Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17]CC1.CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:21]1[CH2:22][CH2:23][C:18](=[O:17])[CH2:19][CH2:20]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCN(c2cnccn2)CC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
A mixture of 20 g (0.1746 mol) of chloropyrazine, 36 g (0.260 mol) of K2CO3, 76 g (0.5308 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, and 80 ml of dimethylformamide is stirred at 100° C. for 3 days. The reaction mixture is cooled, diluted with water, and extracted with ethyl acetate. The combined extracts are washed with water, dried over Na2SO4 and concentrated in vacuo. The residue, 400 ml of 10% sulfuric acid solution and 100 ml of tetrahydrofuran are stirred at ambient temperature for 4 days, diluted with water, basified (NaOH) and extracted with methylene chloride. The extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ether gives 8.4 g of title compound: IR (KBr) 1720 and 1580 cm-1 ; NMR (CDCl3) δ 8.24-7.88 (m, 3H), 3.98 (t, 4H), and 2.56 (t, 4H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([CH2:30]O)[CH:24]=[C:23]4[CH3:32])=[N:16][CH:17]=2)=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([CH2:30][N:43]3[CH2:44][CH2:45][CH:40]([CH3:39])[CH2:41][CH2:42]3)[CH:24]=[C:23]4[CH3:32])=[N:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC1CCNCC1
Reactant: Cc1cc(CO)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(CN2CCC(C)CC2)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16 μL (0.20 mmol) of thionyl chloride was added at RT to a solution of 50 mg (0.13 mmol) of {6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methylquinolin-2-yl}methanol and 52 μL (0.65 mmol) of pyridine in 3 mL of DCM and the mixture was stirred for 2 hours at RT. The reaction mixture was diluted with DCM, and the organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The residue was taken up in 3 mL of DMF, combined with 60 μL (0.51 mmol) of 4-methylpiperidine and stirred for 16 hours at RT. The reaction mixture was evaporated down in vacuo, diluted with DCM, and the organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, gradient DCM/MeOH/sat. aqueous ammonia 100:0:0 95:5:0.5) and HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). Yield: 4 mg (7% of theoretical); C30H28ClN3 (M=466.016); calc.: molpeak (M+H)+: 466/468 (Cl); found: molpeak (M+H)+: 466/468 (Cl); Rf value: 0.38 (silica gel, DCM/MeOH/sat. aqueous ammonia 9:1:0.1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[CH3:3].Cl[C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=1>>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:13]2[CH:14]=[C:15]([NH2:19])[N:16]=[CH:17][N:18]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: Nc1cc(Cl)ncn1
Product: CN(C)Cc1cccc(Nc2cc(N)ncn2)c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 152A but using 3-dimethylaminomethyl-phenylamine, 6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixture for 2 h at 150° C. The crude product is purified by trituration in diethyl ether followed by silica gel column chromatography (DCM/MeOH+1% NH3aq, 92:8) of the resulting beige solid to afford the title compound as a white solid. ESI-MS: 242.1 [MH]−; tR=0.95 min (purity: 100%, gradient J); TLC: Rf=0.11 (DCM/MeOH+1% NH3aq, 92:8).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].O>C1COCC1>[C:23]1([O:22][C:20](=[O:21])[NH:1][C:2]2[C:11]3[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc2c1CC(O)CC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1CC(O)CC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a stirred solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (30.0 mg, 0.18 mmol) and pyridine (21.8 mg, 0.28 mmol) in 1.0 mL THF was added phenyl chloroformate (30.2 mg, 0.19 mmol), and the mixture was stirred for 1 hour at room temperature. To the product mixture was added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate and hexane to afford (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)carbamic acid phenyl ester (25.2 mg, 48% yield).
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[OH:6][C@@:7]([C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([C:47]([NH:49][CH3:50])=[O:48])[CH:43]=2)[CH:38]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[CH2:8][C:9](OC)=[O:10].Cl>C(OCC)(=O)C.O.C1COCC1.C(O)C>[OH:6][C@@:7]([C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([C:47]([NH:49][CH3:50])=[O:48])[CH:41]=[CH:40]2)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[CH2:8][CH2:9][OH:10]
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
0.095 g (2.51 mmol, 8 eq) of sodium borohydride was added to 1.3 mL of ethanol and 1.3 mL of THF. 0.14 g (1.26 mmol, 4 eq) of calcium chloride was added at 0˜5° C., and the mixture was stirred at the same temperature for 30 minutes. 0.188 g (0.314 mmol) of methyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate was added at 0˜5° C., and the mixture was stirred for 30 minutes. The mixture was stirred at room temperature for 4.5 hours. 7 mL of water was added dropwise at 35° C. or lower. 2.5 mL of 1N hydrochloric acid was added dropwise, followed by dilution with 10 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 2 mL of an aqueous saturated sodium bicarbonate solution and 2 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, the concentration residue was loosened with 2 mL of IPE, crystals were filtered, and washed with 1 mL of IPE. Vacuum drying (40° C.) to a constant weight afforded 0.16 g of 6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (yield 90%).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N+:10]([CH3:18])[N:9]([CH3:19])[C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+].[CH3:28]I.O>CS(C)=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:28][O:6][C:7]1[C:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N+:9]([CH3:19])[N:10]([CH3:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: Cn1c(-c2ccccc2)c(O)c(-c2ccccc2)[n+]1C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(-c2ccccc2)n(C)[n+](C)c1-c1ccccc1
Temperature: 60 °C
Yield: 53 %

Procedure:
4-Hydroxy-1,2-dimethyl-3,5-diphenylpyrazolium perchlorate (7 g, 0.02 mole) in DMSO (2.5 ml) is added to 5% sodium hydroxide (0.84 g, 0.02 mole) in DMSO (100 ml), dropwise with stirring. The mixture is warmed to 60°C for 5 minutes, then stirred at room temperature for 4 hours. The reaction mixture (75 ml) is treated with methyl iodide (0.43 g, 0.013 mole) and the mixture is stirred at room temperature for 16 hours, then heated at 40°C for 2 hours. On pouring into water, a solid precipitates with melting point 88°C. One crystallization from methanol gives the product with melting point 132°-132.5°C in 53% yield.
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:5]([C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([O:13]C)=[O:12])=[O:7])=[CH:4][C:3]=1[Br:18].O.[OH-].[Li+].[K+].[Br-]>O.O1CCCC1>[NH2:1][C:2]1[C:3]([Br:18])=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[O:7])=[CH:15][C:16]=1[Br:17]
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)c1cc(Br)c(N)c(Br)c1
Agent: [Br-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Br)cc(C(=O)[C@@H]2C[C@H]2C(=O)O)cc1Br
Yield: 76 %

Procedure:
Prepared analogously to Example 2 from methyl trans-2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarboxylate by saponification with lithium hydroxide hydrate in a water-tetrahydrofuran mixture (2/3 v/v) in a yield of 76% of theoretical. Colorless crystals. IR (KBr): 3473.2, 3345.9 (NH2); 1714.4 (C═O) cm−1.
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Na].[C:11]([C:14]1[N:15]2[CH:18]([S:19][CH2:20][C:21]=1[CH2:22][S:23][C:24]1[N:28]([CH3:29])[N:27]=[N:26][N:25]=1)[CH:17]([NH:30][C:31](=[O:39])[CH2:32][C:33]1[S:34][C:35](=[O:38])[S:36][CH:37]=1)[C:16]2=[O:40])([OH:13])=[O:12]>CN(C)C=O>[CH3:29][N:28]1[C:24]([S:23][CH2:22][C:21]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:40])[CH:17]3[NH:30][C:31](=[O:39])[CH2:32][C:33]3[S:34][C:35](=[O:38])[S:36][CH:37]=3)[C:14]=2[C:11]([O:13][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:12])=[N:25][N:26]=[N:27]1
Reactant: CC(C)(C)C(=O)OCI
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Temperature: 5 °C
Yield: 30.7 %

Procedure:
A solution of iodomethyl pivalate (8.65 g.) in dimethylformamide (70 cc.) is added to a solution of the sodium salt of 2-carboxy-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (18.2 g.) in dimethylformamide (115 cc.) over the course of 15 minutes, whilst maintaining the temperature at 5° C. The mixture is allowed to react for one hour at 5° C. and is then concentrated to dryness under reduced pressure (0.5 mm Hg). The residue is taken up in ethyl acetate (500 cc.). The mixture is washed successively with water (600 cc.), a saturated aqueous sodium bicarbonate solution (500 cc.) and water (900 cc.). It is dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg). The residue obtained is chromatographed on silica (450 g.), elution being carried out successively with a mixture of cyclohexane and ethyl acetate (6/4 by volume) (1 liter) and then with a mixture of cyclohexane and ethyl acetate (4/6 by volume) (4 liters). The eluates are concentrated to dryness under reduced pressure (20 mm Hg). A residue (12.7 g.) is obtained in the form of a frothy solid which is crystallised from a mixture of ethyl acetate and ether (1/1 by volume) (120 cc.). A white crystalline product (7.4 g.) is obtained, which when dried at 30° C. under 0.5 mm Hg retains about 3% of ethyl acetate. The product is treated overnight with water (250 cc.) while stirring and the crystals are filtered off and then dried (35° C.-0.5 mm Hg). 3-[(1-Methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-2-pivaloyloxymethoxycarbonyl-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (6.6 g.), m.p. 100° C. is thus obtained. [α]D20 = -21.6° ± 0.8° (c= 1, dimethylformamide).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(O[N:31]1[C:36](=[O:37])[CH2:35][CH2:34][C:32]1=[O:33])=[N+](C)C)C>CN(C=O)C>[CH2:35]1[C:36](=[O:37])[N:31]([O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:8])[C:32](=[O:33])[CH2:34]1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(ON1C(=O)CCC1=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To the solution of 4-iodobenzoic acid (1)(1.24 g, 5.0 mmol) and triethylamine (0.71 mL, 5.0 mmol) in DMF (30 mL) was added TSTU (1.51 g, 5.0 mmol). The solution was stirred at room temperature for 2 hours. The reaction was quenched by addition of 10% HCl (50 mL). The precipitate was collected by filtration, washed with water and dried in vacuo to yield the title compound (2) as a white powder (1.42 g, 82%); m.p. 130-132° C.; vmax/cm−1(neat) 1769 (C═O, ester), 1719 (C═O, amide); (Found C, 38.40; H, 2.41; N, 4.15. C11H8INO4 requires C, 38.28; H, 2.34; N, 4.06%.); δH (300 MHz, CDCl3) 7.92 (2H, d, J 12.0 Hz, H2/6), 7.85 (2H, d, J 12.0 Hz, H3/5), 2.92 (4H, s, CH2); δc (75 MHz, CDCl3) 169.0 (OCO), 162.0 (NCO), 138.7 (C2/6), 132.0(C3/5), 125.3 (C1), 103.3(C4), 26.0 (CH2); m/z (E.I.), 345 (M+, 5%), 231 (100%), 202 (20%), and 76 (48%); HRMS for C11H8INO4 requires 344.9493 found 344.9493.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH3:17])=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(N)C>C(Cl)(Cl)(Cl)Cl.C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:12]([NH:11][C:10]([CH3:16])([CH3:15])[C:9]#[CH:17])(=[O:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC1(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCN
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C#CC(C)(C)NS(=O)(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
To a solution of 5-(4-Chloro-phenyl)-3,3,4-trimethyl-2,3-dihydro-isothiazole 1,1-dioxide, 1.5 g (5.5 mmol) in 150 mL of carbon tetrachloride was added 1.5 g (8.25 mmol) of N-bromosuccinimide and 0.13 g of 2,2′-azobis(2-methyl-propionitrile). The mixture was heated to reflux for 4 h then cooled to ambient temperature. Chloroform was added and the solution was washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. To a solution of the residue in 75 mL of absolute ethanol was added 3.6 mL (55.0 mmol) of ethylamine (70% solution in water). The reaction mixture was stirred 24 h at ambient temperature then concentrated to dryness. The residue was purified by chromatography on silica gel with methanol/chloroform as eluant to yield 0.21 g (12%) of the desired product, shown below, as a tan oil. 1H-NMR is consistent with structure; MS (ion spray) 313.0 (M−1); Anal. Calc'd for C14H19ClN2O2S.0.1CHCl3: C, 51.83; H, 5.89; N, 8.57. Found: C, 51.58; H, 6.38; N, 8.04.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:33][CH2:34]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:11]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(S(C)(=O)=O)CC3)nc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (40 mg, 0.075 mmol) in dichloromethane (1 mL) at 0° C., DIPEA (0.2 mL, 1.1 mmol), and methanesulfonyl chloride (0.007 mL, 0.009 mmol) were added. The mixture was then stirred at room temperature for 3 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 97/3) to 26 mg of the title compound. (64% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.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.O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: OB(O)c1cccc(F)c1
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: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(-c2cccc(F)c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of (3-fluorophenyl)boronic acid (790 mg, 3.57 mmol, 1.0 eq), 3-bromobenzoic acid (790 mg, 3.93 mmol, 1.1 eq) and Na2CO3 (142 mg, 1.03 mmol, 2.5 eq) in a mixture of EtOH (2.5 mL), DMF (10 mL) and H2O (2.5 mL) was added Pd(PPh3)4 (170 mg, 0.18 mmol, 0.05 eq). The mixture was stirred at 100° C. overnight. Water was added and the aqueous layer was extracted with EtOAc and the organic extract was discarded. The aqueous layer was acidified to pH 4-5 with 1M HCl and extracted with EtOAc. The combined organic extracts were filtered through silica gel and evaporated in vacuo to give the title compound as a white solid (440 mg, 56%).
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[CH:9]=[CH:10][C:11]=2[N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:24]([O:26]CC)=[O:25].Cl.O1CCCC1>C(O)C>[CH3:23][C:8]1[CH:9]=[CH:10][C:11]([N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:16])=[C:12]2[C:7]=1[CH:6]=[C:5]([C:24]([OH:26])=[O:25])[NH:4]2
Reactant: CCOC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A solution of ethyl 1-(methoxymethyl)-4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (4.0 g), 6N hydrochloric acid (20 ml), tetrahydrofuran (20 ml) and ethanol (60 ml) was stirred at 80° C. for 4 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was dissolved in a mixed solvent of tetrahydrofuran (40 ml) and methanol (40 ml), an aqueous solution (20 ml) of 85% potassium hydroxide (2.2 g) was added to this solution, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was acidified with aqueous citric acid solution. The precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (3.3 g, yield 99%) as colorless crystals. MS: 351 (MH+). melting point 223-225° C.
Reaction SMILES: [OH:1][C:2]1([C:8]#[C:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH2:19][C:20]#[CH:21])=[C:12]([NH2:22])[N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:23]N1C(=O)CCC1=O.C([O-])(=O)C.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[Cl:23][C:15]1[N:16]([CH2:19][C:20]#[CH:21])[C:17]2[C:13]([N:14]=1)=[C:12]([NH2:22])[N:11]=[C:10]([C:9]#[C:8][C:2]1([OH:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[N:18]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: C#CCn1cnc2c(N)nc(C#CC3(O)CCCCC3)nc21
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1c(Cl)nc2c(N)nc(C#CC3(O)CCCCC3)nc21
Reaction time: 28.5 h

Procedure:
The formula (9) compound: 2-[2-(1-hydroxycyclohexyl)-1-ethyn-1-yl]-N9-propargyladenine (200 mg, 0.67 mmol) was dissolved in dimethylformamide (7 mL), and N-chlorosuccinimide (180 mg, 1.3 mmol) and potassium acetate (20 mg, 0.20 mmol) was added thereto, and the mixture was stirred for 28.5 hours. A saturated sodium thiosulfate aqueous solution was added thereto to stop the reaction, and then the mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was suspended in chloroform, and the solid was collected by filtration to give the product of interest (49 mg, 0.15 mmol, 22%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[H-].[Na+].[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1>CN(C=O)C.CCOC(C)=O>[Cl:14][C:15]1[N:16]=[N:17][C:18]([O:8][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)=[CH:19][CH:20]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CC(Oc2ccc(Cl)nn2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidin-4-ol (106 mg, 0.67 mmol) in DMF (6.7 mL) was added 60% wt NaH (35 mg, 0.87 mmol). The solution was stirred at RT for 30 min, then 3,6-dichloropyridazine (100 mg, 0.67 mmol) was added and the reaction was stirred for 1 h. The crude reaction mixture was diluted in EtOAc. The organic layer was washed with water (5×), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-chloro-6-(2,2,6,6-tetramethylpiperidin-4-yloxy)pyridazine, intermediate 1-3 (135 mg). The crude material used without further purification. LCMS Rt=1.22 min (condition B); MS (M+1)=270.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.53 (s, 1H), 7.37 (d, J=9.1 Hz, 1H), 6.91 (d, J=9.1 Hz, 1H), 5.68-5.78 (m, 1H), 2.20 (dd, J=12.4, 4.0 Hz, 2H), 1.32 (s, 6H), 1.27-1.29 (m, 2H), 1.20 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH:16]1[C:21](=O)[CH2:20][CH2:19][O:18][CH2:17]1.[CH2:23](COC)OC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH:16]1[C:21](=[CH2:23])[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: COCCOC
Reactant: COC(=O)c1ccc(OC)c(OC2COCCC2=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=C1CCOCC1Oc1cc(C(=O)OC)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
18.2 g of methyltriphenylphosphonium bromide are suspended in 200 ml of dimethoxyethane under a nitrogen atmosphere and 1.5 g of sodium hydride (80% in paraffin) are then added in portions. The mixture is stirred at RT for 3 h and a solution of 13 g of methyl 4-methoxy-3-(4-oxotetrahydropyran-3-yloxy)benzoate are then added dropwise in the course of 30 min. The mixture is stirred overnight, then poured onto water and extracted 3 times with ethyl acetate. After drying over sodium sulfate, the organic phase is concentrated in vacuo and the residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether 4:6. The chromatographically pure fractions are combined, concentrated and dried in a high vacuum. 3.6 g of the title compound are obtained as a pale yellow oil.