Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH3:4].Cl[CH2:11][C:12]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[C:19]2[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:37][CH3:38])[CH:18]=2)[N:13]=1.O>CN(C)C=O>[CH2:3]([C:5]1[N:6]([CH2:11][C:12]2[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=3)[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:37][CH3:38])[CH:18]=3)[N:13]=2)[CH:7]=[CH:8][N:9]=1)[CH3:4]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2ccnc2CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Oily sodium hydride (60%, 0.323 g) was added to a solution of 2-ethylimidazole (0.776 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 15 minutes. Then ethyl 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate(3.0 g) was added. The mixture was stirred at 80° C. for 1 hour and poured into water, and the resulting crystals were collected by filtration and recrystallized from ethanol to give ethyl 2-(2-ethylimidazol-1-ylmethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (2.5 g, 74%). Colorless prisms. mp. 163°-164° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]=[CH:9][N:8]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(OCCOCc2ccccn2)ccnc1CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCCOCc2ccccn2)ccnc1CCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
0.71 g (6 mmol) of thionyl chloride was added to a solution of 0.40 g (1.5 mmol) of 2-hydroxymethyl-3-methyl-4-(2-pyridylmethoxyethoxy)pyridine in 10 ml of chloroform under cooling with ice to obtain a mixture. This mixture was stirred at 0° C. for 2 hours. After the completion of the reaction, the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 50 ml of chloroform four times. The extract was dried over magnesium sulfate and filtered. The obtained filtrate was concentrated and dried in a vacuum to obtain 0.42 g of crude 2-chloromethyl-3-methyl-4-(2-pyridylmethoxyethoxy)pyridine as a semicrystal.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[Br-].C(CCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(O)=O.[C:38]([N:57]1[CH:61]=[C:60]([CH:62]=O)[N:59]=[CH:58]1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[C:64]([OH:76])(=[O:75])[CH2:65][C:66]([CH2:71][C:72](O)=O)(C(O)=O)O>C1COCC1>[C:38]([N:57]1[CH:61]=[C:60]([CH:62]=[CH:72][CH2:71][CH2:66][CH2:65][C:64]([OH:76])=[O:75])[N:59]=[CH:58]1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -75 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
13.5 ml (14.3 mmol) of a solution of lithium hexamethyldisilazane at 1.06 M in THF are added to 3.27 g (7.38 mmol) of (4-carboxybutyl)triphenyl-phosphonium bromide in suspension in 45 ml of THF cooled to −75° C. The reaction medium is stirred at −75° C. for 20 minutes and then at 0° C. for 15 minutes. After a return to −75° C., 1.50 g (4.43 mmol) of 1-trit-yl-1H-imidazole-4-carbaldehyde in suspension in 15 ml of THF are introduced. After a return to ambient temperature, the reaction medium is stirred for 20 hours and then at 90° C. with microwave-heating for 5 minutes. The reaction medium is filtered and concentrated in a rotary evaporator and then taken up in 1/1 heptane/EtOAc. The organic phase is washed with a saturated aqueous solution of NaHCO3. The aqueous phase obtained is acidified to pH=5 with an aqueous solution of citric acid at 5% and then extracted with a 1/1 heptane/EtOAc mixture. The organic phase is dried over MgSO4, filtered and concentrated in a rotary evaporator. 0.58 g of 6-(1-trityl-1H-imidazol-4-yl)hex-5-enoic acid in the form of a beige powder are obtained with a yield of 31%.
Reaction SMILES: Cl.C([O:6][C:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[S:27])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)=[O:18])[C@H:11]([NH:28][C:29]([C:31]2[S:32][C:33]3[CH2:34][N:35]([CH3:40])[CH2:36][CH2:37][C:38]=3[N:39]=2)=[O:30])[CH2:10]1)=[O:8])(C)(C)C>O1CCOCC1>[ClH:26].[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17](=[O:18])[C:16]([NH:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([C:7]([OH:8])=[O:6])[CH2:10][C@H:11]2[NH:28][C:29]([C:31]2[S:32][C:33]3[CH2:34][N:35]([CH3:40])[CH2:36][CH2:37][C:38]=3[N:39]=2)=[O:30])=[S:27])=[N:21][CH:22]=1
Reactant: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)OC(C)(C)C)CC[C@@H]3NC(=S)C(=O)Nc3ccc(Cl)cn3)sc2C1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@@H]3NC(=S)C(=O)Nc3ccc(Cl)cn3)sc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 170.8 %

Procedure:
4N HCl in dioxane (10 mL) was added to a solution of the compound obtained in Example 377 (293 mg) in dioxane (8.0 mL), and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced mixture, and the residue was suspended in diisopropyl ether and then collected through filtration. The collected powder was dissolved in water and then neutralized with saturated aqueous sodium bicarbonate. The aqueous solution was extracted with methylene chloride, and the formed organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. 1N HCl in ethanol (0.50 mL) was added to the residue, and the mixture was subjected to concentration under reduced pressure. The residue was dissolved in water, followed by freeze-drying, to thereby yield the title compound (242 mg).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=1>O1CCCC1>[CH3:19][C:20]1[NH:24][N:23]=[C:22]([NH:25][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:21]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1cc(N)n[nH]1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cc(NC=C2C(=O)Nc3ccccc32)n[nH]1

Procedure:
The named compound is prepared by substituting 5-methyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1345 gms. of 5-methyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[O:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:29]4[CH:30]=[CH:31][O:27][CH:28]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccoc1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccoc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 3-furaldehyde to provide 19 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([NH:19]C=O)/[CH:5]=[C:6](/[CH2:10][P:11]([O:16]CC)([O:13]CC)=[O:12])\[CH2:7][CH:8]=[CH2:9].C[Si](C)(C)I.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>ClCCl.C(O)C>[NH2:19][CH:4](/[CH:5]=[C:6](/[CH2:10][P:11]([OH:16])([OH:13])=[O:12])\[CH2:7][CH:8]=[CH2:9])[C:3]([OH:22])=[O:2]
Reactant: C=CC/C(=C\C(NC=O)C(=O)OC)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)I
Agent: Cl
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCO
Product: C=CC/C(=C\C(N)C(=O)O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.74 g of E-2-formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid methyl ester is dissolved in 12 ml of dichloromethane, and 0.7 ml of trimethyliodosilane is added dropwise thereto. After stirring at room temperature for 4 hours, 1N sodium thiosulphate solution is added until the colour of the reaction solution becomes lighter. 10 ml of a 4.5N hydrochloric acid solution are then added to the reaction mixture, which is then stirred at room temperature for 30 minutes. The aqueous phase is separated off, washed twice with 20 ml of dichloromethane each time, and concentrated by evaporation in vacuo. The residue is dissolved in 10 ml of4.5N hydrochloric acid, stirred at room temperature for 16 hours, and then concentrated by evaporation in vacuo. The residue so obtained is taken up in 40 ml of ethanol and filtered until clear, and then 10 ml of propylene oxide/ethanol (1:1) are added dropwise. The resulting white precipitate isfiltered off and purified by column chromatography (Dowex 50×8/H2O). Concentration yields E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid in the form of a white crystallisate, m.p. 154°-157°, 1H-NMR (D2O): 2.64 (d, 2H, P--CH2); 3.15 (m, 2H, C(5)--H); 5.20 (m, 2H, C(7)--H); 5.50 (dd, 1 H, C(3)--H); 5.90 (m, 1 H, C(6)--H).
Reaction SMILES: C(N(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26]C3CCCOC3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)CCC.Cl.[O:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:39]([O:38][C:6]1[CH:7]=[CH:8][C:9]([CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH2:23][CH2:24][CH2:25][OH:26])(=[O:21])=[O:22])=[CH:18][CH:19]=2)=[CH:10][CH:11]=1)[CH2:40][CH2:41][CH2:42][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:9][CH2:8][CH2:7][CH2:6][CH2:11][CH3:10]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(S(=O)(=O)CCCOC3CCCOC3)cc2)cc1
Reactant: C1CCOC1
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C=Cc2ccc(S(=O)(=O)CCCO)cc2)cc1
Temperature: 50 °C

Procedure:
9.02 g (13.8 mmol) of 3i are dissolved in 140 ml of tetrahydrofuran. After addition of 100 ml of 2M hydrochloric acid the mixture is heated at 50° C. for 4 hours. The mixture becomes turbid and on cooling a colorless precipitate separates, which is filtered off and first washed with a little THF and then with water. The solid is dried in a vacuum desiccator. 4.50 g of colorless powder of m.p. 137° C. are obtained. The mother liquor is concentrated, extracted a number of times with dichloromethane, the extracts are dried with magnesium sulfate, the solvent distilled off and the resulting oily residue is chromatographed with isohexane/acetic ester mixtures on a silica gel column. A total of 5.90 g (75%) of product are isolated.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[CH:11][C:3]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(F)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cnc2[nH]ccc2c1Cl
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution 4-chloro-5-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.04 g) in tetrahydrofuran (4.77 mL) was added dropwise tetra-n-butylammonium fluoride (0.372 mL, 1.0M in tetrahydrofuran) at ambient temperature. After stirred for 1 hour, the mixture was poured into brine (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layeres were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane/EtOAc=1/1) to give 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (520 mg) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1nc2c(Br)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(Br)cccc5s4)cc3CC[C@@H]12
Yield: 78.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-bromobenzothiazole (114 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 142 mg (79%) of the title compound as an off white solid. mp 206°-210°. FDMS: m/e=474. α[D]589 =+56.25 (c=0.59, chloroform).
Reaction SMILES: [NH4+].[Cl-].[CH2:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:15])[CH:11]=2)[O:6]1)[CH3:4].C(C1CCC2C(=C(N)C=CC=2)O1)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>CO.C(Cl)Cl.[Fe]>[CH2:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH:11]=2)[O:6]1)[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1CCc2cc(N)ccc2O1
Agent: [Fe]
Agent: CCC1CCc2cccc(N)c2O1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CCC1CCc2cc(NS(C)(=O)=O)ccc2O1
Temperature: 85 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
The mixture of the title compounds from Step 4 (600 mg) was suspended in MeOH (6 mL) and sat. NH4Cl solution (2 mL). Fe (810 mg, 14.5 mmol) was added and the mixture was heated to 85° C. for 2.5 h. It was then filtered and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure to give a crude mixture of 2-ethyl-3,4-dihydro-2H-chromen-6-amine and 2-ethyl-3,4-dihydro-2H-chromen-8-amine. This mixture was dissolved in DCM (10 mL) and TEA (0.8 mL) and methanesulfonyl chloride (400 mg, 3.50 mmol) were added. The mixture was stirred at rt for 1 h. It was then extracted with DCM (45 mL×2), dried over Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography (PE/EA 50:1 to 20:1 to 10:1) to give the title compound (190 mg, 12% for three steps) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 6.99-6.80 (m, 2H), 6.78 (d, J=8.7 Hz, 1H), 6.16 (s, 1H), 3.95-3.90 (m, 1H), 2.96 (s, 3H), 2.83-2.76 (m, 2H), 2.04-1.97 (m, 1H), 1.81-1.64 (m, 3H), 1.05 (t, J=7.2 Hz, 3H). LCMS: 273 (M+NH4)+
Reaction SMILES: [CH3:1]N(C)C1(C2C=CC=CC=2)CCC(=O)CC1.[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:27][CH2:28][OH:29].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>[OH-].[Na+]>[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]1[CH2:1][O:29][CH2:28][CH2:27][C:21]2=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Cc1ccc2[nH]cc(CCO)c2c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2[nH]c3c(c2c1)CCOC3
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Dimethylamino-4-phenylcyclohexanone (325 mg, 1.5 mmoles) and 2-(5-methyl-1H-indol-3-yl)-ethanol (“5-methyltryptophol”, 262 mg, 1.5 mmoles) were initially introduced into abs. MC (10 ml) under argon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.3 ml, 1.55 mmoles) was then added very rapidly. The mixture was stirred at room temperature for 24 hours. For working up, 1 M NaOH (20 ml) was added to the reaction mixture and the mixture was stirred for 30 min. The organic phase was separated, and the aqueous phase which remained was extracted with MC (3×20 ml). The combined organic phases were washed with water (2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added to the solid residue obtained after the solvent had been distilled off, and the mixture was heated, and stirred for 15 hours. The suspended solid was filtered out with suction. One of the two possible diastereoisomers of 1,143-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole was obtained (430 mg, m.p. 259-270° C.). 350 mg of this were dissolved in hot ethanol (300 ml), and a similarly hot solution of citric acid (300 mg, 1.56 mmoles) in ethanol (10 ml) was added. After approx. 15 minutes, crystals precipitated out at the boiling point. After cooling to approx. 5° C., the mixture was left to stand for 2 hours. The resulting solid was filtered out with suction. It was possible to obtain the hemicitrate of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole in this way in a yield of 380 mg (white solid, m.p. 243-265° C.).
Reaction SMILES: [CH3:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([O:20]CCO)=[CH:16][CH:15]=1)([C:4]1[CH:9]=[CH:8][C:7]([O:10]CCO)=[CH:6][CH:5]=1)[CH3:3].C(OCCN=C=O)(=O)C(C)=C>>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([CH3:3])[CH3:1])=[CH:9][CH:8]=1
Reactant: CC(C)(c1ccc(OCCO)cc1)c1ccc(OCCO)cc1
Agent: C=C(C)C(=O)OCCN=C=O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 26 h

Procedure:
A total of 200 g (0.345 mol) of dry Photonol 7025 is placed into a 1L three neck flask equipped with mechanical agitation, and gas-inlet tube. The system is flushed with dry nitrogen and then dry oxygen. To the BPA are added 375 g of dry acetonitrile and allowed to mix until the BPA has completely dissolved. Subsequently 2 drops of stannous octoate and 500 ppm MEHQ are, added. Via a dropping funnel are added 107.1 g (0.690 mol) of isocyanatoethyl methacrylate. The reaction is allowed to proceed at room temperature for 24-28 hours. The progress of the reaction is followed by the disappearance of the NCO absorption at 2270 cm-1 in the infrared spectra. The acetonitrile is removed under reduced pressure, and the resultant viscous liquid dicapped SPA 890 is used as is.
Reaction SMILES: C([O:9][CH2:10]/[C:11](/[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[OH:9][CH2:10]/[C:11](=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)/[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24]
Reactant: CC(C)(C)OC(=O)/C(=C/CCCCc1ccccc1)COC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C(=C/CCCCc1ccccc1)CO
Temperature: 0 °C
Yield: 50.5 %

Procedure:
(E)-2-t-Butoxycarbonyl-7-phenylhept-2-enyl benzoate (5.9 g, 15 mmol) is dissolved in MeOH (75 mL) and cooled to 0° C. K2CO3 (2 g, 15 mmol) is added with stirring and the reaction is allowed to warm to 23° C. After 2 hours the reaction is neutralized with HOAc and the reaction is concentrated to approximately half of its volume. After diluting with ether (500 mL), the solution is washed with water (50 mL) and brine (50 mL). The resulting solution is dried (MgSO4) and concentrated in vacuo. The crude reaction mixture is purified by column chromatography (silica, 25% ether in petroleum ether) to give t-butyl (E)-2-hydroxymethyl-7-phenylhept-2-enoate (2.2 g, 51%): 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.20-7.15 (m, 3H), 6.75 (t, J=7.7 Hz, 1H), 4.28 (d, J=6.8 Hz, 2H), 2.65-2.60 (m, 3H), 2.26 (q, J=7.5 Hz, 2H), 1.71-1.61 (m, 2H), 1.53-1.43 (m, 11H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([OH:20])=O)[C:13]2[C:8](=[CH:9][C:10]([CH3:21])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].FC1C(O)=C(F)C(F)=C(F)C=1F.[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:37]2[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]2)=[O:20])[C:13]2[C:8](=[CH:9][C:10]([CH3:21])=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1cc(OCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(C)cc2n1

Procedure:
To a solution of 990 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid ethyl ester in 5 ml DMF were added 945 mg pentafluorophenol and 984 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. Tert-Butyl 1-piperazinecarboxylate (437 mg) was mixed with 0.8 ml N-ethylmorpholine and 10 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 988 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:14](Cl)(=O)C(Cl)=O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cnc2cc(Br)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 246.5 %

Procedure:
A 50 mL flask equipped with a reflux condenser and a nitrogen line was charged with 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (1.00 g, 4.15 mmol), DCM (20 mL), oxalyl chloride (0.72 mL, 1.46 mmol), and chilled in a ice-water bath. Four drops of DMF were added to the reaction, and the flask was stirred at ambient temperature overnight. The reaction mixture was concentrated to dryness, chilled in an ice water bath, and 30 mL MeOH were added under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature overnight, concentrated to dryness, and re-suspended in saturated, aqueous sodium bicarbonate solution. The suspension was extracted with DCM and EtOAc, the combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the desired product (0.918 g) as a tan solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][C:13](Cl)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(OCC)(=O)C.O>[Cl-].[Na+].O>[CH2:1]([NH:8][C:9](=[O:24])[C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of 5.0 g (14.8 mMol) of N-benzyl-6-chloro-4-o-tolyl-nicotinamide and 25 ml morpholine was heated to 100° C. for 3.5 hours. After cooling to room temperature, extractive work-up with ethyl acetate, water and brine gave 5.7 g (100%) N-benzyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide as a yellow powder.