Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]([Cl:24])[C:4]=1[CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]1=[O:17].B(Br)(Br)Br>ClC(Cl)C.ClCCl>[Cl:2][C:3]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([Cl:24])[C:4]=1[CH2:5][C@@H:6]1[CH2:10][CH2:9][N:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]1=[O:17]
Reactant: COc1cc(Cl)c(CC2CCN(N3CCCCC3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1N1CCCCC1
Yield: 76.5 %

Procedure:
Cool a solution of 3-(2,6-dichloro-4-methoxy-benzyl)-1-piperidin-1-yl-pyrrolidin-2-one hydrochloride (0.27 g) in dichloroethane (10 mL) to −20° C. and add 1 M solution of boron tribromide in dichloromethane (2.5 mL). Stir the reaction at −20° C. for 1 hour and at room temperature 12 hours. Partition the mixture with dichloromethane (20 mL) and saturated sodium bicarbonate (15 mL). Separate the organic layer. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum to afford 0.18 g (76%) of the title compound. MS (m/z): 343 (M+).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[O:11][CH:10]([CH2:15][CH3:16])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:15]([CH:10]1[O:11][CH:12]([CH3:14])[CH2:13][NH:8][CH2:9]1)[CH3:16]
Reactant: CCC1CN(Cc2ccccc2)CC(C)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC1CNCC(C)O1
Temperature: 65 °C

Procedure:
To a solution of 4-benzyl-2-ethyl-6-methyl-morpholine (Intermediate 496, 2.0 g, 9.13 mmol) in methanol (30 mL) was added ammonium formate (2.35 g, 10.77 mmol) followed by 10% Pd/C (1.0 g) and mixture was heated at 65° C. for 1 hour. It was cooled and filtered through celite pad, washed with excess methanol and concentrated. The residue thus obtained was distilled. Yield: 1.0 g (85%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[C-:12]#[N:13].[K+]>CN(C=O)C.C(Cl)Cl.[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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:12]#[N:13])[O:10][C:3]=12
Reactant: [C-]#N
Reactant: Clc1ccnc2cc(I)oc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc2nccc(Cl)c2o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a sealed tube 7-chloro-2-iodofuro[3,2-b]pyridine (0.200 g, 0.72 mmol), KCN (0.093 g, 1.4 mmol), and copper (I) iodide (0.014 g, 0.072 mmol) were dissolved in 2 mL DMF. Pd(Ph3P)4(0.041 g, 0.036 mmol) was added, the tube was flushed with nitrogen, and the reaction in the tube was stirred overnight at 100° C. The reaction was cooled to RT, diluted with DCM, and washed with water. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-50% EtOAc:Hex) to afford 7-chlorofuro[3,2-b]pyridine-2-carbonitrile as a white solid. MS: M+H+=179.4.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=2[O-])=[CH:10][CH:9]=1.C(N(CC)CC)C>>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:5]#[N:6])[N:14]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccccc1Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 14.8 %

Procedure:
Trimethylsilyl cyanide (12.42 g, 16.7 ml, 0.125 moles) was added dropwise to a solution of 2-p-chlorobenzyl-pyridine-N-oxide (11.0 g, 0.05 moles) and triethylamine (7.61 g, 10.5 ml, 0.075 moles) in acetronitrile (40 ml) at 20° C. After complete addition the mixture was heated under reflux for 48 hours, cooled to room temperature and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was washed with water and saturated sodium chloride and dried over anhydrous magnesium sulphate. Removal of the solvent gave a brown oil which was purified by column chromatography (silica gel eluted with hexane:ethyl acetate 9:1) to give 2-p-chlorobenzyl-6-cyanopyridine (1.69 g, 15%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:10](=O)[CH3:11].[NH2:13][NH2:14]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[C:10]([CH3:11])=[N:13][NH:14]2
Reactant: CC(=O)c1c(F)ccc(C)c1Cl
Reactant: NN
Solvent: CS(C)=O
Product: Cc1ccc2[nH]nc(C)c2c1Cl

Procedure:
A solution of 1-(2-chloro-6-fluoro-3-methylphenyl)ethanone (10 g, 53.6 mmol) and hydrazine (5.05 mL, 161 mmol) in DMSO (50 mL) was heated at 80° C. overnight. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to provide crude 4-chloro-3,5-dimethyl-1H-indazole as a white solid, which was used in the next step directly. MS (ESI+) m/z 180.9 (M+H)+. NaH (60% dispersion in mineral oil, 3.87 g, 97 mmol) was added portion wise to a solution of crude 4-chloro-3,5-dimethyl-1H-indazole (9.7 g, 53.7 mmol) in THF (200 mL) at −20° C. The mixture was allowed to warm to 0° C. and stir for 20 min, then TsCl (14.33 g, 75 mmol) was added. The reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was cooled to −20° C. and sat. NH4Cl aqueous solution was added to quench excess base. The resulting mixture was extracted with CH2Cl2 (2×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was triturated with EtOAc and filtered to provide 4-chloro-3,5-dimethyl-1-tosyl-1H-indazole. 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (d, J=8.34 Hz, 1 H) 7.84 (m, J=8.34 Hz, 2 H) 7.39 (d, J=8.59 Hz, 1 H) 7.25 (m, J=7.83 Hz, 2 H) 2.73 (s, 3 H) 2.46 (s, 3 H) 2.38 (s, 3 H); MS (ESI+) m/z 334.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[C:15](C)[C:14](OC)=[C:13](C)[CH:12]=3)[O:8][C:6]=2[N:7]=1.[Br:21]C1C=CC(C(Cl)=O)=CC=1>>[Br:21][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[N:10]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1c(C)cc(-c2nc3cnc(Cl)nc3o2)cc1C
Product: Clc1ncc2nc(-c3ccc(Br)cc3)oc2n1

Procedure:
The title compound was prepared as described in example 1, steps (a) and (b), using 4-bromo benzoyl chloride in step (a).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[N+:14]([O-])=O>C(O)C.[C].[Pd]>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:8]([NH2:14])=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1
Reactant: Cc1ccc(NCCCN(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NCCCN(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
10% of palladium-carbon (0.48 g) was added to a solution containing N1,N1-dimethyl-N3-(4-methyl-2-nitrophenyl)-1,3-propanediamine (2.37 g) in ethanol (20 ml) and the mixture was stirred for 4 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated, thereby yielding the entitled compound (2.054 g) as dark green solid.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:47])[N:29]([CH3:46])[CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:47])[N:29]([CH3:46])[CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1
Reactant: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (806.9 mg, 1.20 mmol) (obtained as described in Reference Example 58(3)) in anhydrous tetrahydrofuran (40 ml) were added successively acetic acid (0.09 ml, 1.57 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (1.44 ml, 1.44 mmol) in an ice bath, and then the mixture was stirred in the ice bath for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (15:1) as the eluant to afford 3-hydroxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (428.2 mg, yield 84%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=O.P(Cl)(Cl)([Cl:26])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[Cl:26]
Reactant: COc1ccc(OC)c(CCc2ccc3nc[nH]c(=O)c3c2)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1ccc(OC)c(CCc2ccc3ncnc(Cl)c3c2)c1

Procedure:
150 mg of 6-[2-(2,5-dimethoxyphenyl)ethyl]-3H-quinazolin-4-one are heated together with 5 ml of phosphorus oxychloride and 100 mg of phosphorus pentachloride at reflux for 30 minutes. The mixture is concentrated in vacuo and then partitioned between ice-cold 2 M aqueous pH 7 buffer and ethyl acetate. The organic layer is separated, dried and evaporated in vacuo to yield crude 6-[2-(2,5-dimethoxyphenyl)ethyl]-4-chloroquinazoline, which can be directly used in the following step or purified by chromatography (silica gel, cyclohexane/ethyl acetate=1/1). The crude intermediate is added to a solution of sodium isopropoxide (prepared from 8.3 mg of sodium in 20 ml of isopropanol) in isopropanol. The mixture is refluxed for 1 hour, concentrated in vacuo and poured onto water. Extraction with ethyl acetate yields the crude title compound, which is purified by chromatography on silica gel (cyclohexane/ethyl acetate=2/1) to give a colourless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Br[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([NH:39][CH2:40][CH3:41])=[N:31][CH:30]=1>>[CH2:40]([NH:39][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:30][N:31]=1)[CH3:41]
Reactant: CCNc1ncc(Br)c2ccccc12
Reactant: CC(C)(O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CCNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(C(C)(C)O)CC4)cc3n2)c2ccccc12

Procedure:
Following the procedures for 108, 2-(1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol and 4-bromo-N-ethylisoquinolin-1-amine were converted to 137. LCMS: M+H+=547. 1H NMR (400 MHz, DMSO) δ 9.03 (d, J=8.5, 1H), 8.67 (s, 1H), 8.28 (d, J=8.3, 1H), 7.68 (dd, J=16.9, 6.5, 2H), 7.51 (t, J=7.5, 1H), 7.37 (s, 1H), 4.04 (s, 1H), 3.93 (d, J=4.8, 4H), 3.80 (d, J=6.3, 6H), 3.65-3.54 (m, 2H), 2.99 (d, J=10.9, 2H), 2.07 (s, 1H), 1.97 (t, J=11.5, 2H), 1.67 (d, J=10.9, 2H), 1.36-1.12 (m, 6H), 1.04 (s, 6H)
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]#[CH:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:17])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCOC(C)=O.O.[Si]([N:29]=[N+:30]=[N-:31])(C)(C)C>>[CH:1]1([C:5]2[C:14]([C:15]3[CH:16]=[N:31][NH:30][N:29]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:17])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: C#Cc1cc(C(=O)OC)c(C)cc1C1CCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2cn[nH]n2)c(C2CCC2)cc1C
Temperature: 170 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate (compound 446.2, 180 mg, 0.69 mmol) was dissolved in TMSN3 (1 ml) in sealed tube. The reaction was heated to 170° C. for 24 hours behind a blast shield then cooled down to 0° C. EtOAc (10 ml) and water (20 ml) were added. The resulting mixture was stirred at RT for 1 hr. The organic phase was then washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (SiO2; 0-30% EtOAc in Hexane) to give 92 mg (49%) of the title compound as a liquid. m/z (ES+) (272) (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 3.90 (s, 4H), 2.69 (s, 3H), 2.27-2.15 (m, 2H), 2.13-2.03 (m, 2H), 1.99-1.90 (m, 1H), 1.86-1.76 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(Cl)Cl.C(C(C)=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2
Reactant: BrCCCBr
Reactant: CN1C(=O)Cc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(OCCCBr)ccc21

Procedure:
A mixture of 11.9 g of 5-hydroxy-1-methyl-2-indolinone, 29.2 g of 1,3-dibromopropane, 11 g of potassium carbonate, 1 g of potassium iodide and 75 ml of ethylmethyl ketone is refluxed for 20 hours. The mixture is then diluted with 300 ml of methylene dichloride, washed with water and the solvent is removed under reduced pressure.
Reaction SMILES: C([OH:3])C.[F:4][C:5]([F:49])([F:48])[C:6]1[CH:7]=[C:8]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:9][N:10]([C:35]1[N:36]=[N:37][N:38]([CH3:40])[N:39]=1)[C@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]2)[C:13]2[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[CH:32][C:12]1=2.[OH-].[Na+].C(O)(=O)C>O>[OH2:3].[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:8]([CH2:9][N:10]([C:35]2[N:36]=[N:37][N:38]([CH3:40])[N:39]=2)[C@@H:11]2[C:12]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:13]=3[N:14]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)[CH2:15][CH2:16][CH2:17]2)[CH:7]=[C:6]([C:5]([F:4])([F:49])[F:48])[CH:43]=1
Reactant: COC(=O)[C@H]1CC[C@H](CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)cc(C)c32)CC1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Charge a 250 mL flask equipped with an overhead stirrer, with ethanol (100 mL), (trans)-methyl 4-(((S)-5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)cyclohexanecarboxylate (10.0 g, 15.32 mmoles) and NaOH (2 M, 15.0 mL, 30.0 mmoles). Warm the resulting mixture to about 40° C. and stir at that temperature for about 4 hrs. Allow the reaction mixture to cool to RT. Add acetic acid (2.7 mL, 45.4 mmoles) and warm to 40° C. Add water (40 mL) slowly over 2.5 h to provide a thick, white slurry. Continue heating for an additional 1.5 h and then allow the slurry to cool to RT. Collect the solid by filtration and sequentially wash the solid with ethanol:water (20 mL, 1:1), water (20 mL). Suspend the solid in water (70 mL); collect the solid via filtration; then wash the solid with water (2×20 mL). Repeat to the water slurry two additional times. Collect the resulting solid and dry at 60° C. to provide the titled compound as a white solid (6.1 g).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:46].[Ca+2].[OH-:48]>C(Cl)Cl>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)(=[O:48])=[O:46])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCCCC(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCCCC(=O)OC)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of Step B above, (1.0 g, 2.05 mmoles) was dissolved in dry methylene chloride (25 ml) to which was added one equivalent of m-chloroperbenzoic acid in methylene chloride (10 ml). After 1 hour stirring at room temperature, additional m-CPBA (450 mg) was added. The reaction was complete in two hours Calcium hydroxide (1.0 g) was added and the reaction mixture was stirred for 10 minutes. The mixture was filtered and the filtrate concentrated. The residue was purified by chromatography to yield the title compound. NMR (CDCl3): 0.90 (3H, m), 1.50 (2H, m), 1.74 (4H, m), 2.33 (6H, m), 2.55 (3H, s), 3.03 (2H, m), 3.37 (2H, m), 3.68 (3H, s), 4.12 (2H, m), 6.39 (2H, d), 7.60 (2H, d), 8.12 (4H, m), 12.73 (1H, s).
Reaction SMILES: [H][H].[CH3:3][N:4]([CH2:11][CH:12]([OH:17])[CH2:13][N:14]=[N+]=[N-])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Pd].C(O)C>[CH3:3][N:4]([CH2:11][CH:12]([OH:17])[CH2:13][NH2:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: CN(CC(O)CN=[N+]=[N-])c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(CC(O)CN)c1ccccc1
Yield: 99 %

Procedure:
Hydrogen was introduced into a mixture of 1.85 g of 3-(N-methyl-N-phenylamino)-2-hydroxypropylazide (prepared as described in Preparation 89), 0.9 g of 10% w/w palladium-on-carbon and 30 ml of ethanol for 1.5 hours. At the end of this time, the atmosphere was replaced with nitrogen, the palladium-on-carbon catalyst was removed from the reaction mixture by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to give 1.6 g of the title compound which decomposed at 136° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][NH:6][C:7](=[O:20])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH3:22]>CO>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:7]([NH:6][CH2:5][CH2:4][C:3]([NH2:22])=[O:2])=[O:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)CCNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCC(N)=O
Reaction time: 48 h

Procedure:
A solution of 11 g of t-butyloxycarbonyl-L-prolyl-β-alanine methyl ester in 80 ml of methanol was saturated with ammonia gas at 0° C and stored for 2 days at room temperature. The solution was concentrated in vacuo and the residue crystallised from methanol/water. Yield: 9.8 g; melting point 175°-4 177° C; [α]D25 = -44.5° (c = 1 in dimethylformamide).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:9][CH2:10][CH2:11][CH2:12][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCOc1cccc(Br)c1
Yield: 57.5 %

Procedure:
A mixture of 5.0 g (0.029 mol) of 3-bromophenol, 29 ml (0.29 mol) of 1,3-dibromopropane and 12 g (0.087 mol) of potassium carbonate in 75 ml of acetone was stirred at reflux for 22 ours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was purified by HPLC using 3% ethyl acetate-hexane to give 4.9 g (58% yield) of 3-(3-bromopropoxy)bromobenzene. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14](B2OCC(C)(C)CO2)[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH:24]O>CO>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:24])[C:8]2[O:9][C:10]([F:13])([F:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: OO
Reactant: COC(=O)c1cc2c(c(B3OCC(C)(C)CO3)c1)OC(F)(F)O2
Solvent: CO
Product: COC(=O)c1cc(O)c2c(c1)OC(F)(F)O2
Reaction time: 0.5 h

Procedure:
6.0 g of 7-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester were dissolved using 200 ml of methanol and 30 ml of a 33% aqueous solution of H2O2 added. Stirring was continued for 30 minutes at room temperature. The reaction mixture was then concentrated to 20 ml and 100 ml of water and 100 ml of a saturated aqueous NaCl-solution added. The reaction mixture was then extracted three times using 100 ml of CH2Cl2 each, dried using MgSO4, and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 1.8 g of the title compound, colorless oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[I-].[Na+].C(N(CC)C(C)C)(C)C.[CH3:36][O:37][C:38]1[C:39]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[N:40][CH:41]=[N:42][CH:43]=1>C(#N)C>[CH3:23][N:22]([CH3:24])[S:19]([CH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:8][CH2:7][CH2:6][N:47]1[CH2:48][CH2:49][N:44]([C:39]2[C:38]([O:37][CH3:36])=[CH:43][N:42]=[CH:41][N:40]=2)[CH2:45][CH2:46]1)(=[O:21])=[O:20]
Reactant: COc1cncnc1N1CCNCC1
Reactant: CN(C)S(=O)(=O)Cc1ccc2[nH]cc(CCCOS(C)(=O)=O)c2c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(CS(=O)(=O)N(C)C)cc23)CC1
Yield: 60.9 %

Procedure:
To a solution of crude 3-[5-[[(dimethylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl methanesulfonate (1.4 mmol, 1.0 equiv.) in 10 mL of anhydrous acetonitrile was added 0.225 g (1.50 mmol, 1.1 equiv.) of sodium iodide, 0.26 mL (1.50 mmol, 1.1 equiv.) of N,N-diisopropylethylamine and 0.291 g (1.50 mmol, 1.1 equiv.) of 1-(5-methoxy-4-pyrimidinyl)piperazine. The mixture was heated to reflux for sixteen hours. The reaction mixture was concentrated in vacuo and the residue was taken up in 50 mL of ethyl acetate. The organic layer was washed with a 10 mL portion of 10% potassium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide to obtain 0.403 g (62%) of 1-[3-[5-[[(dimethylamino)sulfonyl]-methyl]-1H-indol-3-yl]propyl]-4-(5-methoxy-4- pyrimidinyl)piperazine. The hydrochloride salt was prepared by addition of 3N ethanolic HCl. Two recrystallizations from methanol gave 0.323 g (64%) of 1-[3-[ 5-[[(dimethyl-amino)sulfonyl]methyl]-1H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine hydrochloride hydrate, m.p. 210° C. (d). Elemental analysis calculated for C23H32N6O3S/3 HCl/0.5 H2O: C, 46.74; H, 6.14; N, 14.22; found: C., 46.82; H, 6.42; N, 14.09.