Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10])=[C:2]=[O:3].C[Si](C)(C)[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][Si](C)(C)C)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[C:2]=[O:3])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:10])=[C:2]=[O:3]
Reactant: O=C=NCCCCCC(=O)Cl
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(O[Si](C)(C)C)cc2)cc1
Product: O=C=NCCCCCC(=O)Oc1ccc(-c2ccc(OC(=O)CCCCCN=C=O)cc2)cc1

Procedure:
From 35 g (0.2 mol) of 6-isocyanatohexanoic acid chloride and 23 g (0.07 mol) of 4,4'-bis(trimethylsiloxy)biphenyl.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15]([Br:17])[N:16]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.[Cu]I.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>[NH2:18][C:12]1[C:11]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=2)=[N:16][C:15]([Br:17])=[CH:14][N:13]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#Cc1cccc(O)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(Br)nc1C#Cc1cccc(O)c1
Temperature: 120 °C
Yield: 71 %

Procedure:
3-Ethynylphenol (560.5 mg, 310.9 μL, 4.745 mmol) was added dropwise to a solution of 3,5-dibromopyrazin-2-amine (1 g, 3.954 mmol), triethylamine (4.001 g, 5.511 mL, 39.54 mmol), copper (I) iodide (90.37 mg, 0.4745 mmol) and Pd(PPh3)4 (228.5 mg, 0.1977 mmol) in DMF (10 mL) and the resulting solution heated at 120° C. for 3 hours. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and 1 MHCl/brine (1/1) and the layers separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts washed with brine (×2), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 120 g column, eluting with 0 to 40% EtOAc/Petroleum Ether, dry loaded) to give the sub-title product as a yellow solid (815 mg, 71% Yield). 1H NMR (400.0 MHz, DMSO) δ 6.88 (dd, 1H), 7.00 (br s, 2H), 7.11-7.11 (m, 1H), 7.17 (d, 1H), 7.25 (t, 1H), 8.12 (s, 1H) and 9.77 (s, 1H) ppm; MS (ES+) 292.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([O:54][C:55]([NH:57][C@H:58]([C:60]([NH:62][C@H:63]([C:65](O)=[O:66])[CH3:64])=[O:61])[CH3:59])=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([NH:57][C@H:58]([C:60]([NH:62][C@H:63]([C:65]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:66])[CH3:64])=[O:61])[CH3:59])=[O:56])([CH3:53])([CH3:52])[CH3:51]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 71 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-alanyl-L-alanine. Yield 71%. [α]D =+7.4° (c=0.82, tetrahydrofuran).
Reaction SMILES: [CH3:1][Si:2]1([CH2:7][CH:8]([C:13]#[N:14])[CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3]1>[OH-].[OH-].[Pd+2]>[NH2:14][CH2:13][CH:8]([CH2:7][Si:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: C[Si]1(CC(C#N)CC(=O)O)CCCC1
Agent: [Pd+2]
Agent: [OH-]
Product: C[Si]1(CC(CN)CC(=O)O)CCCC1
Yield: 48.4 %

Procedure:
4-(1-Methyl-1-silacyclopentan-1-yl)-3-cyanobutanoic acid (555 mg, 2.63 mmol) was subjected to catalytic reduction in the presence of Pd(OH)2 in the same manner as that of Example 20, the solvent was evaporated, and the residue was recrystallized to obtain 4-amino-3-[(1-methyl-1-silacyclopentan-1-yl)methyl]butanoic acid (274 mg, 48%) mentioned in the title as colorless powdery crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(OC)cc2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methoxyphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 8) 80.0 mg (0.183 mmol) in 3 ml of EtOH and 2 ml of THF was added 40.0 mg (1.00 mmol, 1.0 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCI. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.45 (2H, s), 7.24 (2H, d, J=8.6 Hz), 7.02-6.89 (3H, m), 5.98 (1H, t, J=4.4 Hz), 3.79 (3H, s), 2.31 (2H, d, J=4.7 Hz), 1.29 (6H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(OC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To 1-(t-butyloxycarbonyl),4-(5-cyano,2-pyridinyloxy)piperidine (1.6 g) in dichloromethane (20 mL) was added trifluoroacetic acid (1.2 mL) and the reaction stirred at room temperature for 1 hour. The reaction was quenched by evaporation of trifluoroacetic acid dissolving the residue in water, basifying with sodium hydrogen carbonate and extracting the dichloromethane. The organic layer was then washed with water, brine, dried (MgSO4) and evaporated to yield 4-(5-cyano,2-pyridyloxy)piperidine as a white crystalline solid (337 mg), MS: m/z 279 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:19][CH2:18]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:22][CH2:21]1
Reactant: COc1ccccc1CN1CCN(CCCCl)CC1
Reactant: O=C1CCCc2c(O)cccc21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccccc1CN1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 57.1 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-methoxybenzyl)-piperazine; yield 57.1% of theory; m.p. of the dihydrochloride (recrystallized from 1N hydrochloric acid) 241°-243°C;
Reaction SMILES: [C:1]([C:4]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH2:15][CH2:16][CH3:17])[C:8]([OH:14])=[CH:9][CH:10]=2)[O:5]1)(=[O:3])[CH3:2].[Br:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[C:1]([C:4]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH2:15][CH2:16][CH3:17])[C:8]([O:14][CH2:25][CH2:24][CH2:23][Br:22])=[CH:9][CH:10]=2)[O:5]1)(=[O:3])[CH3:2]
Reactant: BrCCCBr
Reactant: CCCc1c(O)ccc2c1OC(C(C)=O)(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCBr)ccc2c1OC(C(C)=O)(C(=O)OC)CC2
Reaction time: 72 h
Yield: 44 %

Procedure:
A 50 ml single neck round bottom flask was charged with 640 mg (2.2 mmole) of the compound from Example 39, 6.63 g or 3.33 ml (32.8 mmole) of 1,3-dibromopropane, 690 mg (5 mmole) of anhydrous potassium carbonate, 150 mg (1 mmole) of sodium iodide, and 4 ml of methyl ethyl ketone. The flask was equipped with a magnetic stirring bar and a condenser topped with a calcium chloride drying tube, and refluxed with stirring for 72 hours. The insoluble solids were removed by filtration and the filtrate was concentrated by rotary evaporation. Purification of the residual oil by high pressure liquid chromatography (15% ethyl acetate-hexane) gave 400 mg (44%) of the title compound as a clear oil, homogenous by this layer chromatrography (20% ethyl acetate-hexane).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:29])([F:28])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[NH:23][O:24][C:25](=[O:27])[N:26]=2)[CH:17]=1.[CH3:30][C:31]([CH3:37])([CH2:35][CH3:36])[C:32](Cl)=[O:33]>N1C=CC=CC=1>[CH3:30][C:31]([CH3:37])([CH2:35][CH3:36])[C:32]([N:26]1[C:25](=[O:27])[O:24][N:23]=[C:22]1[C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([F:12])([F:28])[F:29])[CH:21]=[CH:20][N:19]=1)=[O:33]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: O=c1nc(-c2cc(OCC(F)(F)F)ccn2)[nH]o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CCC(C)(C)C(=O)n1c(-c2cc(OCC(F)(F)F)ccn2)noc1=O
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To 2 ml of pyridine were added 0.25 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-one, and 0.22 g of 2,2-dimethylbutanoyl chloride was added at room temperature. After stirring for 2 hours, the mixture was further stirred at 60° C. for 2 hours. The resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.13 g of 4-(2,2-dimethylbutanoyl)-3-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-one (present compound (25)).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1C
Reactant: c1c[nH]cn1
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccccc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([O:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1.C(N(CC)C(C)C)(C)C.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([O:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 85 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 0.4 g, 1.46 mmol) in DMF (2 mL), was added (3R,4S)-benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate (enantiopure Intermediate 12, 0.40 g, 1.60 mmol) and N,N-diisopropylethylamine (0.3 mL, 3.1 mmol). The mixture was heated at 85° C. overnight. After cooling, the mixture was added water, stirred for 3 h, filtered, rinsed with water, and dried to give (3R,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methoxypyrrolidine-1-carboxylate (0.62 g, 87% yield) as a brown solid. MS (ES+) m/z: 487.1, 488.3 (M+H); LC retention time: 3.82 min (analytical HPLC Method).
Reaction SMILES: CC1SC=C(/C=C(/[C@H]2[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[C:23]([CH3:31])([CH3:30])[C:21](=[O:22])[C@H:20](C)[C@@H:19](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1.N1CCCCC1.C(Cl)Cl.CC(C)=O>C(Cl)Cl>[CH3:31][C:23]([CH3:30])([C:21](=[O:22])[CH2:20][CH3:19])[C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:27]
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCC(=O)C(C)(C)[C@@H](O)CC(=O)O
Reaction time: 16 h

Procedure:
1 g (2.03 mmol) of epothilone A is dissolved in 168 mL of CH2Cl2. After adding 86 μl (0.88 mmol) of piperidine and 254 μl (0.88 mmol) of titanium tetra-isopropylate, the reaction solution is strirred for 16 h at RT. After concentration in vacuo, the product is purified by FC (200 g of silica gel, CH2Cl2→CH2Cl2/acetone=4:1) giving a colorless oil: Rf (CH2Cl2/acetone=85:15): 0.55; M+H=494.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:15][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:3]=1
Reactant: NC1CCOCC1
Reactant: Fc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Brc1ccnc(NC2CCOCC2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
4-Bromo-2-fluoropyridine (1.38 g, 7.84 mmol) was dissolved in DMSO (20 mL), and (tetrahydro-pyran-4-yl)amine (0.912 g, 9.02 mmol) was added, followed by cesium carbonate (5.11 g, 15.7 mmol). The mixture was heated to 90° C. and agitated 3 hours. After cooling, the mixture was diluted with ethyl acetate (200 mL) and washed with water (5×), brine, dried and evaporated to give 4-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (1.12 g, 4.36 mmol, 55.5% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6](Cl)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[I-].[Na+].[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)(C)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Reactant: C1CNCCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: Clc1ccc(C(c2ccccc2)N2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chlorobenzhydryl chloride (5.32 g, 22.4 mmol), isopropanol (80 ml) and sodium iodide (3.41 g, 22.8 mmol) was stirred at room temperature for 30 minutes. Thereto was added homopiperazine (11.2 g, 112 mmol), and the mixture was stirred at 95° C. for 18 hours. The solvent was distilled off, and the concentrate was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The thus-obtained crude product was used for the next reaction without purification.
Reaction SMILES: C[O-].[Na+].[C:4]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][O:6]1)=[O:5].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].C(OCC)(=O)CC>O.CO>[N+:14]([C:17]1[CH:18]=[C:19]([CH:20]2[C:4](=[O:5])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:6])[CH:22]=[CH:23][CH:24]=1)([O-:16])=[O:15]
Reactant: O=C1OCc2ccccc21
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(=O)CC
Product: O=C1c2ccccc2C(=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
Sodium methoxide solution (27% in methanol, 400 g, 2 mol) was added over 40 minutes at 20–30° C. to a stirred mixture of phthalide (67 g, 0.5 mol), 3-nitrobenzaldehyde (75.5 g, 0.5 mol), ethyl propionate (250 ml) and methanol (150 ml). The mixture was stirred at ambient temperature for 15 minutes then it was heated under reflux for 2.5 hours, cooled to ambient temperature and poured into water (2300 ml). The aqueous mixture was washed with ether (5×500 ml) then acetic acid (60 ml) was added. The resulting solid was collected by filtration, washed with water (200 ml) and dried in vacuo to give 2-(3-nitrophenyl)indan-1,3-dione (87.92 g) as a dark red-brown solid, m.pt. 216–226° C., which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23]
Reactant: Cc1n[nH]c(=O)c(-c2cccc(F)c2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2cccc(F)c2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3.49 g of 5-(4-chlorophenyl)-4-(2,3-difluorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 3.66 g of 3-chloro-5-(4-chlorophenyl)-4-(2,3-difluorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (xii) of the present invention).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[C:16](=O)([O:19]C)[O:17][CH3:18]>O1CCCC1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:14]#[N:15])[C:16]([O:17][CH3:18])=[O:19])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C#N)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
0.66 g (16.5 mmols) of sodium hydride and 2.6 g (15.0 mmols) of 4-tert-butylphenylacetonitrile were suspended in 50 ml of tetrahydrofuran. To the suspension was added dropwise 1.95 g (16.5 mmols) of dimethyl carbonate dissolved in 10 ml of tetrahydrofuran while stirring at room temperature. The mixture was refluxed with heating for 2 hours, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the residue was acidified by diluted hydrochloric acid and twice extracted with 30 ml of ethyl acetate. The ethyl acetate extraction solutions were mixed, washed with a saturated brine solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue thus-obtained was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), giving 1.8 g of the desired product (yield 52%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH2:41][C:42]([NH:44][C:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C:19]([N:21]([CH2:31][C:32]1[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[S:35][CH:36]=1)[C@@H:22]([CH3:30])[CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[O:20]>>[S:35]1[CH:36]=[C:32]([CH2:31][N:21]([C@@H:22]([CH3:30])[CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[CH2:41][C:42](=[O:43])[NH:44][C:45]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 52 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:13])[C:8]=1[Si:9]([CH3:12])([CH3:11])[CH3:10])[NH2:5].[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH:22]1[C:33](O)=[O:34])=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:33]([CH:22]2[C:23]3[C:28](=[CH:27][C:26]([O:31][CH3:32])=[CH:25][CH:24]=3)[CH2:29][CH2:30][N:21]2[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[O:34])[CH:6]=[C:7]([F:13])[C:8]=1[Si:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: C[Si](C)(C)c1c(F)cc(N)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (700 mg, 3.48 mmol), 2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1176 mg, 3.83 mmol), DMAP (467 mg, 3.83 mmol) and DIEA (3.04 mL, 17.39 mmol) in ethyl acetate (6.0 mL) was added T3P (6.14 mL, 10.43 mmol) at room temperature, and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitate was washed with diethyl ether/hexane to give tert-butyl 1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (994.1 mg, 2.026 mmol, 58.3%) as white crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[C:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II>C(Cl)Cl.O=[Mn]=O>[C:1]1([CH2:7][C:8]#[C:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC#CCc1ccccc1
Agent: O=[Mn]=O
Agent: II
Solvent: ClCCl
Product: O=CC#CCc1ccccc1
Temperature: 25 °C

Procedure:
4-Phenyl-2-butyn-1-ol (550 mg; 3.76 mmol, obtained as described in Bull. Soc. Chim. Fr, 1954, 816) was dissolved in DCM (10 mL) and MnO2 (1.64 g; 18.8 mmol) was added. The mixture was stirred at rt and the reaction was monitored by TLC (EtOAc/c-Hex 10/90, staining with iodine). MnO2 was regularly added (1.64 g; 18.8 mmol; three times). MnO2 was removed by filtration on a bed of celite. After washing the celite with DCM, the filtrates were then concentrated under reduced pressure. Purification of the crude by flash chromatography on silica (gradient EtOAc/c-Hex 5:95 to 30:70) gave the title compound as an range oil (60 mg, 11% yield). 1H NMR (CDCl3) δ: 9.22 (s, 1H), 7.26 (m, 5H), 3.80 (s, 2H).