Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:21]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH4+].[OH-]>C1COCC1.CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: CN1CCN(Cc2ccc(N)c(C(=O)O)c2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(N)c(C(N)=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzoic acid (crude 1.28 g, 3.00 mmol) in THF (18 mL) and DMF (7 mL), EDCl (0.77 g, 4.00 mmol), and HOBT (0.50 g, 3.30 mmol) were added and stirred at room temperature for 20 minutes. Then, N-methylmorpholine (0.33 g, 3.30 mmol) and NH4OH (aq. 50% v/v, 3.50 mL, 50.0 mmol) were added. The mixture was stirred at room temperature for 48 hours. The solvent was evaporated, the residue was purified by column chromatography (silica gel 230-400 mesh; 5-10% 2 M ammonia in methanol and dichloromethane as eluent) to give 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzamide as a white solid. Yield: 0.416 g (55% for two steps).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([S:15]([C:18]2[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:21]1[S:22][C:18]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1)(=[O:24])=[O:25]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)c2ccccc2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(S(=O)(=O)c3ccccc3)s2)c1Br
Yield: 59 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzenesulfonyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-benzenesulfonylthiophene-2-sulfonyl chloride in 59% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 139-142° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].[ClH:23]>CC(O)C.[Pd]>[ClH:23].[CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C2CCN(C3CCCC3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Yield: 60 %

Procedure:
1-Cyclopentyl-4-(4-nitrophenyl)piperidine (303) (6.5 g, 24 mmol) was dissolved in IPA (70 mL) and 2M HCl (aq) (18 mL), and 10% Pd/C (2 g) was added. The resulting mixture was agitated on Parr shaker under 50 psi hydrogen for 18 hours. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure to give 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (4.0 g, 14 mmol, 60% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)=[CH:28][CH:27]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: Nc1ccc(Cl)cc1
Product: COc1nc(Nc2ccc(Cl)cc2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 15 %

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloroaniline in analogy to example 1c). It was obtained in 15% yield as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([CH:27]=[O:28])[CH:24]=[N:25][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:11][N:7]1[C:6]2[CH:12]=[C:2]([C:21]3[CH:22]=[C:23]([CH:27]=[O:28])[CH:24]=[N:25][CH:26]=3)[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10]
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: Cn1c(=O)oc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1c(=O)oc2ccc(-c3cncc(C=O)c3)cc21

Procedure:
A mixture of 5-Bromo-3-methyl-3H-benzooxazol-2-one (684 mg, 3 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carbaldehyde (699.2 mg, 3 mmol), polymer supported PalladiumTetrakis (0.11 mmol/g, 682 mg, 0.075 mmol), Na2CO3 (2 M in eater, 3 mL, 6 mmol) in DME (6 mL) was heated to reflux for overnight. After filteration and concentration, the residue was purified by flash column and yielded yellow solid. ESI-MS m/z: 255.0 [M+1]+, Retention time 1.03 min.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:15])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[N:3]=1
Reactant: N#Cc1c(-c2ccco2)nc(N)[nH]c1=O
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccc3ccccc3n2)nc(N)nc1-c1ccco1
Reaction time: 16 h
Yield: 16.2 %

Procedure:
To a stirred solution of 400 mg (1.98 mmol) 2-amino-4-furan-2-yl-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile in 15 ml DMF were added 1.93 g (5.94 mmol) cesium carbonate and 847 mg (3.96 mmol) 2-(chloromethyl)quinoline hydrochloride and stirring continued for 16 h ours at 100° C. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether/methanol to afford 110 mg (16%) 2-amino-4-furan-2-yl-6-(quinolin-2-ylmethoxy)-pyrimidine-5-carbonitrile as an orange crystalline solid. ES-MS m/e (%): 344 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1.[CH:27](=O)[CH3:28]>>[CH2:27]([N:15]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:9]([CH3:12])=[CH:8][CH2:7][C:6]([CH3:14])([CH3:13])[C:5]=2[CH:4]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH3:28]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Yield: 57.9 %

Procedure:
Following General Procedure D, ethyl 4-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 39, 0.055 g, 0.16 mmol) was reacted with acetaldehyde (90 μL, 1.6 mmol) to give 0.035 g (58%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Al+3].[Cl-].[Cl-].[Cl-]>[NH4+].[OH-]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:26]2[CH:27]=[CH:28][C:23]([OH:29])=[CH:24][CH:25]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: COc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cccc(C2(c3ccc(O)cc3)CCCN(Cc3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
To a solution of 1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol (17.6 g, 73.1 mmol) in (CH2)2Cl2 (200 mL) was added phenol (16.7 g, 178 mmol) followed by portionwise addition (highly exothermic) of AlCl3 (23.3 g, 178 mmol). The reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and was slowly poured into a mixture of crushed ice (50 mL) and 30% aq. NH4OH (120 mL). The mixture was stirred vigorously for 20 minutes and was then filtered through celite. The celite cake was washed with CH2Cl2 (200 mL). The organic layer was separated and the aqueous layer was washed with CH2Cl2 (3×100 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with hexanes/EtOAc (1:1) to afford 16.3 g of 4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenol 1HNMR (400 MHz, CDCl3) δ 7.39-7.21 (comp, 5 H), 7.19-7.05 (comp. 3H), 6.84 (s, 1H), 6.79 (d, 1H), 6.67-6.61 (comp, 3H), 3.73 (s, 3H), 3.50 (s, 2H), 2.86-2.79 (comp, 2H), 2.45-2.38 (comp, 2H), 2.21-2.19 (comp, 2H), 1.60-1.51 (comp, 2H); MS (M+1) 374.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)C=O.C(O[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C.Cl>C(O)C>[CH2:18]([O:17][CH:13]([O:14][CH2:15][CH3:16])[C:8]1[CH:7]=[CH:4][CH:3]=[C:2]([Br:1])[CH:9]=1)[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Solvent: CCO
Product: CCOC(OCC)c1cccc(Br)c1
Temperature: 25 °C
Yield: 108.4 %

Procedure:
To a stirred solution of 3-bromobenzaldehyde (22.38 g, 121 mmol) in ethanol (150 mL) was added triethylorthoformate (27 g, 181 mmol) and concentrated HCl (0.5 mL). The mixture was heated to reflux for 3 hours and allowed to cool to ambient temperature. The reaction mixture was poured into ice/H2O and extracted thoroughly with hexanes. The combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo to give 34 g of 3-bromobenzaldehyde diethyl acetal as a colorless liquid.
Reaction SMILES: O[C:2]1([CH2:13][C:14](=[O:16])[CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][C:3]1=O.C(OCC)(=O)C.O>C1COCC1>[CH3:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[C:2]2[CH2:13][CH:14]([OH:16])[CH3:15]
Reactant: CC(=O)CC1(O)C(=O)Nc2ccc(C)cc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2[nH]cc(CC(C)O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
The aldol product 47 (10 mmol) was dissolved in absolute THF (20 ml) under an Ar atmosphere. BH3xTHF (30 ml, 1 M solution, 30 mmol) was then added to the mixture, while cooling with a water bath, and the mixture was stirred at room temperature for 15 hours. The course of the reaction was monitored by TLC. When the reaction had ended, the reaction solution was added to a mixture of ethyl acetate (50 ml) and H2O (50 ml). After separation of the phases, the aqueous phase was extracted twice with 30 ml portions of ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was filtered over silica gel with ethyl acetate. The crude product obtained after removal of the solvent was purified by column chromatography on silica gel (eluent:ethyl acetate/cyclohexane: 1:2).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[S:31]([O-])(=O)(=O)[CH3:32].C[S-].[Na+]>>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][S:31][CH3:32])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)[O-]
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(CO)cc1
Agent: C[S-]
Agent: [Na+]
Product: CSCc1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Yield: 64 %

Procedure:
By a method similar to that in Example 395, 3-acetyl-6-bromo-2-(4-hydroxymethylbenzyl)-4-phenyl-2H-isoquinolin-1-one was converted to mesylate and reacted with sodium thiomethoxide to give the title compound (239 mg, 64%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH2:17])([C:14](O)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C(Cl)Cl.Cl>[ClH:19].[ClH:19].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH2:17])([C:14]([Cl:19])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(C(=O)O)CCN(Cc2ccccc2)CC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: NC1(C(=O)Cl)CCN(Cc2ccccc2)CC1

Procedure:
HCl is passed into a suspension of 10 g of finely powdered 1-benzyl-4-amino-4-piperidinecarboxylic acid in 111 ml of CH2Cl2 at 0° C. for 1 hour. 26 g of PCl5 in 200 ml of CH2Cl2 are added in several portions to this mixture, with vigorous stirring and while passing in further HCl. After the mixture has been stirred at 0° C. for 4 hours, the reaction product is filtered off with suction over a glass frit, with exclusion of moisture, and washed thoroughly with petroleum ether (60°-80° C.) and CH2Cl2. The crude product thus obtained is used in the next reaction stage without further purification.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[CH3:13][N:14]1[C:18]([CH2:19][C:20]([NH2:22])=[S:21])=[CH:17][N:16]=[CH:15]1>>[CH3:13][N:14]1[C:18]([CH2:19][C:20]2[S:21][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)=[CH:17][N:16]=[CH:15]1
Reactant: Cn1cncc1CC(N)=S
Reactant: O=C1c2ccccc2CC1Br
Agent: Cl
Product: Cn1cncc1Cc1nc2c(s1)Cc1ccccc1-2

Procedure:
Starting compounds: 2-bromo-1-indanone, (1-methyl-5-imidazolyl)thioacetamide hydrochloride
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].[Si:18]([O:25][CH2:26][CH2:27][C@@H:28]1[CH2:40][C:39]2[C:38]3[C:37](Cl)=[N:36][CH:35]=[N:34][C:33]=3[S:32][C:31]=2[CH2:30][CH2:29]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][CH2:26][CH2:27][C@@H:28]1[CH2:40][C:39]2[C:38]3[C:37]([O:1][CH:2]4[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]4)=[N:36][CH:35]=[N:34][C:33]=3[S:32][C:31]=2[CH2:30][CH2:29]1)([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (181 mg, 0.84 mmol, 1.40 equiv) in 8 mL of distilled THF was added sodium hydride (60% dispersion in mineral oil, 72 mg, 1.80 mmol, 3.00 equiv) at 0° C. and stirred for another 30 min under nitrogen. Then (12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene (230 mg, 0.60 mmol, 1.00 equiv) was added and stirred overnight at room temperature. The reaction was then quenched with saturated aqueous NH4Cl, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to give 240 mg (71%) of tert-butyl N-(4-[[(12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a yellow oil. MS: m/z 562 [M+H]+.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4([C:29](=[O:38])[NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:28][CH2:27]4)=[O:25])=[CH:19][C:18]=3[F:39])[N:13]=[CH:12][N:11]=2)C=CC=CC=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C)C=O>[F:39][C:18]1[CH:19]=[C:20]([NH:23][C:24]([C:26]2([C:29]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[O:38])[CH2:27][CH2:28]2)=[O:25])[CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:40])[N:11]=[CH:12][N:13]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)Oc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)N1CCOCC1
Reaction time: 26 h
Yield: 82.9 %

Procedure:
[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamic acid phenyl ester (40 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and morpholine (0.045 ml) was added thereto, followed by stirring for 26 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (18.3 mg, 82.9%).
Reaction SMILES: [CH2:1](Br)[CH3:2].[CH3:4][O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][C:13](=[O:21])[CH2:14]2)[CH2:9]1)=[O:7].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:19][C:18]([CH:17]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][C:13](=[O:21])[CH2:14]2)[CH2:9][N:8]1[C:6]([O:5][CH3:4])=[O:7])=[O:20])[CH3:2]
Reactant: COC(=O)N1CC2CCC(=O)CC2CC1C(=O)O
Reactant: CCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Temperature: 50 °C

Procedure:
In Scheme X, Step A, the compound of structure (i) is esterified by reaction with a compound of formula Et-Br (where Et represents an ethyl group) to provide the intermediate of compound (i-b). For example 2-methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with triethylamine and bromoethane. The reaction is heated at 50° C. for about 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and 1N HCl. The organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide ethyl-2-methoxycarbonyl-6-oxodecahydroisoquinoline-3-carboxylate, the compound of structure (i-b). This crude material may then be purified under standard conditions well known in the art. For example, the crude material is dissolved in 10% ethyl acetate/heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate/heptane). The plug is eluted with, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents are combined and concentrated under vacuum to provide the purified compound of structure (i-b).
Reaction SMILES: [C:1]([NH:9][C:10](=[N:13][CH3:14])SC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[C:1]([NH:9][C:10]([NH:13][CH3:14])=[N:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCCCN
Reactant: CN=C(NC(=O)c1ccccc1)SC
Product: CNC(=NCCCCCCCCN)NC(=O)c1ccccc1

Procedure:
A mixture of N-benzoyl-N'-methyl-S-methylisothiourea and an excess of 1,8-diaminooctane is maintained at 60° for 5 hours to give a solid product which is washed with ether to leave N-benzoyl-N'-methyl-N"-(8-aminooctyl)guanidine.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Br:12][C:13]1[N:14]([CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[N:17]=1.N1C=CN=C1>CN(C=O)C>[Br:12][C:13]1[N:14]([CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][O:25][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[N:17]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cn(CCC(O)CO)c(Br)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCC(O)CCn1cc([N+](=O)[O-])nc1Br)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Triisopropylsilyl chloride (2.50 mL, 11.7 mmol) was added to a solution of diol 131 (3.11 g, 11.1 mmol) and imidazole (1.66 g, 24.4 mmol) in anhydrous DMF (30 mL) under N2 and then the mixture was stirred at room temperature for 18 h. The resulting mixture was added to ice-water (200 mL) and extracted with EtOAc (4×200 mL). The extracts were washed with water (200 mL) and then evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-20% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 20-33% EtOAc/petroleum ether gave 4-(2-bromo-4-nitro-1H-imidazol-1-yl)-1-[(triisopropylsilyl)oxy]-2-butanol (132) (4.60 g, 95%) as a white solid: mp (CH2Cl2/pentane) 90-91° C.; 1H NMR (CDCl3) δ 7.89 (s, 1H), 4.24 (dd, J=7.7, 6.2 Hz, 2H), 3.74 (dd, J=9.6, 3.5 Hz, 1H), 3.62 (m, 1H), 3.53 (dd, J=9.6, 6.8 Hz, 1H), 2.59 (d, J=3.8 Hz, 1H), 1.95-1.82 (m, 2H), 1.17-1.03 (m, 21H). Anal. (C16H30BrN3O4Si) C, H, N.
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=O)[C:8]2=[O:22])=CC=1.C1(CN2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)CC1.[CH2:45]([NH2:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([NH:52][C:15](=[O:17])[C:14]1[CH:19]=[CH:20][N:21]=[C:12]([N:9]2[CH2:10][CH2:11][N:7]([CH2:6][CH:5]3[CH2:23][CH2:24]3)[C:8]2=[O:22])[CH:13]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Product: O=C(NCc1ccccc1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 31 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with benzylamine, N-benzyl-2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 31% yield: mp 121-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.36 (d, J=5.4 Hz, 1H), 7.40 (d, J=5.1 Hz, 1H), 7.32-7.24 (m, 5H), 6.73 (br s, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.06 (t, J=8.1 Hz, 2H), 3.59 (t, J=8.1 Hz, 2H), 3.14 (d, J=6.9 Hz, 2H), 1.00-0.87 (m, 1H), 0.57-0.51 (m, 2H), 0.24-0.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.7, 156.9, 153.2, 148.2, 142.9, 137.7, 128.8, 128.0, 127.7, 115.9, 108.8, 48.6, 44.2, 41.6, 41.5, 31.0, 9.0, 3.4; MS (ES+) m/z 351.3 (M+1).