Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Br[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>C(#N)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:21][C:22](=[O:25])[CH2:23][CH3:24])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CCC(=O)CBr
Solvent: CC#N
Product: CCC(=O)COc1cc(N)c(Cl)cc1C(=O)NCCN(CC)CC
Reaction time: 2 h
Yield: 87.1 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (5.3 g, 10 mmoles) in acetonitrile (100 ml) was treated with 1-bromo-2-butanone (1.5 g, 10 mmoles) and stirred at 20° for 2 hours. The residue after concentration was treated with water and extracted with ethyl acetate and methylene chloride-2-propanol (5:1). The insoluble solid material was collected and combined with the organic extracts. Concentration of this mixture gave sticky crystalline material which was recrystallized from acetonitrile-water (4:1) to give the title product (3.1 g, 86%), mp. 103.0°-104.5°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:25])=[CH:22][Mg]Br>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:14]([OH:15])[CH:20]=[C:21]([CH3:25])[CH3:22])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=C[Mg]Br
Reactant: O=Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CC(C)=CC(O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 51 %

Procedure:
In an analogous manner to the procedure of Example II, 2.88 g (11.20 mmol) of 5-benzyloxy-2-nitrobenzaldehyde in 30 ml of THF are reacted at −78° C. with 31.7 ml (15.67 mmol) of a 0.5 M 2-methyl-propenylmagnesium bromide soln in THF to give 1.8 g (51%) of 1-[5-(benzyloxy)-2-nitrophenyl]-3-methyl-2-buten-1-ol.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:11])[CH:9]=[CH2:10].[CH3:12][CH:13]=[CH:14][PH:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[CH2:8]([O:11][PH:15]([CH2:14][CH:13]=[CH2:12])=[O:16])[CH:9]=[CH2:10]
Reactant: C=CCO
Reactant: CC=C[PH](=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCO[PH](=O)CC=C
Yield: 29.1 %

Procedure:
202 g of triethyl amine (2 mols) were added while stirring at 0° to 5° C. to a solution of 116 g of allyl alcohol (2 mols) in 1 l of anhydrous chloroform and then 249 g of methylvinyl phosphinic acid chloride (2 mols) were added dropwise over a period of about 1 hour. After suction filtration, the solid residue (triethyl amine hydrochloride) was dissolved in water, the emerging oily layer was separated and combined with the filtrate. To remove the chloride ions the filtrate was shaken 4 times, each time with 600 ml of water, dried over sodium sulfate and the chloroform was distilled off in a rotary evaporator. The brown oily residue was distilled under a pressure of 0.01 mm at a temperature of the oil bath of 40° C. 85 g of a colorless liquid were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[OH:24][C@@H:25]1[CH2:29][NH:28][C:27](=[O:30])[CH2:26]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:29][C@@H:25]([OH:24])[CH2:26][C:27]3=[O:30])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: O=C1C[C@H](O)CN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@@H](O)CC4=O)cc3)CC2)c(C)c1
Yield: 38.6 %

Procedure:
Using (4-bromophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.87 g) described in Preparation Example 170 and (S)-4-hydroxypyrrolidin-2-one (556 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (760 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.Cl[C:13](C(O[Na])=O)([F:15])[F:14].C1OCCOCCOCCOCCOCCOC1>CC#N>[Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=[N:8]\[C:9](=[O:11])[CH3:10])/[N:6]([CH:13]([F:15])[F:14])[CH:7]=1
Reactant: O=C(O[Na])C(F)(F)Cl
Reactant: CC(=O)Nc1ccc(Br)cn1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CC#N
Product: CC(=O)/N=c1\ccc(Br)cn1C(F)F

Procedure:
To a stirred solution of N-(5-Bromo-pyridin-2-yl)-acetamide (1 g, 4.6 mmol) in 30 ml CH3CN was added ClCF2COONa (848 mg, 5.58 mmol), followed by 18-Crown-6 (244 mg, 0.93 mmol). The reaction mixture was heated to reflux for 12 hrs. Then the reaction mixture was cooled down and the solvent was removed under reduced pressure. To this was added methylene dichloride and washed with water. Organic layer was dried over any sodium sulphate and concentrated under reduced pressure to furnish the crude N-[5-Bromo-1-difluoromethyl-1H-pyridin-(2E)-ylidene]-acetamide. This was carried to the next step without purification.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.C(O)(=O)C.[CH2:19]([NH2:22])[CH2:20][CH3:21]>O>[CH2:19]([NH:22][C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1)[CH2:20][CH3:21]
Reactant: CCCN
Reactant: CCOC(=O)c1cnc(SC)nc1O
Solvent: CC(=O)O
Solvent: O
Product: CCCNc1ncc(C(=O)OCC)c(O)n1

Procedure:
2-Methylthio-5-ethoxycarbonyl-4-hydroxypyrimidine (2 mmol, 428 mg) was heated on an oil bath at 160° C. with n-propylamine acetate (1 ml) for 1 hour. The semi solid was cooled and then treated with 50 ml boiling water, and the solid product was filtered off (yield 400 mg, 88%)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:25])[N:3]=[CH:4]2)=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccnc1
Reactant: NC(=O)c1c(N)ncn1Cc1ccc(F)cc1
Product: NC(=O)c1c(NC(=O)c2cccnc2)ncn1Cc1ccc(F)cc1
Yield: 79 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 1.50 g (6.38 mmol) of 4-amino-1-(4-fluorobenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 58 and nicotinic acid instead of cyclopentylacetic acid to obtain 1.70 g of 1-(4-fluorobenzyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>>[O:12]=[C:11]1[NH:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(N)c(N)c1
Product: N#Cc1ccc2[nH]c(=O)[nH]c2c1

Procedure:
3,4-Diaminobenzonitrile (3.171 g, 23.8 mmol, Oakwood) was reacted with 1,1′-carbonyldiimidazole (3.862 g, 23.8 mmol, Aldrich) under the conditions of Example 1b to give the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 160 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]#[N:13])[CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:15][OH:16].C(N(CC)CC)C>CO>[NH2:13][C:12](=[N:15][OH:16])[C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH:11]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cncc(C#N)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1cncc(C(N)=NO)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Ethyl-(5-cyano-3-pyridyl)carboxylate) (WO 96/30372) (1.8 g, 10.2 mmol) was dissolved in methanol (50 mL), the solution was cooled to 0° C. then hydroxylamine hydrochloride (0.71 g, 10.2 mmol) and triethylamine (1.4 mL, 10.2 mmol) were added and the mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (graded elution of dichloromethane/methanol 95:5 to 93:7) to give the title compound as a white solid which contained 0.3 equivalents of triethylamine hydrochloride (2.5 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][CH:47]=2)=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:64][CH:65]4[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]4)=[O:52])=[CH:48][CH:47]=2)=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]benzoic acid, (Intermediate 129; 123 mg, 0.3 mmol) DIPEA (261 uL, 1.5 mmol) and 4-amino N-methylpiperidine (43 mg, 0.375) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was eluted from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave a pale yellow amorphous solid. (100 mg, 66%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:29]([OH:30])([CH3:31])[CH3:28])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(C)(C)O)nc3N21
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
A solution of 0.30 g (0.81 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 5 ml tetrahydrofuran was cooled to −78 deg C. and treated with 0.61 ml (0.98 mmol) n-butyllithium solution (1.6 M in n-hexane). After 30 min, 80 μL (71 mg, 1.22 mmol) acetone was added. After 30 min, the reaction was quenched with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The solvent was removed on a rotary evaporator and the residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to afford the compound as a light yellow foam (24.4%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[C:9]1([CH3:24])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[NH2:16].O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:16]/[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: Cc1ccccc1C(N)c1ccccc1C
Reactant: O=Cc1ccccn1
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(/N=C/c1ccccn1)c1ccccc1C

Procedure:
In air, 2-pyridinecarboxaldehyde (36.0 mg, 32.0 μL, 0.336 mmol, 1.00 equiv) was added to a solution of di-o-tolylmethanamine (73.1 mg, 0.346 mmol, 1.03 equiv) in CH2Cl2 (5 mL). After heating at reflux for 30 min with azeotropic removal of water using a Dean-Stark trap, the reaction mixture was concentrated under reduced pressure and dried under high vacuum to give ligand (L-3), (E)-N-(Pyridin-2-ylmethylene)-1,1-dio-tolylmethanamine, as a yellow oil (0.102 g, 98% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([OH:14])=[O:13])[C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29](Cl)=[O:30]>C1COCC1>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29]([O:13][C:12]([C@@H:10]1[CH2:11][C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1([CH3:16])[CH3:15])=[O:14])=[O:30]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OC(=O)c2c(Cl)cc(Cl)cc2Cl)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (1R,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcyclobutanecarboxylic acid (about 0.450 g, 1.97 mmol) and DIPEA (about 1.01 ml, 5.92 mmol) in THF (about 4 ml) and 2,4,6-trichloro benzoyl chloride (0.35 ml, 2.17 mmol) were added at 0° C. and the reaction mixture was allowed to stir at room temperature for about 6 hours, after completion of the reaction (monitored by TLC), the solvent was evaporated and crude product proceeded as such for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:10][C@@H:9]2[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[C@H:9]([OH:10])[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1O[C@@H]1c1cccc(Cl)c1
Reactant: c1ccc2c(c1)CCN2
Product: OC[C@@H](O)[C@H](c1cccc(Cl)c1)N1CCc2ccccc21
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
[(2R,3R)-3-(3-chlorophenyl)oxiran-2-yl]methanol (4.8 g, 26 mmol) and indoline (d 1.063, 2.9 mL, 26 mmol) were heated neat at 135° C. in a sealed flask. After 1.5 hours, the cooled mixture was pre-adsorbed on silica gel (25 g). Flash column chromatography (silica 375 g, 20%, 40%, 80% ethyl acetate/hexanes) provided (2S,3S)-3-(3-chlorophenyl)-3-(2,3-dihydro-1H-indol-1-yl)propane-1,2-diol (5.8 g, 73%) as a white solid. MS (ES) m/z 304 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[CH3:11][Si:12]([CH3:21])([CH3:20])[C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1>>[CH2:9]([C:6]1([NH:19][C@H:16]2[CH2:15][CH2:14][C@@H:13]([Si:12]([CH3:21])([CH3:20])[CH3:11])[CH2:18][CH2:17]2)[NH:5][CH:4]=[N:3][CH:2]=[C:7]1[I:8])[CH3:10]
Reactant: C[Si](C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CCc1ncnc(Cl)c1I
Product: CCC1(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)NC=NC=C1I

Procedure:
Prepared as in Example 1 from 4-chloro-5-iodo-6-ethylpyrimidine and cis-4-trimethylsilylcyclohexylamine (yellow oil). The following compounds were further prepared analogously:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:23])[CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[S:5][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:23])[CH2:9][N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc(NC(=O)CN2CCNCC2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(2-(4-methylthiazol-2-ylamino)-2-oxoethyl)piperazine-1-carboxylate (0.072 g, 0.21 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h, then the solvents were removed under reduced pressure to afford N-(4-methylthiazol-2-yl)-2-(piperazin-1-yl)acetamide (a semi-solid material) that was dried in vacuo. To a mixture of this material (supposedly 0.20 mmol) and isopropanol (3.5 ml) was added 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) followed by diisopropylethylamine (0.14 ml, 0.80 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 20% ethyl acetate in dichloromethane. The title compound was obtained as an orange solid (0.044 g, 54%). 1H-NMR (500 MHz, DMSO-d6) 2.26 (s, 3H, CH3), 2.65 (br s, 4H, piperazine N(CH2)2), 3.10 (br s, 4H, piperazine N(CH2)2), 3.33 (s, 2H, NCH2CO), 6.76 (s, 1H, thiazole 5-H), 6.96 (br s, 2H, NH2), 8.07 (s, 1H, 6-H), 11.75 (s, 1H, CONH);
Reaction SMILES: [H-].[Na+].[CH3:3]I.[C:5]([O:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C)C=O>[C:5]([O:9][C:10]([N:12]([CH3:3])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CI
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
A procedure similar to that described in Preparation 7 was repeated, except that 0.46 g of sodium hydride (as a 55% w/w dispersion in mineral oil), 15 ml of dehydrated dimethylformamide, 0.66 ml of methyl iodide and a solution of 1.9 g of N-t-butoxycarbonyl-4-methoxy-2-nitroaniline (prepared as described in Preparation 22) in 15 ml of dehydrated dimethylformamide were used, to give 2.0 g of the title compound having an Rf value=0.34 (on thin layer chromatography on silica gel; developing solvent: a 1:5 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl.[CH2:14]([N:21]([CH2:25][CH2:26]Cl)[CH2:22][CH2:23]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.CS(C)=O>[CH2:14]([N:21]1[CH2:25][CH2:26][C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)([C:11]#[N:12])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Yield: 84.7 %

Procedure:
To a suspension of 9.8 g of 60% sodium hydride in oil in 140 ml of THF and 60 ml of DMSO is added dropwise, at rt, a solution of 11.3 g of 4-chlorophenylacetonitrile and 20 g of benzyl[bis(2-chloroethyl)]amine hydrochloride in 140 ml of THF and 60 ml of DMSO, and the mixture is then heated at 70-80° C. for 2 hours. After cooling, the reaction mixture is poured onto ice and extracted with ether, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture (90/10; v/v). 19.6 g of the expected compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: COc1ccc(B(O)O)cc1
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C)nn3c(-c4ccc(F)c(F)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 85 °C
Reaction time: 6 h
Yield: 97.7 %

Procedure:
(S)-(1-(7-(3,4-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (62 mg), 4-methoxyphenylboronic acid (27 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (8 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred for 6 hours under argon atmosphere at 85° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure, concentrated and purified by column chromatography to yield the target compound (58 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([CH3:34])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:32]=1[CH3:33]>CCCCCC.CC(O)C>[NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([CH3:34])[C:5]2[O:9][C@@:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:32]=1[CH3:33]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2
Solvent: CCCCCC
Solvent: CC(C)O
Product: Cc1c(C)c2c(c(C)c1N)C[C@@](C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2

Procedure:
1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphenylmethyl)-4-piperidinamine was subjected to preparative high-performance liquid chromatography (column: CHIRALCEL OD (20×250 mm, Daicel Chemical Industry, Ltd.), mobile phase: hexane-2-propanol=95:5); flow rate: 80 mL/min., column temperature: 30° C.) to provide the title compound.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Cl)ccc1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,5-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,5-dichlorobenzoyl)-3,4-dibromohexahydrophthalimide.