Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:25][CH2:26][NH2:27])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C[O-].C([N+](C)(C)C)C1C=CC=CC=1>CN(C=O)C.C(OCC)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:24][CH2:25][CH2:26][NH:27][C:9](=[O:11])[C@@H:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:12]([CH3:14])[CH3:13])=[CH:19][CH:18]=1
Reactant: CC(C)[C@H](NC1CCCCC1)C(=O)O
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC1CCCCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
A solution of 335 mg (1.68 mmol) 2-(cyclohexylamino)-3-methylbutyric acid (Example 69, Step A), 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride, 0.29 mL (1.68 mmol) N,N-diisopropylethylamine, and 1.5 mL (3.36 mmol) benzyltrimethylammonium methoxide (40% solution in methanol) in 4 mL dry DMF was cooled to 3° C., and 637° mg (1.68 mmol) O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate was added and the resulting mixture stirred at 3° for 30 minutes, warmed to 25° C., and stirred an additional 30 minutes at which time it was diluted with 20 mL diethyl ether, and washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 4:1 ethyl acetate:hexanes as eluant, followed by conversion to the hydrochloride salt by treating with excess diethyl ether which had been saturated with hydrogen chloride gas to give 29 mg (4%) of titled compound: mp 49-53° C. APCI-MS m/z 443.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:11]=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].O1CCCC1.O.[OH-].[Li+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[CH:13]=[C:12]([C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:11]=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1ccc(C(=O)OC(C)C)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCC(=O)c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The product from Example 10 (270 mg) was suspended in 10 ml of isopropyl alcohol and warmed. 20 ml of tetrahydrofuran was added. 200 mg of lithium hydroxide monohydrate in 3 ml of water was added followed by an additional 5 ml of water. The reaction mixture was stirred at room temperature for about 20 hours and 20 ml of 10% hydrochloric acid was added. The organic solvents were removed using a rotary evaporator and the residue was extracted with two 50 ml portions of ethyl ether. The ether extracts were combined, dried over sodium sulfate, filtered and the solvent removed under a nitrogen gas stream. The product is a white solid identical with the product disclosed in Example 15 in U.S. Pat. No. 4,469,885.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:9]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[CH:20]=[CH:19][C:10]([C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:8]=2)[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COc1c(C)c(Cc2ccc(C(=O)N3CCCCC3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCCCC3)c(-c3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
N-[4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoyl]piperidine (70 mg, 0.1428 mmol) was dissolved in a mixed solvent of acetonitrile (6 ml) and water (2 ml), then CAN (231 mg, 0.4293 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (26 mg, 0.0565 mmol, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[C:13]([CH2:25][OH:26])=[N:12][C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:14]1[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:27]([CH3:29])[CH3:28])[N:12]=[C:13]1[CH2:25][OH:26]
Reactant: [H][H]
Reactant: CC(C)c1nc(CO)n(Cc2ccccc2[N+](=O)[O-])c1Sc1cc(Cl)cc(Cl)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CO)n(Cc2ccccc2N)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
In ethyl acetate was dissolved 170 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(o-nitrobenzyl)-1H-imidazole (103c), platinum sulfided carbon was added. After replacement with hydrogen atomosphere, catalytic hydrogenation was performed at atmospheric pressure at room temperature. After 1 hour, the mixture was filtered through Celite, and the filtrate was distilled off under reduced pressure To the residue, diethyl ether was added, the precipitated crystals were collected by filtration, and 77 mg of Compound I-119 was obtained (yield 49%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](OC(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39](=[O:43])[NH:40][CH2:41][CH3:42])[CH:34]=[CH:33]2)#[N:2].[Na].O>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39](=[O:43])[NH:40][CH2:41][CH3:42])[CH:34]=[CH:33]2)#[N:2]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc4cc(OCC5CCN(OC(=O)OC(C)(C)C)CC5)c(C#N)cc34)ccc21
Agent: [Na]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)n1ccc2cc(Oc3ccnc4cc(OCC5CCNCC5)c(C#N)cc34)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 373.3 %

Procedure:
After dissolving 6-cyano-4-(1-ethylcarbamoylindol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline (180 mg, 0.0753 mmol) in trifluoroacetic acid (1 ml), the solution was stirred at room temperature for 0.5 hour. Saturated sodium bicarnobate water was added, extraction was performed with ethyl acetate and tetrahydrofuran, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, after which ethanol was added to the obtained amorphous substance for crystallization. After dilution with hexane, the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (132 mg, 0.2811 mmol, 88.96%) as colorless crystals.
Reaction SMILES: C(O)CCC.[CH2:6]([N:8]([CH2:18][CH3:19])[C:9]1[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=1)[CH:13]=O)[CH3:7].[N+:20]([CH2:23][C:24](OCC)=[O:25])([O-:22])=[O:21].N1CCCCC1>C(O)(=O)C>[N+:20]([C:23]1[C:24](=[O:25])[O:17][C:11]2[C:12]([CH:13]=1)=[CH:15][CH:16]=[C:9]([N:8]([CH2:18][CH3:19])[CH2:6][CH3:7])[CH:10]=2)([O-:22])=[O:21]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCCCO
Product: CCN(CC)c1ccc2cc([N+](=O)[O-])c(=O)oc2c1
Temperature: 25 °C

Procedure:
A mixture containing n-butanol (20 mL), 4-diethylamino salicylaldehyde (1.4 g, 7.2 mmol), ethyl nitroacetate (0.8 mL, 7.2 mmol), molecular sieves 4 Å (100 mg), piperidine (0.1 mL) and acetic acid (0.2 mL) was refluxed for a period of 24 h. Upon cooling to room temperature, a bright yellow solid formed, which was collected and dissolved in DMF (15 mL) at 80° C. It was filtered again to remove the molecular sieves. The filtrate, upon addition to 100 ml of ice-cold water, yielded 3-nitro-7-diethylamino coumarin as a bright yellow solid: 1.40 g, 73%. A small amount of this compound was recrystallized from DMF to give an analytical sample; mp 193-195° C. 1H-NMR (CDCl3, 300 MHz) δ 1.27 (t, J=7.14 Hz, 6H), 3.48 (q, J=7.86 Hz, 4H), 6.50 (s, 1H), 6.70 (d, J=6.71 Hz, 1H), 7.42 (d, J=7.42 Hz, 2H), 8.72 (s, 1H). HRMS m/e calculated for MH+ C13H14N2O4 263.1041; found 263.1032.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.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>[C:7]([C:5]1[S:6][C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])=[CH:3][CH:4]=1)#[N:8]
Reactant: COc1ccccc1B(O)O
Reactant: N#Cc1ccc(Br)s1
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: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(C#N)s1
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
A solution of 5-bromothiophene-2-carbonitrile (1.25 g, 6.65 mmol) in 50 ml of dioxane is degassed with argon, tetrakis(triphenylphosphine)palladium(0) (768 mg, 0.665 mmol) is added and the mixture is stirred for 5 minutes. 2-Methoxybenzene boronic acid (2.02 g, 13.3 mmol) and aqueous 2 N sodium carbonate (13.3 ml) are successively added and the mixture is stirred for 16 hours at 85° C. Extractive work-up (2×50 ml dichloromethane and 2×30 ml water). The organic phase is dried over sodium sulfate, filtrated and evaporated. The residue (4.05 g) is purified via flash chromatography on silica (eluent: 100% hexane>hexane/ethyl acetate 96:4 gradient) to give 1.37 g of 2-(5-cyanothien-2-yl)anisole (96%). M+=215.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33][C@@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1C[C@H](O)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 65.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (65.3 mg, 0.103 mmol) prepared in Example 161c, triethylsilane (0.050 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), to yield the title compound (32.6 mg, 71%) as a colorless solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[N:39][C:40]([NH:43][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH3:22])[C:7](=[O:23])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:41][CH:42]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Product: CCOCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 8.9 %

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.86 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.95 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4-[6-(8-cyclopentyl-6-ethoxymethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.140 g, 14.7%). 1H NMR δ (400 MHz, CDCl3) 8.59 (s, 1H), 8.26 (d, J=9.3 Hz, 1H), 7.97 (d, J=2.7 Hz, 1H), 7.6 (t, J=1.5 Hz, 1H), 7.38 (dd, J=2.7, 9.0 Hz, 1H), 5.89 (m, 1H), 4.55 (d, J=1.2 Hz, 1H), 3.66 (q, J=7.1 Hz, 2H), 3.60 (m, 4H), 3.11 (m, 4H), 2.34 (m, 2H), 2.07 (m, 2H), 1.88 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H), 1.30 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.CN(C)C=O.[C:12]1([N:18]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=CC(=O)[NH:21][C:19]2=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Cl:6][C:1]1[CH:2]=[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19](=[O:20])[N:21]=1
Reactant: O=c1cc(-c2ccccc2)n(-c2ccccc2)c(=O)[nH]1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1nc(Cl)cc(-c2ccccc2)n1-c1ccccc1
Yield: 34.9 %

Procedure:
Oxalyl chloride (3.1 g, 24.4 mmol) was added to a mixture of N,N-dimethylformamide (1.8 g, 24.6 mmol) in dichloromethane (30 ml) at −5° C. to 0° C. under stirring. After the completion of addition the reaction temperature was allowed to reach 20° C. to 25° C. 1,6-Diphenyluracil (4.0 g, 15.2 mmol) was added in portions to the resulted suspension for 2.5 hrs. The reaction mixture was heated to reflux for 4 hours under stirring and continued stirring for 12 hours at room temperature. The reaction mass was poured onto sodium hydroxide solution (150 ml, 0.25 N) and collected the dichloromethane layer. The dichloromethane layer was washed with hydrochloric acid (200 ml, 0.025N), water and saturated sodium chloride solution successively. The organic extract was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (1.5 g, 35%, HPLC purity 99.8%), mp: 141-143° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1F.C([N:33]([CH:36]([CH3:38])[CH3:37])[CH2:34]C)(C)C.[OH2:39]>C(#N)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:33]3[CH2:34][CH2:38][C@H:36]3[CH2:37][OH:39])[N:11]=2)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: O
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CC[C@H]3CO)ccc2c1=O

Procedure:
A mixture of EXAMPLE 1B (1.6 g), (S)-(2-hydroxymethyl)azetidine hydrochloride (660 mg), and diisopropylethylamine (4 mL) in acetonitrile (25 mL) at 25° C. was stirred for 3.5 days, treated with water, and filtered. The filtrant was flash chromatographed on silica gel with 9:1 dichloromethane/methanol.
Reaction SMILES: [CH3:1][S:2]([CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12])=O.C([Cl:17])(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:17][CH2:1][S:2][CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12]
Reactant: CS(=O)C=C1C(C)(C)CCC1(C)C
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1=CSCCl
Yield: 87.9 %

Procedure:
1.0 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl sulfoxide was dissolved in 10 ml of methylene chloride, and 470 mg of acetyl chloride was added dropwise. The mixture was subjected to reaction at room temperature for 12 hours, and then 50 ml of 5% sodium hydrogen carbonate was added thereto The mixture was extracted twice with 50 ml of chloroform, and the organic layers were dried over anhydrous magnesium sulfate and filtered The filtrate was concentrated under reduced pressure, whereby 960 mg of 2,2,5,5-tetramethylcyclopentylidenemethyl chloromethyl sulfide was obtained
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH3:19])[CH:2]=[CH2:3].I[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH2:1]([N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH:14]=[C:13]2[CH3:19])[CH:2]=[CH2:3]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C=CCN(C)CCCC#Cc1ccc2[nH]cc(C)c2c1
Product: C=CCN(C)CCCC#Cc1ccc2c(c1)c(C)cn2-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 17.1, Allyl-methyl-[5-(3-methyl-1H-indol-5-yl)-pent-4-ynyl]-amine and 1-Iodo-4-trifluoromethyl-benzene were converted to yield Allyl-methyl-{5-[3-methyl-1-(4-trifluoromethyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amine as yellow oil, MS: 411 (MH+).
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([OH:21])(=[O:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.O1CC[CH2:25]OO1.[CH2:28](O)[CH2:29][CH2:30][CH3:31]>>[CH2:28]([O:16][C:15]([C:14]1[CH:18]=[C:19]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:21])[O:20][CH2:25]2)=[O:17])[CH2:29][CH2:30][CH3:31]
Reactant: C1COOOC1
Reactant: CCCCO
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CCCCOC(=O)c1ccc2c(c1)COC2=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Oleum (25% SO3, 95 ml) is charged into a reactor (350 ml). Under stirring terephthalic acid (19.0 g; 0.11 mol) is added to the reactor and the mixture is heated to 60° C. After stirring for additional 30 min terephthalic acid (31.0 g; 0.19 mol) is added and the mixture is heated to 100° C. for 1 hour. The mixture is cooled to 25-30° C., trioxane (12.0 g; 0.13 mol) is added in portions and the reaction mixture is heated slowly to 130-135° C. and agitated at this temperature for 1½ hours and for 4 hours at 155° C. The reaction mixture is cooled to 40° C. and added to a reactor containing butanol (150 ml) and heptanes (150 ml) witch has been heated to 95-100° C. The formed precipitates were diluted with butanol (85 ml) and stirring overnight. The precipitate is filtered off and dried.
Reaction SMILES: [CH2:1]([P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH2:2]C=C.C[N+]1([O-])[CH2:19][CH2:18][O:17]CC1.CC(C)=[O:23]>O.[Os](=O)(=O)(=O)=O>[OH:23][CH:19]([CH2:18][OH:17])[CH2:2][CH2:1][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: C=CCCP(=O)(OCC)OCC
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCOP(=O)(CCC(O)CO)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of diethyl but-3-enylphosphonate (10.2 g, 0.053 mol) in acetone (200 ml) and water (40 ml), was added a trace of osmium tetroxide (1 mg). After stirring for 10 minutes at ambient temperature, 4-methylmorpholine-N-oxide (10.75 g, 0.079 mol) was added in one portion. Stirring was continued overnight under an atmosphere of nitrogen. The solution was concentrated under reduced pressure, and final traces of water removed by azeotroping with benzene and ethanol. The residual brown oil was chromatographed on silica gel (dichloromethane-methanol, 95:5 as eluant) to give the title compound as an oil (8.5 g, 71%). IR: υmax (film), 3400, 3000, 2940, 2880, 1450, 1400, 1230, 1170, 1070, 1030, 970, 820, 790 cm-1. 1H NMR: δH ((CD3)2SO) 1.25 (6H, t, J=8Hz, (OCH2CH3)2), 1.3-2.05 (4H, m, CH2CH2P), 3.1-3.5 (3H, m, HOCH2CH(OH)), 4.0 (4H, m, (OCH2CH3)2), 4.6 (2H, m, D2O exchangeable, HOCH2CH(OH)). Found: C, 42.57; H, 8.56%. C8H19O5P requires: C, 42.47; H, 8.46%. m/z:C8H20O5P requires 227.1048; observed: 227.1045 (MH+).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[C:16]1([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](Cl)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:12][C:24]([C:23]2[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(NC(=O)c2ccccc2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.4 %

Procedure:
Pyridine (3.6 mL, 45 mmol) and 3-methoxyaniline (1.54 g, 12.5 mmol) were added to a solution of 2-phenylbenzoyl chloride (3.25 g, 15 mmol) in dichloromethane (30 mL) The reaction mixture was stirred at room temperature for 2.5 hours. 1M HCl solution (45 mL) was added, and the organic layer was washed with 1M NaOH solution (10 mL), aqueous sodium bicarbonate (30 mL), and brine (30 mL). The organic phase was concentrated to dryness to give the title compound as a tan solid (3.92 g). MH+304: 1H (D6-DMSO) δ 3.67 (3H, s), 6.60 (1H, dd, J=8, 2), 7.04 (1H, d, J=8), 7.14 (1H, t, J=8), 7.18 (1H, m), 7.23-7.57 (9H, m), 10.0 (1H, s, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[NH2:42][C:43]1[S:44][CH:45]=[C:46]([CH3:48])[N:47]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:34]([NH:42][C:43]1[S:44][CH:45]=[C:46]([CH3:48])[N:47]=1)=[O:40]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: Cc1csc(N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nc(C)cs4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 126 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and pyridine (0.1 ml) to prepare a solution. A solution of triphosgene (45 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-amino-4-methylthiazole (38 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Iced water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine and was then dried over anhydrous sodium sulfate. The dried organic layer was filtered and was then concentrated. Ether was added to the residue for crystallization, and the crystal was collected by filtration. The crystal was purified by chromatography (chloroform:acetone=2:1) to give 90 mg of the title compound.