]([F:35])([F:34])[F:26])[CH2:29][CH2:30]4)=[O:23])=[CH:14][N:13]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)c1cnc(NC23CC4CC(CC(C4)C2)C3)nc1C(F)(F)F
Reactant: FC(F)(F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc(NC23CC4CC(CC(C4)C2)C3)nc1C(F)(F)F)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a mixture of 2-(adamantan-1-ylamino)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (120 mg) and N,N-dimethyl formamide (2.4 mL) were added 4-(trifluoromethyl)piperidine hydrochloride (87 mg), 1-hydroxybenzotriazole (62 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg), and N,N-diisopropyl ethylamine (0.12 mL) in this order at room temperature, and then the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and the obtained white solid was first dissolved in a mixed solvent of hexane and ethyl acetate, and then solidified again to obtain N-adamantan-1-yl-4-(trifluoromethyl)-5-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}pyrimidin-2-amine (81 mg) as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([N:16]2[C@@H:20]([C:21]3[CH:26]=CC=CC=3)COC2=O)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(N)CC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([NH:16][CH:20]2[CH2:21][CH2:26]2)=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Agent: NC1CC1
Product: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 49.1 %

Procedure:
1-Benzyl-4-(R)-methyl-3-(R)-[(4-(S)-phenyl-2-oxazolidinon-3-yl)carbonyl]pyrrolidine (150 g) was dissolved in cyclopropylamine (650 mL). The mixture was stirred at room temperature for 23 hours and was concentrated under reduced pressure. Diisopropyl ether (800 mL) was added to the residue and the solution was stirred at room temperature for 70 min. The resulting crystals were filtered. The collected crystals were then dissolved in dichloromethane (800 ml) and the solution was extracted with 1 mol/L hydrochloric acid (2×400 mL). The layers of 1 mol/L hydrochloric acid were combined. While the combined layer was chilled in an ice water bath, a 30% aqueous NaOH solution was added to make the solution basic (pH 13). The resulting crystals were filtered, washed sequentially with water and diisopropyl ether, and dried under reduced pressure to give (3R,4R)-1-benzyl-N-cyclopropyl-4-methyl-3-pyrrolidinecarboxamide as white crystals (52.2 g).
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Cl.Cl[CH2:15][C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C.O>[NH2:21][C:18]1[S:19][CH:20]=[C:16]([CH2:15][O:1][N:2]2[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])[N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Nc1nc(CON2C(=O)c3ccccc3C2=O)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
To a solution of 2-hydroxy-1H-isoindole-1,3(2H)-dione (4.13 g, 15.0 mmol) in acetonitrile (150 mL) were added 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (50.1 g, 337 mmol), cesium carbonate (210 g, 643 mmol) and potassium iodide (2.54 g, 15.3 mmol). The heterogenous mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, the insolubles were filtered off, rinsed with water and dried over night to afford 2-[(2-amino-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione as a colourless solid [36.0 g, yield 43%; HPLC/MS: m/z=276 (M+H); log P(HCOOH)=0.74].
Reaction SMILES: [C:1]([O:7][C@@H:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2]C(C)=O.C(N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C(#N)C>[N+:34](=[CH:2][C:1]([O:7][C@@H:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])=[O:6])=[N-:35]
Reactant: CC(=O)CC(=O)O[C@H](C=C(C)C)C(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)=C[C@@H](OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a solution of (1R)-3-methyl-1-trichloromethyl-2-butenyl acetoacetate (1.63 g., 5.68 mmole) from Example IA.2.(a) and triethylamine (0.57 g, 5.68 mmole) in 10 ml of acetonitrile was added dropwise in small portions at 7-10 minute intervals over a total period of 30 minutes a solution of tosyl azide (1.12 g, 5.68 mmole) in 2 ml of acetonitrile. After stirring at room temperature for 21/4 hours, the mixture was poured into 17 ml of aqueous 1N NaOH. After stirring an additional 45 minutes, the mixture was extracted three times with ether, and the combined ethereal extracts were dried over MgSO4. The dried solution was concentrated to give an orange oil. The oil was chromatographed on 8 (20×20 cm) preparative tlc plates (silica gel) with CH2Cl2 as eluent to afford (1R)-3-methyl-1-trichloromethyl-2-butenyl diazoacetate (0.96 g, 62% isolated yield) as a yellow oil; [α]D31 =+59° (hexane).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:18][CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH:6]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:27][CH:28]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCC(C(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoate (273 mg, 0.71 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (2 mL), and the reaction was stirred at room temperature for 2 h. The solution was evaporated to dryness to yield 4-{1-[(acetylamino)methyl]-2-anilino-2-oxoethyl}benzoic acid as an off-white powder that was carried on without further purification. MS (ESI) calcd [M+H]+ 327.1, found 327.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11](O)=[O:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN(C=O)C>O>[CH3:14][C:9]1([CH3:15])[CH2:10][C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8]1
Reactant: CC(C)(CC(=O)O)Nc1ccccc1N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)CC(=O)Nc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
An round bottomed flask was charged with crude 3-(2-aminophenylamino)-3-methylbutanoic acid (2.19 g, 10.52 mmol), HOBT (1.932 g, 12.62 mmol), EDC (2.419 g, 12.62 mmol), and a stirbar. DMF (20 mL, 0.5 M) was added, and the solution was stirred at rt overnight. The solution was diluted with water, extracted three times with methylene chloride, dried with sodium sulfate, concentrated with celite, and purified by silica gel chromatography (eluting with hexanes/ethyl acetate/1% isopropanol) to yield 4,4-dimethyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one as a yellow amorphous solid (0.697 g, 3.66 mmol, 35%).