Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:15]([Br:16])=[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:15]([Br:16])=[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccnn1-c1nn2c(c1Br)CCCC2
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cnn1-c1nn2c(c1Br)CCCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.6 g (12.7 mmol) 5-Amino-1-(3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)pyrazole was suspended in 15 ml acetic acid and treated with 1.23 ml (13.0 mmol) acetic anhydride. The mixture was stirred for 5 hours at room temperature. 1.5 ml (15.9 mmol) acetic anhydride was added and then, with ice-bath cooling, 0.66 ml (15.5 mmol) fuming nitric acid was added, dropwise. After stirring for 12 hours at room temperature, the mixture was concentrated. The residue was dissolved in 30 ml ethanol and treated with 11.2 ml concentrated hydrochloric acid. After heating for 3 hours under reflux, the mixture was concentrated and the residue taken up in water and ethyl acetate. It was made basic with 2N aqueous sodium hydroxide and the organic phase separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with water and once with saturated aqueous sodium chloride. The organic phase was dried and concentrated. The residue was recrystallised from ethyl acetate.
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6](O)=[O:7].S(Cl)([Cl:15])=O>C1C=CC=CC=1.CN(C)C=O>[Br:1][C:2]([Br:12])=[CH:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6]([Cl:15])=[O:7]
Reactant: CC(C)C(CC=C(Br)Br)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)C(CC=C(Br)Br)C(=O)Cl
Yield: 59 %

Procedure:
In 20 g of benzene were dissolved 2.0 g of α-(3,3-dibromoallyl) isovaleric acid, followed by the addition of 4.7 g of thionyl chloride and 2 drops of N,N-dimethylformamide. The mixture was refluxed overnight and, then, distilled to remove the low-boiling fraction. As the residue there was obtained α-(3,3-dibromoallyl)isovaleroyl chloride. This α-(3,3-dibromoallyl) isovaleroyl chloride was dissolved in 30 g of dry benzene and 1.5 g of α-ethynyl-3-phenoxybenzyl alcohol were added. This was further followed by the dropwise addition of 1.6 g of pyridine and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was further stirred at 40°-50° C. for 2 hours, after which it was diluted with diethyl ether, washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. The resultant viscous oil was purified by column chromatography to recover 2.0 g of α-ethynyl-3-phenoxybenzyl α-(3,3-dibromoallyl)isovalerate (Compound [10]) which was shown to have the properties indicated below [yield: 59% based on α-(3,3-dibromoallyl)isovaleric acid].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1
Reactant: C1=COCCC1
Reactant: CC(C)(C)c1cc(Br)ccc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 26.5 h

Procedure:
To a solution of 18.92 g (82.6 mmol) of 4-bromo-2-t-butylphenol (Compound E) in 110 ml of dichloromethane was added dropwise 10.42 g (11.3 ml, 123.9 mmol) of 3,4-dihydro-2H-pyran (DHP). To this clear, colorless solution was added 1.86 g (7.4 mmol) of pyridinium p-toluenesulfonate (PPTS). The resulting mixture was stirred at room temperature under a blanket of argon for 26.5 hours, partitioned between 250 ml of water and 400 ml of hexane, and the layers were separated. The organic phase was washed with 2×250 ml-portions of water and with 150 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) yielded the title compound as a light yellow, crystalline solid. PMR (CDCl3): d 1.39 (9H, s), 1.6-2.1 (6H, m), 3.6-3.7 (1H, m), 3.8-3.9 (1H, m), 5.43 (1H, t, J=2.7 Hz), 7.06 (1H, d, J=8.8 Hz), 7.24 (1H, dd, J=8.8, 2.7 Hz), 7.36 (1H, d, J=2.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.[C:13]([N:16]1[CH2:20][CH2:19][NH:18][C:17]1=O)(=[O:15])[CH3:14]>>[C:13]([N:16]1[CH2:20][CH2:19][N:18]=[C:17]1[NH:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1)(=[O:15])[CH3:14]
Reactant: CC(C)c1cc(N)n(C(C)C)n1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN=C1Nc1cc(C(C)C)nn1C(C)C

Procedure:
5-Amino-1,3-di-isopropyl pyrazole (13.5 g.) and 1-acetyl-2-imidazolidinone (12.2 g.) were reacted as described in Example I to give 13.01 g. of product, mp 139°-140° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:28])([F:27])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1.FC1C=C(C2C=C(F)C3N(C(C(F)(F)C4C=C5C(=CC=4)N=CC(OC)=C5)=NN=3)C=2)C=C(F)C=1>>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:28])([F:27])[C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][C:16]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15]5)=[N:9][N:10]=3)[N:7]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COCCOc1cnc2ccc(C(F)(F)c3nnc4ccc(Cl)nn34)cc2c1
Agent: COc1cnc2ccc(C(F)(F)c3nnc4c(F)cc(-c5cc(F)cc(F)c5)cn34)cc2c1
Product: COCCOc1cnc2ccc(C(F)(F)c3nnc4ccc(-c5cc(F)cc(F)c5)nn34)cc2c1

Procedure:
The title compound was synthesized from 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline and 3,5-difluorophenylboronic acid in a similar manner as that described for 6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline. LRMS (ESI) m/z calcd for C24H18F4N5O2(M+H) 484.1. found 484.2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][N:5]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1cccs1)OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1cccs1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
2,2-Dimethoxy-N-(thiophen-2-ylmethyl)ethanamine (5 g, 24 mmol) was dissolved in anhydrous dichloromethane and pyridine (5.82 mL, 72 mmol) was added to the reaction. The mixture was cooled down to 0° C. and was treated with para-toluenesulfonyl chloride (5.6 g, 29 mmol) added portionwise. The reaction was allowed to stir at 0° C. for 4 h and was then washed 3 times with 1 N HCl, water and a saturated solution of sodium bicarbonate. The organic layer was dried with sodium sulfate. Purification by flash chromatography using a gradient of 5-30% ethyl acetate in hexanes yielded a white crystalline solid (7.4 g) MS (M+H)+ 356.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1C)=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1[C:56](C1C=C(C#C)C=CC=1OC)=[O:57].N(CCOC1CCCCO1)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[O:57][CH3:56])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#Cc1ccc(OC)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Agent: [N-]=[N+]=NCCOC1CCCCO1
Product: COc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 427 (0.42 mmol) and compound 408 (0.42 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 60:40 as the eluent to afford the title compound as light orange foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1Cl)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][Cl:16])[N:14]=1)=[O:8].[F:21]C1C=C(C=CC=1)CN=C=O>>[Cl:16][CH2:15][C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:21])[CH:3]=2)=[O:8])[S:11][CH:12]=1
Reactant: O=C=NCc1cccc(F)c1
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Product: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1

Procedure:
Prepared by same procedure described for Intermediate 2, using 3-fluorobenzyl isocyanate. 1H-NMR (ppm, DMSO-d6): 10.70 (bs, 1H), 7.36 (dd, 1H), 7.07 (m, 4H), 4.63 (s, 2H), 4.34 (d, 2H).
Reaction SMILES: [N:1]1([C:5](=[O:18])[C@@H:6]([NH:10]C(=O)OC(C)(C)C)[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1.O1CCOCC1.CO>Cl>[NH2:10][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:5]([N:1]1[CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)[C@H](N)C(=O)N1CCC1
Reaction time: 5 h
Yield: 73.2 %

Procedure:
(S)-Tert-butyl 1-(azetidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (Compound D) (23.56 g, 90.07 mmol) was stirred in 4M HCl in dioxane (56.3 mL, 225 mmol) for 30 min. Additional dioxane and MeOH was added until the reaction mixture became a clear solution. The solvent was removed under reduced pressure and conc. HCl (3.00 mL, 30.4 mmol) was added. The mixture was stirred for 5 h before the solvent was removed. The residue was purified via Biotage (gradient; EtOAc:MeOH (2% TEA), 99:1 to 90:10, then EtOAc:MeOH (2% TEA) 90:10 to 0/100 KP-SIL 340 g. The solvent was removed under reduced pressure to give the title compound (10.3 g, 70.3%). 1H NMR (600 MHz, CH3OD) δ 1.03, 1.06, 2.07-2.16, 2.33-2.41, 3.71, 3.99-4.07, 4.07-4.14, 4.25-4.33, 4.33-4.41. Total no of protons: 14. LCMS (M+H)+: 157.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:29])[CH2:10][N:11]1[CH2:17][CH:16]2[N:18]([C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][N:23]4[CH3:28])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1.Cl[CH2:31][C:32]([NH:34]C1C=CC=C2C=1C=CC=N2)=O>>[CH3:28][N:23]1[CH:22]=[N:21][C:20]2[C:24]1=[N:25][CH:26]=[N:27][C:19]=2[N:18]1[CH:16]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([CH2:10][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]3[C:2]=1[CH:1]=[CH:31][CH:32]=[N:34]3)=[O:29])[CH2:17]2
Reactant: O=C(CCl)Nc1cccc2ncccc12
Reactant: Cc1ccccc1NC(=O)CN1CC2CCC(C1)N2c1ncnc2c1ncn2C
Product: Cn1cnc2c(N3C4CCC3CN(CC(=O)Nc3cccc5ncccc35)C4)ncnc21

Procedure:
The subtitle compound was prepared from the product of Example 20 step (ii) (0.24 g) and 2-chloro-N-(quinolin-5-yl)acetamide (J. Indian Chem. Soc, 1940, 17, 619-621) (0.234 g) by the method of Example 20 step (iii) as a pale yellow solid. Yield 0.38 g.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH2:25]([O:27][CH2:28][C:29](Cl)=[O:30])[CH3:26].[Cl-].[Na+]>C1COCC1>[CH2:25]([O:27][CH2:28][C:29]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:30])[CH3:26]
Reactant: CCOCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCC(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
36.7 g (207 mmol) of (S)-4-benzyloxazolidin-2-one in 800 ml of THF are introduced into a round-bottomed flask under a stream of nitrogen. The reaction medium is cooled to −78° C. and 83 ml (207 mmol) of 2.5M n-butyllithium hexane are added dropwise. 30 minutes later, 25.4 g (207 mmol) of ethoxyacetyl chloride obtained in Example 81(b) are added, at −78° C. The reaction medium is stirred for 24 hours and then poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. After purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (6/4), 30.6 g (56%) of the expected product are obtained in the form of an orange-colored oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:9]([CH2:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[CH3:20])(=[O:11])=[O:10])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.C(Cl)(Cl)(Cl)[Cl:22].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:9]([CH:12]([Cl:22])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[CH3:20])(=[O:11])=[O:10])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)c(CS(=O)(=O)c2c(Cl)ccc[n+]2[O-])c1
Reactant: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(C(Cl)S(=O)(=O)c2c(Cl)ccc[n+]2[O-])c1
Temperature: 15 °C

Procedure:
To a suspension of 2.2 g (0.01 mole) of 3-chloro-2-[[1-(2,5-dimethylphenyl)-methyl]sulfonyl]pyridine-N-oxide in 10 ml of dimethylformamide (DMF) was added 2 g (0.013 mole) of carbon tetrachloride. The mixture was cooled to 15° C. and then treated with 0.5 g (0.013 mole) of NaOFl. The mixture was stirred and allowed to warm to room temperature for two hours. It was then poured into cold water and the solid was filtered off, having a melting point of 125-127° C. Infrared and NMR spectra were consistent with the proposed structure.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([CH3:15])[C:9]([SH:14])=[CH:10][CH:11]=[CH:12][CH:13]=1>>[C:4]1([CH3:5])[CH:3]=[CH:2][CH:7]=[CH:6][C:15]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:14]
Reactant: Ic1ccccc1
Reactant: Cc1ccccc1S
Product: Cc1ccccc1-c1ccccc1S

Procedure:
The general procedure was used to convert iodobenzene and o-toluenethiol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (383 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.20–6.98 (m, 9H; Ha, Hb, Hc, Hd, He, He′, Hf, Hf′, Hg), 2.27 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 139.90 (C8), 136.10 (C6), 133.70 (C1), 132.94 (C2), 130.54 (C5), 129.55 (C9, C13), 129.07, (C10, C12), 127.85 (C3), 126.66 (C11), 126.27 (C4), 20.54 (C7). Anal. Calcd. for C13H12S: C, 77.95; H, 6.04; S, 16.01; Found C, 78.02; H, 6.01; S, 16.01.
Reaction SMILES: [Mg].[C:2]1(I)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:21])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.BrCCBr>[C:9]1([S:15]([NH:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:24][CH:23]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:21])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CNS(=O)(=O)c1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: Ic1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=S(=O)(NCC(O)(c1ccccc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
5.83 g of magnesium are suspended in 100 ml of dry tetrahydrofuran, and 5 drops of 1,2-dibromoethane are added thereto. After the mixture is stirred at room temperature, a solution of 28.3 g of phenyl iodide in 70 ml of tetrahydrofuran is added dropwise thereto. A solution of 7.65 g of 2-benzenesulfonylamino-1-(4-benzyloxyphenyl)ethanone in 100 ml of tetrahydrofuran is added dropwise to the reaction mixture under ice-cooling and stirring. The mixture is stirred at room temperature, and an aqueous ammonium chloride solution is added thereto. The mixture is extracted with ethyl acetate, and the extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel flash column chromatography (solvent; chloroform), and recrystallized from a mixture of ethyl acetate and n-hexane. 5.37 g of 2-benzenesulfonylamino-1-(4-benzyloxyphenyl)-1-phenylethanol are obtained as colorless crystals. m.p. 147.5°-149° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=O.Cl.[C:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH:30])[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:31]=[C:29]([NH:28][C:24]3[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=3)[C:20]#[N:21])[N:30]=2)=[CH:8]1)[CH3:17]
Reactant: N#Cc1cccc(NC(=N)N)c1
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc(C#N)c3)n2)c2cccnc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one and 1-(3-cyanophenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 1.48 (t, 3H, J=7.2 Hz, CH3), 4.39 (q, 2H, J=7.2 Hz, CH2), 7.27 (m, 1H, Ar—H), 7.36 (d, 1H, J=4.4 Hz, Pyrimidin-H), 7.42 (m, 1H, Ph-H or Ar—H), 7.51 (m, 1H, Ph-H or Ar—H), 7.98 (m, 1H, Ar—H), 8.38 (m, 1H, Ph-H or Ar—H), 8.46 (m, 2H, Pyrimidin-H or Ar—H), 8.63 (s, 1H, Ar—H), 8.94 (m, 1H, Ph-H or Ar—H), 9.85 (s, 1H, NH). MS (ESI+) m/z 341.1489 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[S:15])[CH:3]([N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]1)[CH3:4].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=O>>[F:27][C:26]([F:28])([F:29])[C:22]1[CH:21]=[C:20]([C:18]2[N:1]=[C:2]([CH:3]([N:5]3[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]3)[CH3:4])[S:15][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(C(C)C(N)=S)c1
Product: CCOC(=O)c1cnn(C(C)c2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 90.5 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (227 mg, 1.00 mmol) obtained in Example 14b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (267 mg, 1.00 mmol), the title compound (358 mg, 90%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:28]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1ccc(C)cc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)OCc1ccc(F)cc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2CN(CC)C(=O)OCc2ccc(F)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-methyl-biphenyl-3-yl)-acetic acid ethyl ester and 4-fluorobenzyl chloroformate.
Reaction SMILES: C(OOC(C)(C)C)(C)(C)C.CO.[Br:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br>>[Br:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCc1ccccc1Br
Agent: CC(C)(C)OOC(C)(C)C
Solvent: CO
Product: BrC=Cc1ccccc1

Procedure:
A quantity of 2 g of di-tertbutyl peroxide was dissolved in 100g of β-bromoethyl bromobenzene and the solution was added through a motor-driven syringe into the reactor at a rate of 60g/h, together with 25 g of methanol and with nitrogen which was passed in at a rate of 2 l/h. The reactor used in this example was a glass spiral made of 6 mm wide and 5 m long tube heated to 300°-320°C. The products were collected in a trap immersed in an ice bath while the methyl bromide was trapped in a container positioned in liquid nitrogen. The liquid products were then subjected to fractional distillation under vacuum. There were obtained 58 g bromostyrene and 12 g unconverted reactant. The yield was 95% bromostyrene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([CH:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18](OC)=[O:19])(=O)[CH3:15]>CC1C=CC=CC=1C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]3[N:13]=[C:14]([CH3:15])[C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:18]([OH:19])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1cc(-c2cccc(Br)c2)n[nH]1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)nc2cc(-c3cccc(Br)c3)nn2c1O
Temperature: 135 °C
Yield: 93.6 %

Procedure:
A 3-lit three neck flask was fitted with a mechanical stirrer and a heating mantle. A suspension of 3-(3-bromophenyl)-1H-pyrazol-5-amine (84.9 g, 357 mmol), dimethyl 2-acetylsuccinate (73.8 g, 392 mmol) and tosic acid monohydrate (1.357 g, 7.13 mmol) in o-xylene (1500 mL) was heated to refluxed (135° C. measured internal temp) for 3.5 h. The heating was turned off, the reaction was diluted with hexanes (1000 mL) and was allowed to cool slowly overnight. The solids were collected by filtration. The filter cake was washed with hexanes and dried under vacuum overnight to afford methyl 2-(2-(3-bromophenyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (132.21 g, 334 mmol, 94% yield) as a white powdery solid. 1H NMR (500 MHz, DMSO-d6) δ: 12.47 (s, 1H), 8.18 (t, J=1.7 Hz, 1H), 8.02 (dt, J=7.1, 1.3 Hz, 1H), 7.65-7.60 (m, 1H), 7.45 (t, J=7.9 Hz, 1H), 6.69 (s, 1H), 3.63 (s, 3H), 3.58 (s, 2H), 2.34 (s, 3H). LCMS (M+H)=376.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[S:18]([C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1)(=[O:21])(=[O:20])[NH2:19]>>[S:18]([C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:24][CH:23]=1)(=[O:20])(=[O:21])[NH2:19]
Reactant: NS(=O)(=O)c1ccc(CCBr)cc1
Reactant: COc1ccc2c(c1)N(C1CCNCC1)CC2
Product: COc1ccc2c(c1)N(C1CCN(CCc3ccc(S(N)(=O)=O)cc3)CC1)CC2
Yield: 13.1 %

Procedure:
1-(Piperidin-4-yl)-6-methoxyindoline (350 mg) and 4-sulfamoylphenethyl bromide (340 mg) were treated as in Example 2 to give the title compound (70 mg) as a brown powder (yield: 13%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([O:20][CH2:21][C:22]([O:24]C)=[O:23])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[OH-].[Na+].CCOC(C)=O>CO>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl ({2-[(trans-4-hydroxycyclohexyl)amino]-7-methylquinazolin-8-yl}oxy)acetate (11 g, 0.032 mol) in MeOH (210 mL) was added 2 N aq. NaOH (81.4 mL, 0.163 mol) in one portion. The reaction mixture was stirred at room temperature overnight. TLC (EtOAc) indicated the reaction was complete. The solvent was removed in vacuo. The residue was adjusted to pH 6 with 1 N aq. HCl. The precipitate was filtered, washed with ether (30 mL×2) and dried in vacuo to give the title compound (9.8 g, 92.4%) as an off-white solid. m/e 332.2 (MH+).