Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([O:14][C:15](C)=O)[CH2:7]2.[CH3:18]I>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH3:18])([O:14][CH3:15])[CH2:7]2
Reactant: CI
Reactant: CC(=O)OC1Cc2cc(Br)ccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC1(C)Cc2cc(Br)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
640 mg of 60% of sodium hydroxide was added at room temperature to 20 ml solution of dimethylformamide with 850 mg of 5-bromo-2-methylcarbonyloxy-1-indanone obtained in the above 1). After stirring for 10 min at room temperature, 3.5 ml of methyl iodide was added and the mixture was stirred for 1 hour at room temperature. Then, 2 ml of dimethylformamide containing 5% water was added and further stirred for 1 hour at room temperature.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19]>>[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:19]
Reactant: OCCCCc1ccccc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCCCCc1ccccc1
Reaction time: 29 h

Procedure:
From 4-phenyl-1-butanol (5.0 g; 33 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 29 h. The yield was 1.22 g (68%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Mg].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>O1CCCC1>[F:8][C:9]([F:18])([F:19])[C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])=[CH:12][CH:11]=1
Reactant: C=CCCCBr
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCC(O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromopent-1-ene (6.0 g, 40 mmol) and magnesium (1.44 g, 59.2 mmol) in tetrahydrofuran (40 mL) was stirred at 0° C. for 30 minutes. 4-(Trifluoromethyl)benzaldehyde (4.6 g, 26 mmol) was added drop-wise, and the reaction mixture was stirred at room temperature for 4 hours, then quenched by addition of water (30 mL). After extraction with ethyl acetate (3×15 mL), the combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a yellow oil. This was used without additional purification. Yield: 2.6 g, 11 mmol, 42%. 1H NMR (400 MHz, CDCl3) δ 7.58-7.64 (m, 2H), 7.44-7.50 (m, 2H), 5.72-5.84 (m, 1H), 4.93-5.04 (m, 2H), 4.73-4.79 (m, 1H), 2.05-2.13 (m, 2H), 1.64-1.85 (m, 2H), 1.47-1.60 (m, 1H), 1.34-1.47 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([O-:26])=[O:25])=[C:6]([CH2:9][N+:10]3[N:11]([CH2:18][CH2:19][CH2:20][O:21]C=O)[C:12]([NH:15]C=O)=[CH:13][CH:14]=3)[CH2:7][S:8][C@H:3]12.CO.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[ClH:31].[NH2:1][C@@H:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([O-:26])=[O:25])=[C:6]([CH2:9][N+:10]3[N:11]([CH2:18][CH2:19][CH2:20][OH:21])[C:12]([NH2:15])=[CH:13][CH:14]=3)[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC=O)n3CCCOC=O)CS[C@H]12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCCO
Temperature: 25 °C

Procedure:
Bis(trifluoroacetic acid salts) of 7β-amino-3-[3-formamido-2-(3-formyloxypropyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (5.30 g) was added to methanol (31.8 ml). Concentrated hydrochloric acid was added dropwise thereto with stirring at room temperature. The mixture was stirred for 3 hours. The reaction mixture was pulverized with ethyl acetate (400 ml) to give 7β-amino-3-[3-amino-2-(3-hydroxypropyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:27]1[C@H:29]([C:30]([O:32]CC)=[O:31])[C:28]1([CH3:36])[CH3:35].[CH3:40][O:41][C:42]1[N:47]=[CH:46][C:45](B(O)O)=[CH:44][N:43]=1>>[CH3:40][O:41][C:42]1[N:47]=[CH:46][C:45]([C:2]2[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=2)[CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:14][C:9]=3[N:8]=[C:7]2[C@@H:27]2[C@H:29]([C:30]([OH:32])=[O:31])[C:28]2([CH3:36])[CH3:35])=[CH:44][N:43]=1
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)C1(C)C
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cccc(Cn3c([C@@H]4[C@H](C(=O)O)C4(C)C)nc4cc(OCc5ccc6ccccc6n5)ccc43)c2)cn1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 2-methoxypyrimidine-5-boronic acid in Step A. MS (ESI): mass calcd. for C35H31N5O4, 585.24; m/z found, 586.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 2H), 8.23 (d, J=8.3, 1H), 8.11 (d, J=8.8, 1H), 7.85 (d, J=8.3, 1H), 7.78-7.74 (m, 1H), 7.70 (d, J=8.5, 1H), 7.60-7.55 (m, 1H), 7.51-7.45 (m, 2H), 7.35-7.32 (m, 1H), 7.27-7.25 (m, 1H), 7.25-7.23 (m, 1H), 7.15-7.11 (m, 1H), 7.07-7.04 (m, 1H), 5.52-5.46 (m, 1H), 5.44 (s, 2H), 5.43-5.38 (m, 1H), 4.06 (s, 3H), 2.32-2.29 (m, 1H), 2.11-2.08 (m, 1H), 1.20 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(CC)CC)C.[CH:41]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH2:42]>>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:42][CH2:41][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(C)(=O)=O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a solution of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) in IMS (industrial methylated spirits, 3 mL) was added triethylamine (0.20 mL, 1.47 mmol) and methyl vinyl sulfone (0.09 mL, 1.05 mmol) and the reaction mixture was stirred at RT (room temperature) for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-5% MeOH in DCM). Freeze-drying from methanol and water gave 320 as a pale yellow solid (135 mg, 68%). LCMS: RT=3.10 min, [M+H]+=474. 1H NMR δ (ppm) (DMSO-d6): 8.35 (1H, d, J=8.19 Hz), 8.11 (1H, s), 7.29 (1H, d, J=8.27 Hz), 7.20 (1H, s), 5.85-5.76 (1H, m), 4.41-4.35 (3H, m), 4.14 (3H, d, J=59.98 Hz), 3.68 (2H, s), 3.53-3.41 (3H, m), 3.13 (3H, s), 1.55 (6H, d, J=6.60 Hz). 2 Protons obscured by water peak
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (0.150 g, 0.39 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.093 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 64%). MS (ISP) 407.3 [(M+H)+]; mp 215-217° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([NH:6][C@@H:7]1[C:13]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=2[C:11]2[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:10]=2[CH2:9][CH2:8]1)(=[O:5])=[O:4].Cl[C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C>C(#N)C>[C:31](=[O:32])([O:33][CH3:34])[O:18][C:15]1[CH:16]=[CH:17][C:12]2[C:11]3[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:10]=3[CH2:9][CH2:8][C@H:7]([NH:6][S:3]([N:2]([CH3:1])[CH3:29])(=[O:5])=[O:4])[C:13]=2[CH:14]=1
Reactant: COC(=O)Cl
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1[C@@H](NS(=O)(=O)N(C)C)CC2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc2c(c1)[C@@H](NS(=O)(=O)N(C)C)CCc1cc(OC)c(OC)c(OC)c1-2
Yield: 32 %

Procedure:
A solution of (5S)-5-{[(dimethylamino)sulphonyl]amino}-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ol (1) (0.9; 0.71 mmol), methyl chloroformate (0.061 ml; 0.782 mmol) and triethylamine (0.109 ml; 0.782 mmol) in acetonitrile (8 ml) was stirred under argon atmosphere at 40° C. for 4 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with ethanol/dichloromethane (2/98) to give (5S)-5-{[(dimethylamino)sulphonyl]amino}-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl methyl carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: COc1cc2c(cc1Cl)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Cl)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 5-chloro-6-methoxy-2,3-dihydro-1H-inden-1-one 170 (100 mg, 0.510 mmol) in toluene 15 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (98.4 mg, 0.561 mmol). PTSA (175.9 mg, 1.2 mmol) was added to the reaction mass, which was stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude (E)-5-chloro-6-methoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one (171), which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 22% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([F:15])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].Cl>[Cl-].[Cl-].[Zn+2]>[F:15][C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: COc1cc(F)cc(OC)c1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Product: CCC(=O)c1c(F)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50306.3 %

Procedure:
Under nitrogen atmosphere, 5 ml solution of dichloroethane with 2 g of 3,5-dimethoxy-1-fluorobenzene, and 5 ml solution of dichloroethane with 1.3 mg of propionyl chloride were dropped sequentiallly at −10° C. to 40 ml solution of dichloroethane with 2.4 g of alumimium trichloride and 240 mg of zinc dichloride, and the mixture was stirred at room temperature for 2 hours. 20% hydrochloric acid aqueous solution was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure and the residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=5/1), to obtain 1.5 g of the above compound as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CCC)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [NH2:1]N.[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:19]=[CH:18][C:9]([C:10]([N:12]=[C:13]([N:15](C)C)[CH3:14])=O)=[CH:8][C:7]=1[Cl:20]>C(O)(=O)C>[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:19]=[CH:18][C:9]([C:10]2[N:12]=[C:13]([CH3:14])[NH:15][N:1]=2)=[CH:8][C:7]=1[Cl:20]
Reactant: COC(=O)c1ccc(C(=O)N=C(C)N(C)C)cc1Cl
Reactant: NN
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2n[nH]c(C)n2)cc1Cl
Temperature: 90 °C
Yield: 67.1 %

Procedure:
Anhydrous hydrazine (0.30 mL, 9.6 mmol) was added via syringe to a solution of the intermediate of Step B (4.8 mmol) in glacial acetic acid (6 mL) under a nitrogen atmosphere. The reaction was heated at 90° C. for 30 minutes, then cooled and concentrated in vacuo to a light brown solid. The solid was redissolved in aqueous methanol and the solution neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane and ethyl actate, the extracts were combined and dried over sodium sulfate. Evaporation of the solvents yielded a solid which was triturated with ether to provide the title product (0.81 g) as an off-white solid, m.p. 196-198° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:13][NH:14][O:15][CH3:16].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([N:14]([O:15][CH3:16])[CH3:13])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CNOC
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc(Br)ccc1F
Yield: 90.5 %

Procedure:
A solution of compound 13 (98.0 g, 447 mmol), N,O-dimethylhydroxylamine hydrochloride (52.4 g, 537 mmol), and BOP-Cl (171 g, 671 mmol) in pyridine (490 mL) was stirred at room temperature for 3 h. After this time, the reaction mixture was diluted with water (1 L) and extracted with ethyl acetate (2×1 L). The combined extracts were washed with 1 N hydrochloric acid (3×500 mL), saturated aqueous NaHCO3 (500 mL), brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 14 (106 g, 91%) as a pale yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.70-7.40 (m, 2H), 7.00 (d, J=8.8 Hz, 1H), 3.56 (br s, 3H), 3.35 (br s, 3H); ESI MS m/z 262 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCCC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with pyrrolidine to give (2S)-1-(tert-butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)pyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7–2.05 (m, 8H), 2.1–2.3 (m, 1H), 2.4–2.5 (m, 1H), 2.55–2.7 (m, 1H), 2.8–2.9 (m, 1H), 3.2–3.3 (m, 2H), 3.4–3.7 (m, 5H), 4.1 (br s, 1H); Mass Spectrum: M+H+ 213.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Cl-].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][Zn+]>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.C1COCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1cccc(C[Zn+])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cccc(Cc2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
Prepared according to procedure Z using 2,4-dichloro-5,7-difluoro-3-methylquinoline (350 mg, 1.41 mmol), Pd(PPh3)4 (163 mg, 0.14 mmol), 3-methoxy-benzylzinc chloride (0.5M in THF, 2.96 mL, 1.48 mmol), and THF (3.5 mL). Purification by column chromatography (silica gel, 0-8% EtOAc in hexanes as eluent) gave 4-chloro-5,7-difluoro-2-(3-methoxybenzyl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=334.0 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[CH2:36]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:37]=[CH2:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:36]([S:39]([NH:42][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])=[CH:35][CH:34]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[N:15]=2)=[CH:33][CH:32]=1)(=[O:41])=[O:40])[CH:37]=[CH2:38]
Reactant: C=CCS(N)(=O)=O
Reactant: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)NS(=O)(=O)CC=C)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 84.4 %

Procedure:
4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (44 mg, 0.090 mmol), prop-2-ene-1-sulfonamide (13.07 mg, 0.108 mmol), HATU (51.3 mg, 0.135 mmol), and Hunig's Base (0.079 mL, 0.449 mmol) were stirred in DCM (3 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc to give N-(allylsulfonyl)-4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide (45 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:35][CH2:34][O:33][CH2:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCCCC1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCOC1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12]/[C:13](/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:14]\[CH2:15][CH2:16][OH:17].O>N1C=CC=CC=1>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:17][CH2:16][CH2:15]/[CH:14]=[C:13](\[CH3:12])/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCO
Solvent: O
Solvent: c1ccncc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCOS(=O)(=O)c1ccc(C)cc1

Procedure:
Tosylchloride (3.51 g, 9 mmol) was added to a stirred solution of (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienol (1.66 g, 7 mmol) in pyridine (30 mL) at 0° C. The resulting mixture was placed in a refrigerator overnight, then poured into cold water and extracted with ether. The ethereal extract was washed with diluted hydrochloric acid to remove pyridine. After drying and filtration, the filtrate was evaporated to afford the title compound as an oil which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=N)[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.[NH:26]1CCCCC1>>[NH2:26][CH2:1][CH2:2][CH2:6][CH2:5][NH:4][CH:8]=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=CNCCCCN)cc1

Procedure:
The compound of Example 12 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of piperidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 281.37; found mol. wt. (M+H) 282.2; 562.9 (Dimer)
Reaction SMILES: O.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([N+:14]([O-])=O)[CH:5]=1>C(O)C.[Fe]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([NH2:14])[CH:5]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(F)cc1N
Reaction time: 16 h
Yield: 96.5 %

Procedure:
5-Fluoro-2-methylsulfonylphenylamine can be obtained in the following way: 1.25 ml of water and 0.47 ml of an aqueous 12N hydrochloric acid solution are added to a solution of 1.2 g of 4-fluoro-1-methylsulfonyl-2-nitrobenzene in 80 ml of ethanol. The reaction mixture is then heated at the reflux of the solvent and 0.92 g of powdered iron are added portionwise. The reaction mixture is then stirred at the reflux of the solvent for 2 hours, then at a temperature in the region of 20° C. for 16 hours. It is then filtered through sintered glass and the solid is washed with ethanol. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of water and ethyl acetate and then basified with an aqueous sodium hydrogencarbonate solution, to a pH in the region of 10, and allowed to settle out. The aqueous phase is extracted with 4 times 50 ml of ethyl acetate. The organic extracts are pooled, washed with water, dried over magnesium sulfate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1 g of 5-fluoro-2-methylsulfonylphenylamine is thus obtained in the form of a beige oil which crystallizes (Rf=0.33, silica gel thin layer chromatography, eluent: dichloromethane).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])(C)(C)C.CC1(C)O[C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=[O:38])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:28]([C:30]4[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=4)[C:33]#[N:34])[CH2:27][C:26](=[O:38])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(Cl)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (3-amino-4′-chloro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G12) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow powder (79 mg).