Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromohexane (0.192 g, 1.16 mmol) in DMF (5.3 mL). Heat at 70° C. overnight, then increase the temperature to 100° C. for additional two hours. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1× 50 mL), brine (1× 50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 7% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2334, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.6 min, 97.8% purity.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23]Br)[C:8]=1[CH2:25][CH2:26][CH3:27])[CH3:2].[OH:29][C:30]1[C:35]([CH2:36][CH2:37][CH3:38])=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=1[C:40](=[O:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][O:39][C:34]2[CH:33]=[CH:32][C:31]([C:40](=[O:42])[CH3:41])=[C:30]([OH:29])[C:35]=2[CH2:36][CH2:37][CH3:38])[C:8]=1[CH2:25][CH2:26][CH3:27])[CH3:2]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCOCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 73.8 %

Procedure:
A mixture of 1.89 g (0.004 mole) of [4-acetyl-3-[3-(3-bromopropoxy)propoxy]-2-propylphenoxy]acetic acid ethyl ester, 0.80 g (0.004 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, and 1.14 g (0.0082 mole) of potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 35% ethyl acetate-hexane to give 1.69 g (72% yield) of [4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH:24][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ncnc(Cl)c12
Solvent: CCO
Product: Cc1c(C)n(Cc2ccccc2)c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
0.6 g of 4-chloro-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine and 0.28 ml of m-chloroaniline are heated at reflux in 10 ml of ethanol for 17 hours. The brown solution is concentrated to dryness by evaporation, the residue is taken up in ethyl acetate, and the ethyl acetate solution is washed until neutral with sodium hydrogen carbonate solution and water, dried and concentrated by evaporation. The residue is crystallised from ethyl acetate/hexane. 4-(m-Chloroanilino)-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine is obtained in the form of white crystals having a melting point of 132°-133° C.
Reaction SMILES: Br[CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(#N)C>O>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]2[C@H:11]([OH:12])[C@H:2]([CH2:3][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[S:4][C:5]=2[CH:6]=1
Reactant: OC1c2ccc(Cl)cc2SCC1Br
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: O[C@H]1c2ccc(Cl)cc2S[C@H]1Cn1ccnc1

Procedure:
Add 3-bromo-7-chlorothiochroman-4-ol (5.27 g., 18.8 mmole) and imidazole (12.8 g., 188 mmole) to acetonitrile (100 mL.), and reflux for 4 hours. Pour the reaction mixture into water (500 mL.), and extract with chloroform (500 mL.). Wash the organic layer with water (500 mL.), dry it over anhydrous magnesium sulfate, filter and evaporate in vacuo. Triturate the residue with anhydrous ether, filter and recrystallize from acetonitrile to give (±)-cis-6-chloro-2,3-dihydro-3-hydroxy-2-(1H-1-imidazolylmethyl)benzo[b]thiophene, m.p. 164°-165° C.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][O:10][CH3:11])[CH:5]=[N:4][C:3]=1[C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][N:13]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:6]([CH2:7][CH2:8][CH2:9][O:10][CH3:11])[CH:5]=[N:4][C:3]=2[C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][N:13]=2)=[CH:23][C:22]=1[F:30]
Reactant: COCCCn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: COCCCn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 2-[5-bromo-1-(3-methoxypropyl)-1H-imidazol-4-yl]pyridine-4-carbonitrile and 4-chloro3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C19H16ClFN4O, 372. Found, 371, 373.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9](=O)[C:10]([CH2:14][CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:9]1[C:10]([CH2:14][CH3:15])=[C:11]([CH3:13])[N:12]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
An 100-mL round bottomed flask was charged 2-(5-Chloro-2-thienyl)-5-ethyl-4-methyl-1H-pyrimidin-6-one (4 g, 15.7 mmol). POCl3 (16 ml) was added. The resulting mixture was stirred at 90 C for 6 hr. After cooling to room temperature, the volatile material was removed under reduced pressure and the residue was with NaHCO3 aq (100 ml). Dichloromethane was added. The organic layer was separated and passed through a plug of silica gel, using dichloromethane as eluent to give the title compound as a solid (2.82 g, 66% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:11]=[C:10]([O:12][CH:20]([CH3:22])[CH3:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OC(C)C)cc1F
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a mixture of methyl 2-fluoro-4-hydroxy-benzoate (2.1 g, 12.4 mmol), potassium carbonate (6.8 g, 49.5 mmol) in dry DMF (13 mL) was added 2-iodopropane (2.5 mL, 24.8 mmol) and the reaction mixture was heated at 60° C. for 2 hours. The reaction was cooled and diluted with ether (50 mL) and filtered over Celite®. The filtrate was washed sequentially with water (3×25 mL) and brine solution (25 mL). The organic layer was separated and dried over MgSO4 and solvent was concentrated in vacuo to give a residue which was purified by silica gel column chromatography using 5-45% EtOAc/hexanes to give methyl 2-fluoro-4-isopropoxybenzoate as a colorless oil (2.2 g, 83%). To a solution of methyl 2-fluoro-4-isopropoxybenzoate (2.2 g, 10.3 mmol) in THF (5.5 mL) was added a suspension of lithium hydroxide (0.9 g, 37.1 mmol) in water (5.5 mL). The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and the excess LiOH was removed by filtration. The filtrate was diluted with water (9 ml), and washed with ether (2×5 mL). The aqueous layer was separated and cooled to 0° C. and the pH was adjusted to pH 2 by addition of 6 M HCl solution. The aqueous layer was extracted with EtOAc (3×30 mL). The organics were separated and washed sequentially with water and brine. The organic layer was separated, dried and concentrated in vacuo to give 2-fluoro-4-isopropoxy-benzoic acid (2.45 g, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (t, J=8.8 Hz, 1H), 6.69 (ddd, J=15.1, 10.9, 2.0 Hz, 2H), 4.63 (dt, J=12.1, 6.0 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH:6]=1)=[O:4].C(N=C(N(C)C)N(C)C)(C)(C)C.[N+:33]([CH3:36])([O-:35])=[O:34]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=3[CH:6]([CH2:36][N+:33]([O-:35])=[O:34])[CH:5]([C:3]([O:2][CH3:1])=[O:4])[C:11]=2[CH:12]=1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C1=Cc2ccccc2Oc2ccc(Cl)cc21
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Product: COC(=O)C1c2cc(Cl)ccc2Oc2ccccc2C1C[N+](=O)[O-]

Procedure:
Example 8 of the European Patent EP 1710241 B1 also describes an alternative process for the synthesis of the lactam (VI), see Scheme 4. In this example, (5-chloro-2-phenoxyphenyl)acetic acid methyl ester (compound VIIIa) is reacted with methyl formate in the presence of potassium tert-butoxide to give 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylic acid methyl ester (compound IXa, E/Z mixture 9:1), which is directly cyclized with pyrophosphoric acid to obtain methyl 2-chlorodibenzo[b,f]oxepin-11-carboxylate (compound Xa), referred to us 8-chlorodibenzo[b,f]oxepin-10-carboxylic acid methyl ester in EP 1710241 B1, with 85% yield. This compound is then reacted with nitromethane in the presence of tert-butyl-tetramethylguanidine to give methyl 2-chloro-10-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIa), referred to us 8-chloro-1′-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, with a trans to cis ratio of 8:1, which is directly hydrogenated in the presence of a sponge nickel catalyst to give methyl 10-aminomethyl-2-chloro-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIIa), referred to us 11-aminomethyl-8-chloro-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, which after treatment with potassium tert-butoxide and dimethyl sulphate, is converted into the lactam (VIa) with an overall yield of 81% from compound (Xa), but predominantly corresponding to the undesired cis-isomer (approximately 85:15 ratio with respect to the trans-isomer), being therefore necessary to carry out one of the above described low-yield processes for the conversion of undesired cis-(VI) to trans-(VI).
Reaction SMILES: [C:1]([N:4]1[CH2:23][CH2:22][CH2:21][C@H:5]1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH3:10])=[O:7])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:39]([O:41][C:42](=[O:56])[C:43]([C:51](=[O:55])[CH:52]([CH3:54])[OH:53])([CH2:45][C:46](=[O:50])[N:47]([CH3:49])[NH2:48])[OH:44])[CH3:40]>C(#N)C>[CH2:39]([O:41][C:42](=[O:56])[C:43]([C:51](=[O:55])[CH:52]([CH3:54])[OH:53])([CH2:45][C:46](=[O:50])[N:47]([CH3:49])[NH:48][C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6](=[O:7])[C@@H:5]1[CH2:21][CH2:22][CH2:23][N:4]1[C:1](=[O:3])[CH3:2])[OH:44])[CH3:40]
Reactant: CCOC(=O)C(O)(CC(=O)N(C)N)C(=O)C(C)O
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)C(O)(CC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O)C(=O)C(C)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.00185 moles of acetylprolylalanylproline and 0.20 ml of N-methylmorpholine in 20 ml of acetonitrile is cooled to -20° by means of a Dry Ice acetone bath. To this is added 0.28 ml of isobutyl chloroformate. After stirring for 10 minutes at -20° there is added 0.00185 moles of 2-azaalanyllactyllactic acid ethyl ester in 5 ml of acetonitrile. The reaction mixture is allowed to warm to room temperature after which it is stirred for 2 hours and then concentrated in vacuo. The residue is extracted between 50 ml of methylene chloride and 20 ml of cold 0.25 N hydrochloric acid. The acid layer is backwashed 2 times with 25 ml of methylene chloride. The organic extracts are combined, dried over sodium sulfate and concentrated in vacuo to give a glass. This residue is chromatographed on 75 gm of silica gel. Elution with methanol/methylene chloride (1-4%) gives pure acetylprolylalanylprolyl-2-azaalanyllactyllactic acid ethyl ester.
Reaction SMILES: [CH2:1]=[CH:2][N:3]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]1.N(C(C)(C)C#N)=N[C:11](C)(C)C#N.[C:21]([O:25][CH2:26][CH2:27][CH2:28]C)(=[O:24])[CH:22]=[CH2:23].CCCCCC>CN(C)C=O>[CH:2]([N:3]1[CH2:4][CH2:5][CH2:6][C:7]1=[O:8])=[CH2:1].[C:21]([O:25][CH:26]([CH2:27][CH3:28])[CH3:11])(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)OCCCC
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C=CN1CCCC1=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CC(=O)OC(C)CC
Temperature: 60 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
Along with 228 mg (0.08 mmol) of poly(1-vinyl-2-pyrrolidone) macroinitiator prepared in Example 67, 3.3 mg (0.02 mmol) of 2,2′-azobis(isobutyronitrile) and 1.04 g (8.1 mmole) of n-butyl acrylate (same as above) were placed into a glove box with the inside air replaced by nitrogen, followed by stirring at 60° C. for 6 hours. After the completion of the reaction, the reaction mixture was dissolved in 5 ml of N,N-dimethylformamide (DMF), and the solution was then poured into 300 ml of hexane which was being stirred. The resulting polymer precipitate was collected by suction filtration and dried to obtain block copolymer of poly(1-vinyl-2-pyrrolidone-b-n-butyl acrylate) (yield 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([OH:24])(=[O:23])[C:17]([CH2:19][C:20](O)=[O:21])=[CH2:18]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:13]2[C:20](=[O:21])[CH2:19][CH:17]([C:16]([OH:24])=[O:23])[CH2:18]2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
18.8 g (94.4 mmol) 4-benzyloxyaniline are mixed with 12.28 g (94.4 mmol) itaconic acid. The mixture is heated to 130° C. After 20 min the melted material solidifies. The resulting solid is triturated with ethyl acetate to yield 28.26 g (96%) of a greyish solid. MS: m/e=311 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>CO.O>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:11][NH:14][CH2:13][CH2:12][NH2:15]
Reactant: NCCN
Reactant: COc1ccc(C2CO2)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(C(O)CNCCN)cc1

Procedure:
N-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-ethylenediamine is prepared by reacting 2-(4-methoxyphenyl)oxirane (37.5 g.) dissolved in methanol (52 cc.) with ethylenediamine (30 cc.) dissolved in a mixture of methanol (52 cc.) and water (20 cc.). On distillation under reduced pressure, a product (22.3 g.), b.p. 165°-169° C./0.2 mm.Hg, is obtained, which crystallises on cooling and melts at 68° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[I:19]Cl.O>C(O)(=O)C>[I:19][C:10]1[C:11]([NH2:13])=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:8][CH:9]=1
Reactant: Nc1ccnc(N2CCOCC2)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(N2CCOCC2)ncc1I
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 17.8 %

Procedure:
To a stirred solution of 92.8 g (311 mmol, 60 wt % purity) 2-morpholin-4-yl-pyridin-4-ylamine in 1000 ml glacial acetic acid was added 76.5 g (932 mmol) sodium acetate and the mixture was then cooled to 15° C. in an ice-bath. A solution of 50.4 g (311 mmol) iodine monochloride in 200 ml glacial acetic acid was then added dropwise at a rate such that the reaction temperature remained at 10-15° C. After 40 min the addition was complete. The reaction mixture was then stirred for a further 20 min before being poured onto 1000 ml water. The mixture was concentrated in vacuo and the residue partitioned between THF/ethyl acetate (1:1) and saturated brine. 5 N aqueous sodium hydroxide solution was added until the aqueous phase was pH 14, whereupon some product precipitated. The crystals were collected by filtration to afford 16.9 g (18%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. The mother liquid phases were separated and the organic phase dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether and the resulting crystals collected by filtration to afford a further 47.2 g (50%) of 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. The mother liquor was concentrated in vacuo and the residue was purified by flash chromatography (1/1-1/2 heptane/ethyl acetate) to afford a further 9.4 g (10%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. Meanwhile, the aqueous phase from the initial aqueous extraction was left to stand for 2 days whereupon crystals deposited. These crystals were collected by filtration to afford a further 5.2 g (5%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: CS(O[CH2:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH:8]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:6][C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=3)[CH:8]=2)[CH2:30][CH2:29]1
Reactant: CS(=O)(=O)OCc1cc2ncc(C(F)(F)F)cc2s1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(Cc2cc3ncc(C(F)(F)F)cc3s2)CC1

Procedure:
The solution from Example 25C (2 mL) and 1-(2-methoxyphenyl)piperazine (192 mg) were processed as described in Example 25D to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 3.11 (4H, t, J=4.8 Hz), 3.45 (4H, J=4.8 Hz), 4.19 (s, 3H), 4.30 (s, 2H), 6.90 (4H, m), 7.80 (1H, s), 8.63 (1H, m), 9.20 (1H, m). MS (DCI/NH3) m/z 408.2 (M+H)+. Anal. Calcd for C20H20N3F3OS: C, 58.96; H, 4.95; N, 10.31. Found: C, 58.98; H, 4.95; N, 10.53.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[CH:8]=[C:9]([Cl:26])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[C:12]2[C:24]#[N:25])[CH3:6].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([CH2:50][OH:51])[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>ClCCl>[Cl:26][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([CH:5]([O:51][CH2:50][C:37]3([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=4)[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:41][CH2:42]3)[CH3:6])[CH:8]=1)[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[C:12]2[C:24]#[N:25]
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38.1 %

Procedure:
Fluoroboric acid diethylether complex (0.015 g, 0.095 mmol) was added to a 0° C. solution of (±)-1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (0.945 g, 1.907 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.59 g, 1.907 mmol) in Dichloromethane (10 mL) and was stirred for 20 min at 0° C. TLC indicated the reaction was complete, and the reaction was quenched with aqueous sodium bicarbonate (10 mL). The reaction was extracted with ethyl acetate (3×10 mL) and the organic phase was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 15%-20% ethyl acetate/hexanes to give (±)-tert-butyl 4-((1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (466 mg, 0.726 mmol, 38.0% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.60 (d, J=2.0 Hz, 1H), 7.49 (s, 1H), 7.15 (m, 2H), 7.05 (d, J=2.0 Hz, 1H), 6.94 (app t, J=8.6 Hz, 2H), 5.22 (m, 2H), 5.07 (m, 1H), 3.66 (m, 2H), 3.33 (app t, J=8.3 Hz, 2H), 3.22 (d, J=8.8 Hz, 1H), 3.11 (d, J=8.8 Hz, 1H), 3.02 (m, 2H), 2.07 (m, 2H), 1.79 (m, 2H), 1.42 (d, J=6.3 Hz, 3H), 0.65-0.90 (m, 2H), −0.08 (s, 9H).
Reaction SMILES: [CH2:1](N1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=S)=CC=3F)C=2C=C1)C1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59](=[O:67])[CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12.CC(C)C(C1C=CC=CC=1)C(N=C=S)=O>>[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59](=[O:67])[CH:60]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH3:1])=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ccn3Cc2ccccc2)c(F)c1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Agent: CC(C)C(C(=O)N=C=S)c1ccccc1
Product: CC(C(=O)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)c1ccccc1
Yield: 49 %

Procedure:
Starting from the amine 169 (scheme 33), following the procedures described above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl isothiocyanate with 3-methyl-2-phenylbutanoyl isothiocyanate, title compound 192e was obtained in 49% yield. Characterization of 192e is provided in table 18.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:35]=[CH:34][C:13]2=[C:14]3[C:19](=[C:20]([NH2:22])[N:21]=[C:12]2[CH:11]=1)[N:18]=[CH:17][C:16]([C:23]#[C:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[CH:15]3)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[CH:35]=[CH:34][C:13]2=[C:14]3[C:19](=[C:20]([NH2:22])[N:21]=[C:12]2[CH:11]=1)[N:18]=[CH:17][C:16]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[CH:15]3)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc(C#Cc2cnc3c(N)nc4cc(CO[Si](C)(C)C(C)(C)C)ccc4c3c2)c(C)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CCc2cnc3c(N)nc4cc(CO[Si](C)(C)C(C)(C)C)ccc4c3c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 8-((tert-butyldimethylsilyloxy)methyl)-2-(4-methoxy-2-methylphenyl)ethynyl)benzo[f][1,7]naphthyridin-5-amine (from step 4) (1 equiv.) with a stirring bar. Ethanol and methylene chloride (1:2, 0.2 M) were added, followed by palladium in carbon (activated powder, wet, 10% on carbon, 0.1 equiv.). The contents were vacuumed followed by hydrogen flush for three times. The reaction mixture was stirred vigorously under hydrogen balloon at room temperature overnight. Afterwards the reaction mixture was filtered through a celite pad, and the celite pad was washed subsequently with methylene chloride and EtOAc until filtrate has no UV absorption. Combined organic washes were concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded 8-((tert-butyldimethylsilyloxy)methyl)-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-5-amine as a yellow solid.