Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[C:4]([C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:54]=[CH:55][CH:56]=2)[C:18]([NH:20][C:21]2[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][S:44]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[CH:38]=[CH:37][C:22]=2[O:23][CH2:24][CH2:25][N:26]2C(=O)C3=CC=CC=C3C2=O)=[O:19])[S:11][CH:12]=1)([CH3:7])([CH3:6])[CH3:5].C(O)C>O1CCCC1>[C:4]([C:8]1[N:9]=[C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:54]=[CH:55][CH:56]=2)[C:18]([NH:20][C:21]2[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][S:44]([C:47]3[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=3)(=[O:45])=[O:46])[CH:38]=[CH:37][C:22]=2[O:23][CH2:24][CH2:25][NH2:26])=[O:19])[S:11][CH:12]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCCN3C(=O)c4ccccc4C3=O)c2)n1
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCCN)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, hydrazine monohydrate (190 μl, 3.8 mmol) was added to a mixture of N-[2-[2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxy]ethyl]phthalimide (1.5 g, 1.9 mmol), ethanol (5 ml) and tetrahydrofuran (20 ml), and the resulting mixture was stirred overnight at room temperature and then heated under reflux for 3 hours. Ice-water was added to the reaction solution, and then the product formed was extracted with chloroform. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and distilled water in that order, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was purified by silica gel column chromatography (eluent=chloroform:acetone=2:1), made into hydrochloride by adding 4 N hydrochloric acid/ethyl acetate, and then crystallized from diethyl ether to give 3-[(4-tert-butyl-2-thiazolyl)methoxy]-5'-[3-(4-chlorophenylsulfonyl)-propyl]-2'-(2-aminoethoxy)benzanilide 1.4 hydrochloride.0.7 hydrate (160 mg, 0.23 mmol, 12%) as white crystals.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:4].[OH-].[Li+].Cl>CO>[CH:25]1([CH2:24][N:6]2[CH2:7][C@@H:8]([NH:10][C:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[OH:23])=[O:12])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Reaction time: 24 h
Yield: 74.2 %

Procedure:
To a stirred solution of (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (350 mg, 0.85 mmol) in methanol (8 mL) was added lithium hydroxide (204 mg, 8.53 mmol) and the mixture was stirred at room temp. for 24 h. The reaction mixture was then acidified with dilute hydrochloric acid, extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (using 15% EtOAc in hexane as eluent) to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]pyrrolidine-2-carboxylic acid (250 mg, 74.0% yield) as a white solid. MS calcd. for C23H29N2O4 [(M+H)+] 397.0, obsd. 397.6.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][NH2:19])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[CH2:22]([NH:26][C:27]([NH:19][CH2:18][CH2:17][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:8]=[CH:9]2)=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: NCCOc1ccc2c(ccn2Cc2ccc(Cl)cc2)c1
Reactant: CCCCN=C=O
Solvent: c1ccncc1
Product: CCCCNC(=O)NCCOc1ccc2c(ccn2Cc2ccc(Cl)cc2)c1
Reaction time: 0.25 h

Procedure:
To a mixture of 1-(4-chlorobenzyl)-5-(aminoethoxy)-indole (1.0 g) in pyridine (I ml), butyl isocyanate (0.5 ml) was added at ambient temperature. After stirring for 15 minutes, excess pyridine was evaporated in vacuo and the residue recrystallized from ethanol to yield the title product, m.p. 163°-164° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[CH:10][N:9]=1.[OH-].[K+].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([N+:16]([O-:18])=[O:17])=[CH:10][N:9]=2)[CH:6]=1
Reactant: Clc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])cnc1-n1cnc(Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
Step O (1): A mixture of 4-chloro-1H-imidazole (2.72 g, 26.5 mmol), 2-chloro-3-methoxy-5-nitropyridine (5.0 g, 26.5 mmol), and KOH flakes 1.488 g, 26.5 mmol) in anhydrous DMSO (25 mL) was heated at 80° C. for 5 h. The reaction mixture was allowed to cool to rt and was poured into 1.0 L of water with vigorous stirring. The mixture was stirred at rt for 16 h. The precipitate was collected by vacuum filtration using a coarse sintered glass funnel. The solid was dried under high vacuum for 24 h to provide 2-(4-chloro-1H-imidazol-1-yl)-3-methoxy-5-nitropyridine (5.22 g, 20.50 mmol, 77% yield) as a light brown solid. LC-MS (M+H)+=255.0. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.94 (d, J=2.44 Hz, 1 H) 8.51 (d, J=1.83 Hz, 1 H) 8.42 (d, J=2.44 Hz, 1 H) 8.02 (d, J=1.83 Hz, 1 H) 4.12 (s, 3 H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([I:16])[C:13](=[O:17])[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([I:16])[C@H:13]([OH:17])[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(I)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C(I)=C[C@H]1CO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-iodo-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 51, 10 g, 21.39 mmol) following the procedure described for Intermediate 8. The desired product was obtained as a colorless oil (8.87 g, 88%).
Reaction SMILES: [Br:1]Br.[CH:3]([CH:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[C:8]([CH3:17])([CH3:16])[CH:7]1[CH3:18])([CH3:5])[CH3:4].N1C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH3:17])([CH3:16])[CH:7]([CH3:18])[CH:6]2[CH:3]([CH3:5])[CH3:4])=[CH:10][C:11]=1[CH3:15]
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc2c(cc1Br)C(C(C)C)C(C)C2(C)C
Reaction time: 1 h

Procedure:
40 ml Bromine is added at 10° C. to a solution of 100 g 1-isopropyl-2,3,3,5-tetramethyl indan (obtained according to Example I or II) and 1 ml pyridine in 50 ml carbon tetrachloride. Then the reaction mixture is stirred during one hour and poured out into an aqueous solution of approximately 25 g sodium thiosulphate. The organic layer is separated, washed with 25% sodium hydroxide and evaporated. The residue is distilled under diminished pressure yielding 105 g 6-bromo-1-isopropyl-2,3,3,5-tetramethyl indan. B.p. 145°-150° C./1 mm Hg. 25 g Dimethyl formamide is added to a solution of 1-isopropyl-2,3,3,5-tetramethyl-6-indanyl magnesium bromide, prepared from 9 g magnesium and 100 g of the 6-bromo indan obtained above. The reaction mixture is then heated to reflux during 30 min., poured out into a mixture of ice and diluted sulphuric acid and extracted with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure yielding 30 g 6-formyl-1-isopropyl-2,3,3,5-tetramethyl indan. B.p. 135° C./1 mm Hg.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([F:26])[C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[N:8]=[N:7]1.[CH3:27]I>CN(C=O)C.O>[F:2][C:3]1[CH:24]=[C:23]([O:25][CH3:27])[CH:22]=[C:21]([F:26])[C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[N:8]=[N:7]1
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3c(F)cc(O)cc3F)c2n1
Reactant: CI
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(Cn2nnc3c(-c4ccco4)nc(N)nc32)c(F)c1
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
A solution of 3-(2,6-difluoro-4-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride (130 mg, 0.34 mmol) in DMF (5 mL) at 0° C., was treated with CsCO3 (223 mg, 0.68 mmol), stirred for 10 min, treated with methyl iodide (21 μL, 0.34 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with water (10 mL) and filtered to give the title compound (122 mg, 100%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:13]=[CH:14]/[C:15](OC)=[O:16])[CH:5]=[C:6]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:7]=1.[BH4-].[Li+].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:13][CH2:14][CH2:15][OH:16])[CH:3]=1
Reactant: COC(=O)/C=C/c1cc(Br)cc(C2(C#N)CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Product: N#CC1(c2cc(Br)cc(CCCO)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To methyl (E)-3-[3-bromo-5-(1-cyanocyclopropyl)phenyl]prop-2-enoate (590 mg, 1.927 mmol) in THF (15 mL) at 0° C. was added lithium borohydride (125.9 mg, 5.781 mmol). The reaction was allowed to warm to room temperature and stirred overnight. HCl (2M, aq. soln.) was added and the reaction stirred for 5 minutes until the fizzing subsided. NaHCO3 (sat. aq. soln.) was added and the mixture extracted three times with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified on silica (Companion, 40 g) eluting with 10-80% EtOAc:Petrol ether to give 1-[3-bromo-5-(3-hydroxypropyl)phenyl]cyclopropane-1-carbonitrile as a yellow oil (64 mg, 67%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])=[O:2].[H][H]>[Pd].CO>[CH:1]([NH:3][C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])=[O:2]
Reactant: [H][H]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1NC=O
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1c(-c2ccc(N)cc2)c[nH]c1NC=O
Yield: 61.4 %

Procedure:
0.23 g (0.834 mmol) of 2-formylamino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide is added at a temperature in the region of 25° C. to a suspension of 0.030 g (0.0285 mmol) of 10% palladium on carbon in 15 cm3 of methanol. After hydrogenation for 5 hours in an autoclave under 2 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.125 g of 2-formylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide, in the form of a green solid. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 5.13 (broad s, 2H); 5.43 (broad m, 1H); 6.27 (d, J=2.5 Hz, 1H); 6.60 (d, J=9.0 Hz, 2H); 6.80 (broad m, 1H); 6.99 (d, J=9.0 Hz, 2H); 8.34 (d, J=1.5 Hz, 1H); 10.9 (broad s, 1H); 11.25 (broad s, 1H)
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[Cl:25][C:26]1[CH:27]=[C:28]([NH:41][C:42]2[C:43]3[CH:51]=[C:50]([NH2:52])[N:49]=[CH:48][C:44]=3[N:45]=[CH:46][N:47]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1.CC(N(C)C)=O>C1COCC1.O.ClCCl.CO>[Cl:25][C:26]1[CH:27]=[C:28]([NH:41][C:42]2[C:43]3[CH:51]=[C:50]([NH:52][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:49]=[CH:48][C:44]=3[N:45]=[CH:46][N:47]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1
Reactant: Nc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1)OCC
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To a stirred mixture of CDI (0.53 g, 3.25 mmol) and dry THF (2 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (0.64 g, 3.25 mmol) in THF (1 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 15 min (whence evolution of gases ceased). A solution of compound 219 (1.03 g, 2.50 mmol) in a mixed solvents of dry THF (2.5 mL) and DMA (2.5 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=20:1) and found only ca. 60% reaction occurred after 50 min. Thus, another batch of reagent was prepared from CDI [0.53 g, 3.25 mmol; dry THF (2 mL)] and 2-(diethoxyphosphoryl)acetic acid [0.64 g, 3.25 mmol); THF (1 mL)] and added to the reaction. It was stirred further for 3 h at 40° C. The reaction mixture was poured into water (300 mL) and stirred with petroleum ether (400 mL) at room temperature for 12 h. Petroleum ether layer was decanted. More petroleum ether (200 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (5×20 mL) and dried to give diethyl 2-(4-(3-chloro-4-(3-chlorobenzyloxy)phenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (228) (1.37 g, 93%); mp 106-109° C.; 1H NMR δ (CDCl3) 9.41 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1 H), 7.91 (d, J=2.6 Hz, 1H), 7.66 (s, 1H), 7.54 (dd, J=8.8, 2.6 Hz, 1H), 7.48 (s, 1H), 7.40-7.29 (m, 3H), 6.99 (d, J=8.9 Hz, 1H), 5.15 (s, 2H), 4.30-4.18 (m, 4H), 3.15 (d, J=21.1 Hz, 2H), 1.39 (t, J=7.0 Hz, 6H). δ [(CD3)2SO]: 10.82 (s, 1H), 10.25 (s, 1H), 8.99 (poorly resolved d, J=0.6 Hz, 1H), 8.41 (s, 1H), 8.58 (s, 1 H), 7.95 (d, J=2.6 Hz, 1H), 7.71 (dd, J=9.0, 2.6 Hz, 1H), 7.56 (br s, 1H), 7.50-7.38 (m, 3H), 7.27 (d, J=9.0 Hz, 1H), 5.26 (s, 2H), 4.15-4.04 (m, 4H), 3.34 (d, partially obscured by water peak, 2H), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C26H26Cl2N5O3P.0.5H2O: C, 52.10; H, 4.54; N, 11.68%. Found C, 52.09; H, 4.60; N, 11.70%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:25](=[O:27])[CH3:26])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Solvent: c1ccncc1
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCOC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled, well stirred solution of 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone(formula IV-2 wherein R=H3CO, n=8, in the free form) (0.3 part) in pyridine (1 volume part) was added acetic anhydride (0.1 volume part). After stirring at room temperature for 1 hour, the mixture was diluted with water, and the aqueous solution was extracted with diethyl ether. The extract was washed successively with water, dilute hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was crystallized from aqueous ethanol to give 2,3-dimethoxy-5-methyl-6-(10'-acetoxydecyl)-1,4-benzoquinone (formula IV-2 wherein R=H3CO, n=8, in the form of acetate) (0.31 part) as orange needles melting at 38° C.
Reaction SMILES: O.[P:2]([O:14][CH2:15][C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[C:27](CC=CN)[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:18][C@@H:17]1[OH:33])([O:5][P:6]([O:9][P:10]([OH:13])([OH:12])=[O:11])([OH:8])=[O:7])(=[O:4])[OH:3]>CS(C)=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-]>[P:2]([O:14][CH2:15][C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[CH:27][C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:18][C@@H:17]1[OH:33])([O:5][P:6]([O:9][P:10]([OH:12])([OH:13])=[O:11])([OH:8])=[O:7])(=[O:3])[OH:4]
Reactant: NC=CCc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Dye-PC NHS ester (3 equivalents) dissolved in DMSO or other water miscible solvent is added to a solution of 5-(3-aminoallyl)-2′-deoxyuridine-5′-triphosphate in 0.1M sodium carbonate/bicarbonate buffer (pH 8.5). Mixture is stirred at room temperature for 2-3 h and crude reaction is purified by reversed-phase HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH:28]=2)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.FC1C=C(CC2C=CC(OC)=CC=2C2CCC3C(=CC=C(OC)C=3)C=2)C=CC=1OCCN1CCCCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:17][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[CH:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH2:28]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1ccc2c(c1)CCC(c1cc(OC)ccc1C(=O)c1ccc(OCCN3CCCCC3)c(F)c1)=C2
Agent: COc1ccc2c(c1)CCC(c1cc(OC)ccc1Cc1ccc(OCCN3CCCCC3)c(F)c1)=C2
Product: COc1ccc2c(c1)CCC(c1cc(OC)ccc1Cc1ccc(OCCN3CCCCC3)c(F)c1)C2

Procedure:
Synthesized from [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][4-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenyl]methanone according to an analogous synthetic method to Example 337 described below, 1-{2-{2-fluoro-4-[4-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)benzyl]phenoxy}ethyl}piperidine (228 mg) was used according to an analogous synthetic method to Example 30 described below to provide 1-{2-{2-fluoro-4-[4-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)benzyl]phenoxy}ethyl}piperidine (200 mg). This compound (197 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (180 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][CH2:14][CH:15]([NH:29][CH2:28][CH:25]4[CH2:27][CH2:26]4)[CH2:16][CH2:17]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: NCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(NCC4CC4)CC3)cc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 43.5 %

Procedure:
To a solution of 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-one (0.2 g, 0.545 mmol) in 1,2-dichloroethane (3 mL) were added cyclopropanemethylamine (71 μL, 0.812 mmol) and sodium triacetoxyborohydride (0.15 g, 0.71 mmol). The resulting suspension was stirred at RT for 17 h, then diluted with water and DCM. The aqueous layer was separated and extracted with DCM. The combined organic layers were dried (Na2SO4), then concentrated in vacuo to give the title compound as an off-white solid (0.10 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=O)[CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:16])[CH:12]=[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1ccccc1
Reaction time: 1 h

Procedure:
Aniline (0.20 mol) and ethylacetoacetate (0.20 mol) are mixed in toluene (200 mL) containing 0.04 g of p-toluenesulfonic acid-hydrate and heated at reflux under a water separator for one hour. The toluene is removed under vacuum to afford the ethyl-3-phenylaminobut-2-enoate which can be used as is for the preparation of the ethyl 2-methyl-3-quinolinecarboxylate.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:28]I>CN(C)C=O.C(OCC)(=O)C>[CH3:28][N:23]([CH2:22][C:13]1([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:12][CH2:11][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][CH2:14]1)[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CNS(C)(=O)=O)(C2CCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.28 h
Yield: 72.2 %

Procedure:
A 10-mL, round-bottomed flask was purged with nitrogen and then charged with a 60% sodium hydride dispersion in mineral oil (0.005 g, 0.125 mmol), and the flask was cooled at 0° C. in an ice-water bath. A solution of the sulfonamide from Step B (0.040 g, 0.107 mmol) in 0.8 mL of dimethylformamide was then added dropwise via syringe. The resulting mixture was stirred at 0° C. for 17 min, warmed to room temperature, and stirred for 10 min. The resulting thick mixture was then charged with methyl iodide (0.033 mL, 0.535 mmol), and the clear mixture was then stirred at room temperature for 5 days. The reaction mixture was then diluted with ethyl acetate and washed with two portions of 1 N HCl solution, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to give the title compound (0.030 g) as a light yellow oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CCN(C(C)C)C(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27](/[CH:3]=[CH:2]/[CH2:1][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)[C:5]2[N:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Br)cc1
Reactant: C=CCN(Cc1ccc(OC(F)(F)F)cc1)c1ccc(C(C)=O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(/C=C/CN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C(C)=O)cn2)cc1
Yield: 56.9 %

Procedure:
A mixture of 1-(6-{allyl[4-(trifluoromethoxy)benzyl]amino}pyridin-3-yl)ethanone (10 g; 28.5 mmol), 4-bromo-anisole (5.6 g; 29.9 mmol), palladium (II) acetate (0.14 g; 0.63 mmol) and tri-o-tolylphosphine (0.57 g; 1.88 mol) in 11 ml of MeCN and 8 ml of DIEA was heated to reflux overnight. Upon cooling, the mixture was concentrated and the residue partitioned between ethyl acetate and 1N NaOH. The organic phase was dried over sodium sulfate and concentrated. Purification by flash chromatography eluting with dichloromethane afforded 1-(6-{[(2E)-3-(4-methoxyphenyl)prop-2-enyl][4-(trifluoromethoxy)benzyl]amino}pyridin-3-yl)ethanone (7.4 g; 54% yield).