Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([N:15]=[N:16][C:17]1([N:23]=[C:24]=[S:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12].[N-]=C=S>CO>[C:11]([N:15]=[N:16][C:17]1([NH:23][C:24](=[S:25])[NH:10][NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: NNC(=O)c1ccccc1
Agent: [N-]=C=S
Solvent: CO
Product: CC(C)(C)N=NC1(NC(=S)NNC(=O)c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 4.02 grams (0.0295 moles) of benzoylhydrazine in 25 ml of methanol in a 50 ml erlenmeyer flask was added 6.82 grams (0.0295 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane and the reaction mixture stirred for 6 days at room temperature. The methanol was evaporated under reduced pressure leaving a pale yellow solid weighing 9.0 grams (75% crude yield). The product melted with decomposition at 190°-193° C. The infrared spectrum of the product had amide bands at 1640 and 1690 cm-1, a strong band at 1550 cm-1 [-N(H)CS] and weak NH bands from 3100-3300 cm-1. The isothiocyanate band at 2040 cm-1 was absent.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:40](=[O:39])[CH2:41][OH:42])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f47) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[S:10]1(=[O:16])(=[O:15])[CH2:14][CH2:13][CH2:12][NH:11]1.[OH-].C[N+](C)(C)CC1C=CC=CC=1>O.C(Cl)(Cl)Cl>[N:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH2:2][N:11]2[CH2:12][CH2:13][CH2:14][S:10]2(=[O:16])=[O:15])=[CH:5][CH:6]=1
Reactant: O=S1(=O)CCCN1
Reactant: C=C(C)c1ccncc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(CN1CCCS1(=O)=O)c1ccncc1
Reaction time: 16 h

Procedure:
A mixture of 4-isopropenyl pyridine (1.79 g) and isothiazolidine-1,1-dioxide (1.81 g) was heated at 130° C. during the addition of "Triton B" (Trade Mark, trimethylbenzylammonium hydroxide) (0.25 g added every hour for four hours; 40% solution in water). After stirring for 16 hours at 130° the mixture was cooled and taken in chloroform (50 cm3) and water (50 cm3). The aqueous phase was extracted with chloroform (3×20 cm3) and the dried (MgSO4) extracts were evaporated to given an oil. Chromatography on silica ("Merck 60. 9385") eluting with ethyl acetate gave 2-[2-(4-pyridyl)prop-1-yl]isothiazolidine-1,1-dioxide which crystallised from ethyl acetate-hexane as needles, m.p. 90°-92° (1.01 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[F:24][C:25]([F:29])([F:28])[CH2:26][NH:27][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22]
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NCC(F)(F)F)[nH]n1
Yield: 56 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using 2,2,2-trifluoroethylamine instead of morpholine, to the title compound (18 mg, 56%) which was obtained as an off white solid. MS: m/e=395.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6](C)[CH:7]=1.Cl[CH2:11][C:12](Cl)=[O:13].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][N:4]1[CH:3]2[O:9][CH2:11][C:12](=[O:13])[NH:1][C:2]2=[CH:7][CH:6]=[CH:5]1
Reactant: O=C([O-])[O-]
Reactant: Cc1cnc(O)c(N)c1
Reactant: O=C(Cl)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C=CC=C2NC(=O)COC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
3-amino-5-methyl-pyridin-2-ol (1.32 g, 10.6 mmol) was dissolved in 50 ml of anhydrous N,N-dimethyl formamide under nitrogen atmosphere, and chloroacetyl chloride solution (1.02 ml, 12.72 mmol) was added thereto dropwise at room temperature. After stirring for 30 minutes, potassium carbonate (3.7 g, 26.5 mmol) was added thereto dropwise at room temperature, and the reaction mixture was heated to 100□ and then stirred for 18 hours. The reaction mixture was cooled to room temperature and the reaction was quenched by adding water. The organic layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain straw yellow solid (424 mg). The resulting solid was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[OH:14].O[CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.O.[OH-].[Na+]>CS(O)(=O)=O.CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]([O:14][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CN1CCC(O)CC1
Reactant: OC(c1ccccn1)c1cc(OC(F)(F)F)ccc1F
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CN1CCC(OC(c2ccccn2)c2cc(OC(F)(F)F)ccc2F)CC1
Temperature: 145 °C
Reaction time: 7 h

Procedure:
A mixture of (2-fluoro-5-trifluoromethoxyphenyl)pyridin-2-ylmethanol (340 mg) and 4-hydroxy-1-methylpiperidine (273 mg) in methanesulfonic acid (1.5 mL) is heated in a sealed tube at 145° C. for 24 hours and then at 155° C. for 7 hours. The mixture is cooled back to room temperature, poured into water which is then made alkaline with concentrated sodium hydroxide solution. The aqueous phase is extracted with diethyl ether. Pooled extracts are dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5) to afford the pure base that is then converted into its dioxalate salt in acetone to give 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]pyridine, dioxalate melting at 45° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCCc1ccccc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 68.8 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0625 g, 0.213 mmol) and (3-bromopropyl)benzene (0.050 mL, 0.329 mmol) in 2 CH3CN/3 CHCl3 (5.0 mL) were reacted to give the desired product (0.0722 g, 72.2%). EI-MS m/z 412(M+) Rt (2.01 min).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([N:12]3[CH:16]=[N:15]C=N3)[CH:10]=2)[NH:5][CH:4]=1)=[O:2].[C:17]([O:21][C:22]([O:24]C(OC(C)(C)C)=O)=O)([CH3:20])([CH3:19])[CH3:18].[CH3:32][N:33](C1C=CC=CN=1)C>C(#N)C>[C:17]([O:21][C:22]([N:5]1[C:6]2=[CH:7][N:8]=[C:9]([N:12]3[CH:16]=[N:15][N:33]=[CH:32]3)[CH:10]=[C:11]2[C:3]([CH:1]=[O:2])=[CH:4]1)=[O:24])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN(C)c1ccccn1
Reactant: O=Cc1c[nH]c2cnc(-n3cncn3)cc12
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1cc(C=O)c2cc(-n3cnnc3)ncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 435.8 %

Procedure:
To a solution of 3-formyl-5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridine (1.1 g, 5.2 mmol) in acetonitrile (30 mL) was added di-tert-butyldicarbonate (1.69 g, 7.8 mmol) and dimethylaminopyridine (63 mg, 0.52 mmol) and the mixture was stirred at ambient temperature under nitrogen for 16 hours. The solvent was evaporated in vacuo and the residue chromatographed on silica eluting with a gradient of 2 to 5% MeOH in DCM to give a yellow solid. This was triturated with ether. The precipitate was collected by filtration to afford the title compound (0.71 g, 49%) as a cream solid. mp 170° C. (dec.). 1H NMR (360 MHz, d4 -MeOH) δ 1.76 (9H, s), 8.49 (1H, s), 8.80 (1H, s), 9.29 (2H, s), 9.34 (1H, s) and 10.12 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[P:17]([O-:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.O.O.O.O.O.O.O.[Cl-]>>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([P:17](=[O:32])([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)n1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1ccccc1
Agent: [Cl-]
Solvent: O
Product: Cc1cccc(C(Nc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A mixture of 6-methylpyridine-2-carboxaldehyde (2.12 g, 17.50 mmol), aniline (1.63 g, 17.50 mmol), diphenyl phosphite (4.92 g, 21.00 mmol), and zirconyl chloride octahydrate (0.56 g, 1.75 mmol) was stirred at room temperature 1 h. The reaction mixture was extracted with CH2Cl2 (3×50 mL), and the CH2Cl2 solution was washed with water (2×20 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give the titled compound (6.96 g, 92%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.51 (t, 1H, J=7.8 Hz), 7.38 (dd, 1H, J=7.6, 2.0 Hz), 7.27-7.22 (m, 4H), 7.19-7.15 (m, 2H), 7.14-7.07 (m, 4H), 7.05-7.02 (m, 3H), 6.80-6.74 (m, 3H), 5.53 (pseudo t, 1H, J=7.4 Hz), 5.36 (dd, 1H, J=21.0, 8.2 Hz), 2.54 (s, 3H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:19]2[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)=[CH:4][CH:5]=1)[CH2:10][CH3:11]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1ccc(C2CCC3(CC2)OCCO3)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Well-dried magnesium (14.5 g) and THF (100 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and heated to 40° C. 1-Bromo-4-propylbenzene (s14) (100.0 g) dissolved in THF (300 ml) was added dropwise in the temperature range of 40° C. to 60° C., and the stirring was continued for another 60 minutes. 1,4-Dioxaspiro[4.5]decan-8-one (s7) (78.4 g) dissolved in THF (150 ml) was slowly added dropwise in the temperature range of −5° C. to 0° C., and the stirring was continued for another 60 minutes. After the reaction mixture was allowed to come to room temperature, it was treated with an aqueous solution of ammonium chloride (3%), and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was mixed with p-toluenesulfonic acid (3.9 g) and toluene (300 ml), and the mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in a mixed solvent of toluene (250 ml) and Solmix A-11 (250 ml), to which Pd/C (5.0 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from heptane to give 8-(4-propylphenyl)-1,4-dioxaspiro[4.5]decane (s15) (68.0 g). The yield based on the compound (s14) was 52.0%.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:7]=[C:8]([CH:16]=[C:17](Br)[CH:18]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(N(CC)CC)C.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>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:3]#[C:2][CH2:1][OH:4])[CH:18]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(C#CCO)cc(C#CCO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
Pd(Ph3P)4 (1.08 g), CuBrSMe2 (0.41 g) and propargyl alcohol (2.95 g, 50.2 mmol) are added successively to a solution of tert-butyl 3,5-dibromobenzoate (A6, 7.7 g, 22.9 mmol) in triethylamine (130 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 3.5 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (50 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (5.7 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (7.5:2.5)], Rf=0.15.
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[Cl:24][C:25]1[CH:26]=[C:27]([C:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][CH3:47])[N:40]=2)=[O:38])[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36]>C(Cl)(Cl)Cl.O>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:30]2[CH:29]=[CH:28][C:27]([C:37]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][CH3:47])[N:40]=3)=[O:38])=[CH:26][C:25]=2[Cl:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COc1nc(C(=O)c2ccc(OCCCCO)c(Cl)c2)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1nc(C(=O)c2ccc(OCCCCOS(=O)(=O)c3ccc(C)cc3)c(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 70 %

Procedure:
Triethylamine (830 μL), trimethylamine hydrochloride (188 mg) and 4-methylbenzenesulfonyl chloride (555 mg) were sequentially added to a solution of [3-chloro-4-(4-hydroxybutoxy)phenyl](5-chloro-6-methoxypyridin-2-yl)methanone obtained in Reference Example 1-34(1) (360 mg) in chloroform (8 mL) under ice-cooling, and the mixture was stirred at room temperature for 4.5 hours. Triethylamine (150 μL) and 4-methylbenzenesulfonyl chloride (185 mg) were sequentially added under ice-cooling, and the mixture was stirred at room temperature for further 1.5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (357 mg, 70%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[N:1]1([CH2:7][CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCN1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 0.573 g (4 mmole) of 2-piperidin-1-yl-ethanol and 8 mL of pyridine at 0 degrees was added 0.763 g (4 mmole) of p-toluenesulphonyl chloride. The mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure and 10 mL of water was added. The mixture was extracted twice with 10 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give toluene-4-sulfonic acid 2-piperidin-1-yl-ethyl ester as a purple oil, which was carried to next step without further purification.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[Cl:18][C:19]1[CH:25]=[C:24]([CH:26]2[CH2:35][CH2:34][C:29]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:28][CH2:27]2)[CH:23]=[CH:22][C:20]=1[NH2:21].C(OCC)(=O)C>C1COCC1>[Cl:18][C:19]1[CH:25]=[C:24]([CH:26]2[CH2:35][CH2:34][C:29]3([O:30][CH2:31][CH2:32][O:33]3)[CH2:28][CH2:27]2)[CH:23]=[CH:22][C:20]=1[NH:21][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(C2CCC3(CC2)OCCO3)cc1Cl
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)cc1Cl)OCc1ccccc1
Yield: 72.2 %

Procedure:
Pyridine (2.18 mL, 26.9 mmol) and benzyl chloroformate (1.53 g, 8.96 mmol) were added sequentially, each in one portion, to a stirred solution of 2-chloro-4-(1,4-dioxaspiro[4.5]dec-8-yl)aniline (2.40 g, 8.96 mmol) in THF (30 mL) at 5° C. and the reaction mixture was stirred at 10° C. for 3 h. Ethyl acetate (75 mL) was added and the mixture was washed with H2O (2×30 mL) and brine. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a solid, which was purified by column chromatography, using a gradient of 20-50% ethyl acetate:isohexane as eluent, to give the title compound (2.6 g, 72%) as a white solid; 1H NMR δ 1.65-1.93 (8H, m), 2.49-2.6 (1H, m), 4.0 (4H, s), 5.25 (2H, s), 7.12 (1H, s), 7.15 (1H, dd), 7.25 (1H, d), 7.37-7.48 (5H, m), 8.08 (1H, d); MS m/e (M−H)− 400.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: CNC
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 95.7 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (4.14 g, 24.0 mmol) in ethanol (62 ml) in a sealed thick-walled tube, was added aqueous 40% dimethylamine solution (22.5 ml, 178 mmol, 7.4 eq) and the mixture heated in a 90° C. oil-bath for 2 days (CAUTION: High pressure). After cooling, additional 40% dimethylamine solution (7.5 ml) was added and heating continued for a further 3 days. The reaction mixture was cooled to room temperature and the contents were tipped onto ice (250 ml). After stirring the suspension was filtered, washed with water (200 ml) and dried under vacuum to give 5-dimethylamino-2-nitroaniline as a bright yellow solid (4.16 g, 96%), mp 138.5-139.8° C. (lit. (8) mp 140° C.).
Reaction SMILES: [O-:1][S:2]([O-:4])=[O:3].[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11](F)=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1.Cl>CCO.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([S:2]([OH:4])(=[O:1])=[O:3])=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)O
Temperature: 70 °C
Yield: 56.9 %

Procedure:
A suspension of Na2SO3 (3.26 g, 25.9 mmol) in EtOH (32 ml) and water (40 ml) was added to a solution of 5-chloro-2-fluoro nitrobenzene (2.0 g, 11.4 mmol) in EtOH (24 ml) and the mixture was heated at 70° C. for 16 h. After cooling, the mixture was acidified to pH=2 with conc. HCl (2 ml) and the solvent was removed in vacuo. The residue was diluted with brine solution (12 ml) and the mixture was heated under reflux for 2 h. The solution was cooled in ice bath and the resulting precipitate was collected by filtration to give the title compound (1.54 g, 57%) which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#N.[C:8](#N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:8]#[C:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccco1
Reactant: N#Cc1ccccc1
Product: C(#Cc1ccco1)c1ccccc1
Reaction time: 18 h
Yield: 74 %

Procedure:
The procedure was identical to Example 1, with the exception that 2-furonitrile (0.175 ml; 0.186 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 18 h at 65° C. showed the presence of 1.26 mmol (74% yield) of 2-(phenylethynyl)furan and no remaining 2-furonitrile in the reaction mixture.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([Cl:12])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10])[NH2:2].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:12][C:6]1[CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:3]2[N:4]([N:13]=[N:2][N:1]=2)[N:5]=1
Reactant: NNc1nnc(Cl)cc1C(=O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)nn2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To an ice-cold suspension of 3-hydrazino-4-carboxy-6-chloro-pyridazine (1.88 g; 0.01 mole) in 15% acetic acid, a solution of sodium nitrite (0.70 g) in water (5 ml) was added dropwise. After stirring for one hour at 5°-10° C. the separated precipitate was filtered, washed with anhydrous ethanol. The solid was suspended in 2 N HCl, the mixture was stirred for 30 minutes, the solid was stirred off, washed with cold water and dried under vacuum at 70° C. to give 1.73 g (87%) of the title compound, m.p. 225° C.