Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC)=O)=NC(OC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[S:41]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]O)[S:42]1>O1CCCC1.C1(C)C=CC=CC=1>[S:41]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[S:42]1
Reactant: OCCCCCC1CCSS1
Reactant: O=C1NC(=O)c2ccccc21
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.6 %

Procedure:
3.25 ml of dimethyl azodicarboxylate were added dropwise to a solution of 5.77 g of triphenylphosphine in 20 ml of tetrahydrofuran, whilst ice-cooling, and then the mixture was stirred at room temperature for 30 minutes. 3.24 g of phthalimide were then added to the reaction mixture, after which a mixture of 20 mmol of 5-(1,2-dithiolan-3-yl)pentanol (prepared as described in Preparation 1) in 30 ml of toluene and 10 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for one hour. The reaction mixture was allowed to stand overnight at room temperature, after which 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were added. The resulting mixture was stirred at room temperature for 7 hours and 30 minutes. 0.88 g of phthalimide, 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were then added to the reaction mixture. The reaction mixture was allowed to stand at room temperature for 4 days. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1:6 and 1:4 by volume mixtures of ethyl acetate and hexane as eluent. The solvent was removed from the eluate by distillation under reduced pressure, and 30 ml of toluene were added to the residue. 1 ml of the resulting mixture was weighed, and the solvent was removed from it by distillation under reduced pressure, to give 165 mg of the title compound as an orange oil having an Rf value of 0.35 (silica gel thin layer chromatography; using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:37])[C:18]([N:20]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][C:28]3[S:32][CH:31]=[N:30][CH:29]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:38][CH3:39].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:37])[C:18]([N:20]([C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][C:28]3[S:32][CH:31]=[N:30][CH:29]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:38][CH3:39]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCCCCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCCCC#Cc1cncs1)C(C)(C)C)CC2
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A solution of 530 mg of 16k in 9 ml of dioxane was mixed with a solution of 300 mg of KOH in 3 ml of water and stirred at 55° C. for ½ hr. The reaction mixture was diluted with 25 ml of water and acidified with 0.5N HCl to pH3 and the product was extracted with ethyl acetate. The extract was once washed with water, dried and concentrated, to give 480 mg of 16l as colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[S:13].C(N(C(C)C)C(C)C)C>>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[N:7]=[C:12]=[S:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1N=C=S
Yield: 47.5 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2-tert-butylaniline (5.0 g, 0.033 mol), thiophosgene (3.80 g, 0.033 mol) and N-ethyl di-isopropyl amine (8.5 g, 0.066 mol) to afford 3.0 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:13][N:11]1[CH:12]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:15][NH2:16])=[CH:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: NN
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2ccc(NN)nn2)cn1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a suspension of 3-chloro-6-(1-methyl-1H-pyrazole-4-yl)-pyridazine (21.0 g, 108 mmol) in ethanol (370 mL) was added hydrazine monohydrate (36 mL). The reaction mixture was stirred at reflux for 18 h, then cooled to room temperature. The precipitate was collected via filtration, washed with cold ethanol and dried in vacuo to provide 18 g of [6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine as a beige solid (87% yield): 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 4.28 (s, 2H), 7.02 (d, 1H), 7.59 (d, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.19 (s, 1H); MS (m/z) 191 [M+H+]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[N:23]=[C:24]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[C:17]=1[F:33])[CH2:13][O:14][CH3:15])(=[O:11])=[O:10].C([O-])(=O)C.[Na+].[Br:39]Br.[OH-].[Na+]>C(O)(=O)C>[Br:39][C:26]1[S:25][C:24]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[N:23][C:22]=1[C:18]1[C:17]([F:33])=[C:16]([N:12]([CH2:13][O:14][CH3:15])[S:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])(=[O:10])=[O:11])[CH:21]=[CH:20][CH:19]=1
Reactant: COCN(c1cccc(-c2csc(C3CCOCC3)n2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCN(c1cccc(-c2nc(C3CCOCC3)sc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Yield: 77.7 %

Procedure:
2,5-difluoro-N-{2-fluoro-3-[2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-N-(methoxymethyl)benzenesulfonamide (1.4 g, 2.808 mmol) was dissolved in acetic acid (28 mL), sodium acetate (461 mg, 5.616 mmol, 2 eq) was added and the mixture was stirred until complete dissolution. Bromine (0.2 mL, 3.9 mmol, 1.4 eq) was then added dropwise over 45 min and stirred at r.t. overnight. The reaction mixture was then added dropwise to a cooled 1 N solution of sodium hydroxide (300 mL) and the mixture was extracted with ethyl acetate. The organic phase was washed with 0.5 N sodium hydroxide, 5% NaHSO3 and brine, dried over Na2SO4 and evaporated to dryness, affording 1.26 g (78%) of the title product as colourless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[CH3:32][N+:33]([CH2:36][CH2:37][OH:38])([CH3:35])[CH3:34]>CO.O>[CH3:32][N+:33]([CH3:35])([CH3:34])[CH2:36][CH2:37][OH:38].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:27])[C:6]([C:28]([O-:30])=[O:29])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)[O-])cn(C5CC5)c4c3F)C2)nn1
Temperature: 25 °C

Procedure:
To a suspension of 1-cyclopropyl-6,8-difluoro-7-[3-(4-Methyl-1,2,3-triazol-1-yl)pyrrolidine-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (415.5 mg, 1 mmol) in 2.5 ml of methanol and 0.8 ml water at room temperature was added slowly 0.31 ml Of 45% N,N,N-trimethyl-2-hydroxyethyl-ammonium hydroxide in methanol (1 mmol). The solution was stirred at room temperature for an additional hour. This was filtered and the supernatant was evaporated under reduced pressure at 30° C. The residue was crystallized from acetone-methanol to yield after drying 420 mg of off-white solid, m.p. 188.7°-190.7° C. 1H NMR (D20) δ: 8.44 (s, 1H), 7.84 (bs, 1H), 7.62 (bd, 13.9Hz, 1H), 5.43-5.22 (m, 1H), 4.35-3.62 (m, 7H), 3.52 (t, 2H), 3.21 (s, 9H), 2.73-2.16 (m, 2H) 2.29 (s, 3H), 1.74-0.9 (m, 4H). Anal. calcd. for C25H32F2N6O4 . 1/2 H2O: C, 56.98; H, 6.31; N, 15.94. Found: C, 56.76; H, 6.26; N, 15.43.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[C:7]([N:11]=[C:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)N=C1CCCC1
Temperature: -55 °C
Reaction time: 6 h
Yield: 76.1 %

Procedure:
Cyclopentanone (13.3 mL, 150 mmol) and tert-butylamine (47.4 mL, 450 mmol) were combined in 110 mL diethyl ether under a nitrogen atmosphere and were then cooled to −55° C. in a dry ice/acetonitrile bath. Titanium tetrachloride (8.2 mL, 75 mmol) was taken up in 70 mL pentane and added dropwise to the above solution, being careful to maintain the temperature at −40° C. the reaction was then stirred at −40° C. for 6 h and was then allowed to warm to room temperature overnight. The reaction mixture was filtered through a short plug of celite and washed with diethyl ether. The filtrate was evaporated in vacuo to yield 15.9 g (76%) of the title product as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:16][N:17]([CH:34]([CH3:36])[CH3:35])[C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[C@H:11]([CH2:13][N:14]([C:40]([CH:37]2[CH2:39][CH2:38]2)=[O:41])[CH3:15])[CH2:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)C2CC2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R*,4R*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (134 mg, 0.264 mmol) in CH2Cl2 (2 mL), cyclopropanecarbonyl chloride (29 μL, 0.317 mmol) and triethylamine (44 μL, 0.317 mmol) are added under N2 atmosphere. The mixture is stirred overnight at RT, diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous one is extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is used in the next step without purification. TLC, Rf (CH2Cl2/MeOH 95:5)=0.2. MS (LC-MS): 476.1 [M+H-Boc]+. tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.42 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]#[C:5][CH2:6][O:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.[CH:19]1([N:26]=[N+:27]=[N-:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(Br)CCCCCC1.[N-]=[N+]=[N-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[N:26]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:27]=[N:28][C:5]=1[CH2:6][O:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:18]
Reactant: [N-]=[N+]=NC1CCCCCC1
Reactant: COC(=O)C#CCOC12CC3CC(CC(C3)C1)C2
Agent: BrC1CCCCCC1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(COC23CC4CC(CC(C4)C2)C3)nnn1C1CCCCCC1
Yield: 36 %

Procedure:
A solution of the product from step b (2.74 g, 11.1 mmol) and cycloheptyl azide (prepared by the reaction of cycloheptyl bromide and sodium azide) (1.54 g, 11.1 mmol) in toluene (14 ml) was heated under reflux for 42 hours. The solvent was removed invacuo and the residue purified by flash column chromatography (hexane:EtOAc 3:1) to yield 5-(adamantan-1-yloxymethyl)-3-cycloheptyl-3H-[1,2,3]triazole-4-carboxylic acid methyl ester (1.53 g, 36%). 1H NMR (CDCl3) 5.27-5.21 (1H, m), 4.73 (2H, s), 3.94 (3H, s), 2.20-2.11 (7H, m), 1.86-1.85 (8H, m), 1.69-1.60 (12H, m). Further eluation gave rise to 5-(adamantan-1-yloxymethyl)-1-cycloheptyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (2.00 g, 47%). 1H NMR (CDCl3) 4.93 (2H, s), 4.74-4.65 (1H, m), 3.94 (3H, s), 2.32-2.04 (8H, m), 2.00-1.54 (19H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]1=[O:23].[OH-:24].[Na+]>O1CCOCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:23])=[O:24])=[CH:17][CH:18]=1
Reactant: [OH-]
Reactant: C[C@H]1[C@@H](CCCc2ccc(Cl)cc2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccc(Cl)cc1)C(=O)O
Temperature: 23 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(4-chlorophenyl)-1-propyl)-4-methylazetidin-2-one (360 mg, 1.07 mmol) in dioxane (3.2 mL) is added 1 M aqueous sodium hydroxide (1.6 mL). The solution is stirred at 23° C. for 72 h, then extracted with hexanes (20 mL). The aqueous layer is acidified to pH 3 with saturated aqueous sodium bisulfate solution, and is extracted with two 30 mL portions of EtOAc. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4-chlorophenyl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (380 mg, 99% yield).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.O>C(C(C)=O)C(C)C>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:11][CH:12]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(=O)OCc1ccc(O)cc1
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=CC(=O)OCc1ccc(O[Si](C)(C)C)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1500 g of methyl isobutyl ketone and 100 g of 4-hydroxybenzyl acrylate werecharged into a separable flask of the same type as used in Reference Example 1, and cooled to -5° C. while replacing the flask inside gas with a nitrogen gas, and then 67 g of trimethylchlorosilane was dropwise added thereto over one hour, and then stirring was continued for 2 hours. After completion of the reaction, the reaction mixture was washedwith water and methyl isobutyl ketone was distilled off, whereby 83 g of p-trimethylsilyloxybenzyl acrylate of the following chemical formula was obtained (yield: 59%): ##STR10##
Reaction SMILES: C1[O:19][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)OC1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32]>C1COCC1>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=3)=[CH:14][N:13]=2)=[CH:9][CH:10]=1)=[O:19]
Reactant: Nc1ccc(Oc2ccc(C3OCCO3)cc2)nc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(5-amino-2-pyridyl)oxy]benzaldehyde ethylene acetal (5.27 g, 20.4 mmol) and triethylamine (3.41 mL, 24.5 mmol) in THF (80 mL) was added dropwise a solution of 3,4-dichlorobenzoyl chloride (4.49 g, 21.4 mmol) in THF (30 mL) under ice cooling. The resulting solution was stirred for 2 hours at the same temperature. The reaction solution was concentrated under reduced pressure, to the residue, 80% acetic acid (55 mL) was added, and the mixture was heated at 80° C. with stirring for 1 hour. The reaction solution was concentrated under reduced pressure and to the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from isopropanol, to thereby yield 5.63 g of the title compound.
Reaction SMILES: [C:1]1(O)[N:6]=[N:5][CH:4]=[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]=12.P(Br)(Br)(Br)=O.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:1]1[N:6]=[N:5][CH:4]=[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]=12
Reactant: Oc1nncc2cnccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=P(Br)(Br)Br
Product: Clc1nncc2cnccc12

Procedure:
A flask was charged with pyrido[3,4-d]pyridazin-1-ol (0.080 g, 0.54 mmol) (see Brzezinski, J. Z.; Bzowski, H. B.; Epsztajin, J. Tetrahedron, 1996, 52, 3261-72) and phosphorus oxybromide (0.62 g, 2.2 mmol) and heated at 80 C 2:30pm. Solid still stuck to walls of flask so 3 mL POCl3 was added and refluxed 4 h and the mixture concentrated in-vacuo. The mixture was quenched with ice and sat NaHCO3 and the brown solid collected. The solid is a mixture of the title compound and 1-bromopyrido[3,4-d]pyridazine (22 mg). MS (ESI pos. ion) m/z: 166 (MH+). Calc'd exact mass for C7H4ClN3: 165.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][NH:18][C@@H:17]3[CH2:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:27]1[C:31]2([CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1>>[N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([CH:34]4[CH2:35][CH2:36][C:31]5([O:30][CH2:29][CH2:28][O:27]5)[CH2:32][CH2:33]4)[C@@H:17]3[CH2:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [N-]=[N+]=NCCC[C@H]1NCC[C@@H]1Nc1nc(Cl)cc(N2CCCCCC2)n1
Product: [N-]=[N+]=NCCC[C@@H]1[C@@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)CCN1C1CCC2(CC1)OCCO2

Procedure:
The same procedure as a series of reactions of Example 9 was carried out, except that 4-azepan-1-yl-N-[(2R,3S)-2-(3-azidopropyl)pyrrolidin-3-yl]-6-chloropyrimidin-2-amine was used in place of the compound 8 and 1,4-dioxaspiro[4.5]decan-8-one was used in place of cyclohexanone in the process of Example 9, to obtain the title compound (1.25 g) having the following physical properties.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:10][CH2:11][CH:12]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:14]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:13]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[Br:39][CH:40]([CH2:47][CH3:48])[CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44]>C(#N)C>[Br-:39].[F:29][C:26]1[CH:25]=[CH:24][C:23]([N:14]2[C:13](=[O:30])[CH:12]([CH2:11][CH2:10][CH:9]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:15]2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:48][CH2:47][CH2:40][CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44])=[CH:18][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CCC(Br)CC[N+](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(O)cc1)c1ccc(F)cc1
Agent: [Br-]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(OCCCCC[N+](C)(C)C)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
370 mg of 3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 3 ml of absolute acetonitrile. 300 mg of KF•alumina (1.15 mol/100 g) and 375 mg of (3-bromopentyl)-trimethylammonium bromide are then added. The reaction mixture is stirred at room temperature overnight and then filtered. The mother liquor is concentrated using a rotary evaporator and the residue is purified using a 5 g SiO2 cartridge (dichloromethane/methanol 4:1). The product is obtained as an oil.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1>[Si:18]([O:7][CH:4]1[CH2:5][CH2:6][CH:1]([OH:8])[CH2:2][CH2:3]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](OC1CCC(O)CC1)(c1ccccc1)c1ccccc1
Temperature: 15 °C
Yield: 54 %

Procedure:
Into a 1000-mL 3-necked round-bottom flask was placed cyclohexane-1,4-diol (20 g, 172.18 mmol, 1.00 equiv), 1,4-dioxane (500 mL) and 1H-imidazole (17.58 g, 258.24 mmol, 1.50 equiv). This was followed by the addition of a solution of tert-butyl(chloro)diphenylsilane (49.69 g, 180.78 mmol, 1.05 equiv) in dioxane (100 mL) dropwise with stirring at 15° C. The resulting solution was stirred for 15 h at 15-20° C. The solids were filtered out. The filtrate was diluted with 200 mL of water. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:60-1:50-1:30-1:20). Purification afforded 32.98 g (54%) of 4-[(tert-butyldiphenylsilyl)oxy]cyclohexan-1-ol (74.1) as a white semi-solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:14].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[ClH:17].[Cl:14][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2ccnc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 11.3 parts of 4-(1H-imidazol-1-yl)benzenemethanol in 375 parts of trichloromethane was acidified with gaseous hydrogen chloride at room temperature. Then there were added dropwise 10.6 parts of thionyl chloride at room temperature. Upon completion, stirring was continued first for 30 minutes at reflux and further for 30 minutes at room temperature. The reaction mixture was evaporated. The residue was taken up a few times in methylbenzene and the latter was evaporated each time. The residue was stirred for 1 hour in 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo overnight, yielding 13.5 parts of 1-[4-(chloromethyl)phenyl]-1H-imidazole monohydrochloride (intermediate 20).