Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[SH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>CN(C)C=O>[C:22]([CH2:21][CH2:20][S:19][C:15](=[S:16])[NH:14][C:12]1[C:11]([O:17][CH3:18])=[CH:10][C:8]2[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6][C:7]=2[CH:13]=1)([OH:24])=[O:23]
Reactant: COc1cc2nc(C(C)(C)C)sc2cc1N=C=S
Reactant: O=C(O)CCS
Solvent: CN(C)C=O
Product: COc1cc2nc(C(C)(C)C)sc2cc1NC(=S)SCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.8 g (0.10 mole) of 2-tert.-butyl-6-isothiocyano-5-methoxy-benzthiazole are dissolved in 150 ml of dimethylformamide and 14 g (0.13 mole) of 3-mercaptopropionic acid are added. The solution is stirred at room temperature under nitrogen for 2 hours, then poured onto 2 kg of ice and stirred until the product has become solid. It is filtered off, washed with water and heated in 700 ml of toluene, decanted from water, dried over sodium sulphate, clarified with active carbon and filtered. The filtrate is diluted at 30°-40° with approximately 700 ml of petroleum ether and cooled slowly to 5°, filtered off and subsequently washed with petroleum ether. N-[2-tert.-butyl-5-methoxy-benzthiazol-6-yl]-dithiocarbamic acid S-(2-carboxyethyl)-ester having a melting point of 154°-156° is obtained: ##STR14##
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=[O:12].[H-].[Na+].[CH3:15]I>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:15])[CH:8]=[C:7]2[CH:11]=[O:12]
Reactant: O=Cc1c[nH]c2c(F)cccc12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C=O)c2cccc(F)c21
Reaction time: 1 h

Procedure:
7-Fluoroindole-3-carboxaldehyde (2.5 g) in dry THF (20 ml) was added to a cold (0°) suspension of sodium hydride (73.2% dispersion in oil; 652 mg) in dry THF (20 ml) under nitrogen and the mixture was stirred for 1h. Methyl iodide (2.5 ml) was added, and the resulting mixture was stirred for 2h at 0°. The mixture was then poured into saturated brine solution (300 ml) and extracted with ether (2×300 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (2.66 g), m.p. 92°-94°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:5]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([C:19](=[O:32])[C:20]([C:25]5[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=5)=[CH:21][O:22]4)=[CH:17][CH:16]=3)[N:12]=2)[CH:7]=1.N1C=NN=N1.C(N(CC)[P:45]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])C>O1CCCC1.C(Cl)Cl>[C:52]([O:51][P:45]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[O:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2[C:19](=[O:32])[C:18]3[C:23](=[CH:24][C:15]([O:14][CH2:13][C:11]4[N:12]=[C:8]([C:6]5[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C:33]([F:34])([F:36])[F:35])[CH:5]=5)[O:9][CH:10]=4)=[CH:16][CH:17]=3)[O:22][CH:21]=2)=[CH:30][CH:29]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(OCc3coc(-c4cc(F)cc(C(F)(F)F)c4)n3)ccc12
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OP(Oc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-3-(4-hydroxyphenyl)chromen-4-one (1 g, 2.01 mmol) in tetrahydrofuran (50 mL) was added 1-H-tetrazole (3% wt in acetonitrile, 65 ml, 22.1 mmol), followed by di-tert-butyl N,N-diethylphosphoramidite (2.57 ml, 4.6 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate. The organic layer was separated, and the aqueous layer extracted twice more with methylene chloride. The combined extracts were dried over sodium sulfate, and solvent removed under reduced pressure. The residue was purified by biotage column chromatography, eluting with ethyl acetate/hexane mixture (1:4) to afford 3-{4-[bis(tert-butoxy)phosphinooxy]phenyl}-7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)chromen-4-one.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:22][CH:23]([CH3:25])[CH3:24])(=[O:21])[C@@H:12]([CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[OH:13].Br[CH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([N:35]2[C:39]([CH3:40])=[CH:38][CH:37]=[C:36]2[CH3:41])[N:29]=1>C1COCC1>[CH3:40][C:39]1[N:35]([C:30]2[N:29]=[C:28]([CH2:27][C@@H:14]([C@@H:12]([OH:13])[C:11]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:33]=[C:32]([CH3:34])[CH:31]=2)[C:36]([CH3:41])=[CH:37][CH:38]=1
Reactant: CC(C)OC(=O)C[C@@H](O)C(=O)OC(C)C
Reactant: Cc1cc(CBr)nc(-n2c(C)ccc2C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C[C@H](C(=O)OC(C)C)[C@@H](O)C(=O)OC(C)C)nc(-n2c(C)ccc2C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a dry flask containing THF (20 mL) at −78° C. was added fresh LHMDS (1.0 M in THF, 10 mL, 10 mmol). After 10 min, a solution of diisopropyl (R)-(+)-malate (5b, 1008 μL, 4.88 mmol) was added dropwise as a solution in THF (5 mL) through a cannula. The reaction was stirred at the same temperature for 10 min then transferred to an ice-bath (0° C.) for 30 min. The reaction was cooled to −78° C. again and 6 (1017 mg, 3.66 mmol) was added slowly (1 drop/sec) as a solution in THF (5 mL) through a cannula. The color of the reaction mixture turned light purple. The reaction was maintained at −78° C. for an additional 30 min then transferred to an ice-bath and slowly warm to room temperature. After 2 h, the reaction was quenched with NH4Cl (1 mL) then partitioned between EtOAc (200 mL) and saturated NH4Cl (150 mL). The inorganic layer was extracted with EtOAc (150 mL). The combined organic layer was washed by H2O (100 mL), brine (100 mL), dried over Na2SO4, and concentrated. The crude yellow oil was purified by flash column chromatography (EtOAc/hexanes, 1:9-1:4) to give 4b (1.76 g, 2.56 mmol, 70%) as a pale yellow oil (without detection of any cis-isomer): 1H NMR (500 MHz, CDCl3) δ 1.14-1.15 (d, J=6.5 Hz, 3H), 1.17-1.18 (d, J=6.0 Hz, 3H), 1.25-1.26 (d, J=6.5 Hz, 3H), 1.29-1.30 (d, J=6.0 Hz, 3H), 2.13 (s, 6H), 2.41 (s, 3H), 3.10-3.15 (dd, J=8.5, 14.0 Hz, 1H), 3.34-3.40 (m, 2H), 3.72-3.76 (dt, J=2.5, 8.0 Hz, 1H), 4.07-4.09 (dd, J=2.5, 7.0 Hz, 1H), 4.96-5.01 (m, 1H), 5.09-5.15 (m, 1H), 5.90 (s, 2H), 6.89 (s, 1H), 7.10 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.5, 21.2, 21.8, 21.9, 22.0, 36.1, 48.0, 68.8, 70.1, 70.6, 107.0, 120.7, 124.1, 128.7, 150.1, 158.7, 171.5, 173.4; LCQ-MS (M+H+) calcd for C23H33N2O5 417. found 417; LC-TOF-MS (M+H+) calcd for C23H33N2O5 417.23895. found 417.23834.
Reaction SMILES: BrC1C=CC(C(CC2C=CC(Br)=CC=2)C(O)=[O:10])=CC=1.C([Cu])#N.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)#[N:24].CC(C[AlH]CC(C)C)C.CN([CH:53]=[O:54])C>>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH2:31][C:28]2[CH:27]=[CH:26][C:25]([C:23]#[N:24])=[CH:30][CH:29]=2)=[CH:38][CH:37]=1)#[N:40].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH:53]=[O:54])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:10]
Reactant: O=C(O)C(Cc1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: N#C[Cu]
Agent: CC(C)C[AlH]CC(C)C
Agent: N#Cc1ccc(CCc2ccc(C#N)cc2)cc1
Product: O=Cc1ccc(CCc2ccc(C=O)cc2)cc1
Yield: 76 %

Procedure:
1,2-Bis-(4-cyanophenyl)ethane was prepared in one step from 2,3-bis-(4-bromophenyl)propanoic acid (Dann, O., (1971) Liebigs Ann. Chem., 749: 68-89) by the action of CuCN in DMF (Das, B. P., et al., (1977) J. Med. Chem., 20: 531-536) in a 50% yield; mp 195-197° C. 1H NMR (DMSO-d6): 7.68 (d, 4H, J=8), 7.40 (d, 4H, J=8), 3.01(s, 4H). 13NMR (DMSO-d6): 146.7, 131.9, 129.3, 118.6, 108.6, 35.8. MS m/e 232 (M++1).1,2-Bis-(4-cyanophenyl)ethane was used without further characterization and on treatment with DIBAL gave a white crystalline solid (CHCl3:ether) 76% mp 121-122° C. of 1,2-bis-(4-formylphenyl)ethane. 1H NMR (DMSO-d6): 9.96 (s, 2H), 7.80 (d, 4H, J=8), 7.44 (d, 4H J=8), 3.05 (s, 4H). 13C NMR (DMSO-d6/D2O): 192.0, 184.0, 134.2, 129.1, 128.8, 36.0. Anal. Calc. for C16H14O2.0.1H2O: C, 80.04; H, 5.96. Found: C, 80.09; H, 5.98. A protocol similar to that described above was employed for the condensation of 1,2-bis-(4-formylphenyl)ethane and 4-(N-isopropylamidino)-1,2-phenylene diamine (18, 35). A 75% yield of a purple solid mp>320° C. 1H NMR (DMSO-d6/D2O): 8.09 (d, 4H, J=8), 8.06 (s, 2H), 7.83 (d, 2H, J=8.4), 7.65 (d, 2H, J=8.4), 7.48 (d, 4H, J=8), 4.03 (br m, 2H), 3.07 (br, 4H), 1.29 (d, 12H, J=6). 13NMR (DMSO-d6/D2O): 162.4, 153.0, 146.6, 138.3, 135.4, 129.8, 127.9, 124.8, 124.1, 123.5, 115.5, 115.0, 45.6, 36.2, 21.2. MS (FAB) 583 (M++1)Anal. calc. for C36H38N8.4HCl.0.5H2O: C, 58.61; H, 5.87; N, 15.19. Found: C, 58.31; H, 5.79; N, 15.02.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[C:13]1([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:24](/[C:23]([NH:22][CH2:21][CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:27])\[C:25]#[N:26])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: N#CCC(=O)NCCCc1ccccc1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])c(O)c1)C(=O)NCCCc1ccccc1

Procedure:
M-39 was prepared with 3-hydroxy-4-nitro benzaldehyde and N-3-phenyl-n-propyl cyanoacetamide under similar conditions as described for M28.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][C:9]([F:27])=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:32].[CH3:33][NH:34][NH2:35]>>[ClH:32].[F:27][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]3([C:5]4[C:6](=[N:35][N:34]([CH3:33])[CH:4]=4)[C:7]=2[CH:8]=1)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3
Reactant: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CNN
Agent: Cl
Product: Cn1cc2c(n1)-c1cc(F)ccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (3.81 g, 8.71 mmol) was added hydrochloric acid (32.7 mL of 4.0 M in dioxane, 130 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with EtOH (1×30 mL). The resulting solid was suspended in EtOH (30.5 mL) and was treated with methylhydrazine (556 μL, 10.5 mmol) at 40° C. for 4 h. The mixture was then heated at 80° C. for 1 h resulting in a yellow solution with an off white precipitate. The solid was collected to give 8-fluoro-2-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride (798 mg, 26%). ESI-MS m/z calc. 273.1. found 274.5 (M+1)+. Retention time 0.83 minutes (3 min run). Note: The yellow mother liquor was evaporated to give a mixture of methyl regioisomers (1.71 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]1[CH:12]=[C:11]([Sn](C)(C)C)[N:10]=[CH:9][N:8]=1)[CH3:5].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CN1CCCC1=O.O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:17][C:18]1[N:23]=[C:22]([C:11]2[CH:12]=[C:7]([NH:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])[N:8]=[CH:9][N:10]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COCC(C)Nc1cc([Sn](C)(C)C)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN1CCCC1=O
Solvent: O
Product: COCC(C)Nc1cc(-c2ccnc(Cl)n2)ncn1
Temperature: 25 °C

Procedure:
To a solution of N-(2-methoxy-1-methylethyl)-6-(trimethylstannyl)-4-pyrimidinamine (i.e., the product of Step B) (0.5 g, 1.51 mmol), 2,4-dichloropyrimidine (0.22 g, 1.51 mmol) and copper iodide (12 mg, 0.061 mmol) in N-methylpyrrolidinone (12 mL) under a nitrogen atmosphere was added bis(triphenylphosphine)palladium(II) dichloride (53 mg, 0.076 mmol). The resulting mixture was stirred at reflux for 2 h. After cooling to room temperature, the solution was diluted with water and extracted with diethyl ether 3 times. The organic layers were combined and washed three times with water, then dried and concentrated. The residue was purified on silica gel using a gradient of 100% hexanes to 40% ethyl acetate in hexanes to afford 270 mg of title compound as a solid.
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH:15]=[CH:16][CH2:17]1)[CH2:12][CH2:11]3)(=O)[NH2:2]>C(Cl)(Cl)Cl>[C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH:15]=[CH:16][CH2:17]1)[CH2:12][CH2:11]3)#[N:2]
Reactant: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(N)=O)CC[C@@H]12
Solvent: ClC(Cl)Cl
Product: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]12
Yield: 6.4 %

Procedure:
A solution of 17β-carbamoyl-5α-androst-2-ene (4.33 g.,) and polyphosphate ester (25.0 g.) in chloroform (250 ml.) was refluxed for 16 hours. The residue, after removal of the chloroform, was neutralised by the careful addition of aqueous 10% sodium carbonate (150 ml.) with cooling and extracted with ether. The etheral solution was washed with water, dried (MgSO4) filtered and evaporated to a partly crystalline residue which, after washing with a small portion of ice-cold ether, afforded a crystalline product (3.34 g.). The etheral washings were chromatographed on a column (1 inch × 6 inches) of florisil. Elution with petrol (200 ml.) afforded further product (660 mg.) gaining a total yield of 4.00 g. A sample (300 mg.) was recrystallised from petrol to afford title compound (260 mg.); m.p. 110°-112°: [α]D + 108°, (c 0.6).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)=[CH:21][CH:20]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: Brc1ccc(I)cc1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(Br)cc3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1-bromo-4-iodobenzene according to the procedure described in example 2. 1H NMR (DMSO-d6): δ 8.25 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.11 (dd, J=8.7, 2.3 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 6.87 (d, J=2.3 Hz, 1H), 3.26 (s, 3H), 1.95 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z 389/391 ([M+H]+); MS (ESI) m/z 387/389 ([M−H]−); Anal. calcd for C19H21BrN2O2: C: 58.62H: 5.44N: 7.20. Found: C, 58.59; H, 5.29; N, 7.03.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26](O)=[O:27])=[C:19]3[N:18]=2)[C:6]1=[O:29].CN(C=O)C.C(Cl)Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O>[F:11][C:9]1[CH:8]=[C:7]2[C:6](=[O:29])[N:5]([CH:10]=1)[CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:25]1=[C:19]3[N:18]=[C:17]([CH:22]=[CH:21][N:20]3[N:23]=[CH:24]1)[N:13]1[C@@H:12]2[CH2:16][CH2:15][CH2:14]1
Reactant: NCCCn1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1NCCCn2cc(F)cc(c2=O)[C@H]2CCCN2c2ccn3ncc1c3n2
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
To a solution of (R)-5-(2-(1-(3-aminopropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.24 mmol) in 1:2 DMF/DCM (9 mL) was added EDCI (0.14 g, 0.71 mmol) followed by HOBT (96 mg, 0.71 mmol) at ambient temperature. After stirring for 10 minutes, TEA (0.099 mL, 0.71 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was treated with EtOAc, washed with saturated NH4Cl, saturated NaHCO3, and brine, then dried (MgSO4), filtered, concentrated. The crude material was purified by silica column chromatography, eluting with 4% MeOH/DCM to yield the title product (35 mg, 39% yield). MS (apci) m/z=383.2 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7][N:8]([CH3:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I-:23].[K+]>CC(C)=O>[I:23][CH2:2][CH2:3][O:4][C:5]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7][N:8]([CH3:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [I-]
Reactant: Cn1nc(-c2ccccc2)c(OCCBr)c1-c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nc(-c2ccccc2)c(OCCI)c1-c1ccccc1

Procedure:
A mixture of 4-(2-bromoethoxy)-1-methyl-3,5-diphenylpyrazole (3.57 g, 0.01 mole), potassium iodide (16.6 g, 0.1 mole) and acetone (50 ml) is stirred and refluxed for 24 hours.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][NH:9][C:10]2[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([O:36][C:37]([F:40])([F:39])[F:38])[CH:27]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]3[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)=[CH:23][CH:24]=2)(=[O:34])=[O:33])=[C:28]([O:36][C:37]([F:39])([F:38])[F:40])[CH:27]=1
Reactant: CN(C)c1nc(NCc2ccc(CN)cc2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc(NCc2ccc(CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)cc2)nc2ccccc12

Procedure:
A solution of N2-(4-aminomethyl-benzyl)-N4,N4-dimethyl-quinazoline-2,4-diamine hydrochloride (50.0 mg, 0.131 mmol), 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (53.3 mg, 0.157 mmol) and diisopropylethylamine (91 μl, 0.524 mmol) in 2-propanol (1.5 mL) was stirred at ambient temperature for 2 hr. The resulting mixture was concentrated, and the residue was purified by column chromatography (silica gel, 10% MeOH in CH2Cl2) to give 4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamide as a white crystalline compound (40 mg, 50%).
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>C1COCC1.CN(C1C=CN=CC=1)C>[C:22]([O:10][C:9]1[CH:11]=[CH:12][C:4](/[CH:3]=[CH:2]/[C:1]([OH:14])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C(=O)O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
Ferulic acid (10 g, 51 mmol) is solubilised in 100 ml of anhydrous THF under argon. Triethylamine (8.7 ml, 61 mmol, 1.2 eq) is added quickly, then DMAP (3.34 g, 27 mmol, 0.5 eq) at ambient temperature and under argon. Finally acetic anhydride (5.9 mL, 61 mmol, 1.2 eq) is added in 3 min, at ambient temperature. This is kept whilst stirring, at ambient temperature, for 18 h, then the medium is transferred into a separation funnel. This medium is diluted with 100 ml of THF, acidified with 40 ml of HCl 5% v/v and the organic phase is washed with 5×40 ml of H2O. The final organic phase is dried over MgSO4, filtered, then evaporated dry in a rotary evaporator (40° C., 30 mbar). 9.5 g of a crude yellow solid are obtained with a crude yield of 79% and a molar purity measured by NMR of 86%. The product is involved in the following step without purification.
Reaction SMILES: C1C2C=CC3C4C=CC=CC=4C=CC=3C=2OC=1CO.[CH:20]1[C:21]2[CH:41]=[CH:40][C:39]3[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH:32]=[CH:31][C:30]=3[C:22]=2[S:23][C:24]=1[C:25](OCC)=[O:26]>C(Cl)Cl.CCCCCC>[CH:20]1[C:21]2[CH:41]=[CH:40][C:39]3[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH:32]=[CH:31][C:30]=3[C:22]=2[S:23][C:24]=1[CH2:25][OH:26]
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2s1
Agent: OCc1cc2ccc3c4ccccc4ccc3c2o1
Solvent: CCCCCC
Solvent: ClCCl
Product: OCc1cc2ccc3c4ccccc4ccc3c2s1
Yield: 98 %

Procedure:
Using the procedure outlined in 14A, ethyl phenanthro[1,2-b]thiophene-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 98.0% yield of phenanthro[1,2-b]thiophene-2-methanol, mp 169°-170.5° (C,H,S), (CH2Cl2 /hexane).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([C:23]1[CH:24]=[C:25]([NH:35][C:36]([NH:38][C@@H:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@H:42]([O:49][C:50]3[CH:51]=[CH:52][C:53]4[N:54]([C:56]([C@@H:59]5[CH2:63][CH2:62][CH2:61][N:60]5[CH2:64][CH2:65][CH2:66][O:67][Si](C(C)C)(C(C)C)C(C)C)=[N:57][N:58]=4)[CH:55]=3)[CH2:41][CH2:40]2)=[O:37])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[N:27]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([C:23]1[CH:24]=[C:25]([NH:35][C:36]([NH:38][C@@H:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@H:42]([O:49][C:50]3[CH:51]=[CH:52][C:53]4[N:54]([C:56]([C@@H:59]5[CH2:63][CH2:62][CH2:61][N:60]5[CH2:64][CH2:65][CH2:66][OH:67])=[N:57][N:58]=4)[CH:55]=3)[CH2:41][CH2:40]2)=[O:37])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[N:27]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5CCCO[Si](C(C)C)(C(C)C)C(C)C)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5CCCO)n4c3)c3ccccc32)cc1
Reaction time: 2 h

Procedure:
TBAF (1M in THF, 100 μL, 0.10 mmol) was added to a solution of Intermediate 84h (70.0 mg, 0.085 mmol) in THF (2.00 mL). The reaction was stirred for 2 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM. Further purification by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (29 mg, 52%). LCMS (Method 5): Rt 3.63 min, m/z 663.3 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.54-1.62 (2H, quin, J 7.0), 1.88-2.15 (6H, m), 2.20-2.37 (4H, m), 2.38 (3H, s), 2.55 (1H, dt, J 12.0, 8.1), 3.32-3.48 (3H, m), 4.11 (1H, t, J 8.0), 4.90 (1H, dd, J 9.1, 5.7), 5.31 (1H, t, J 4.0), 6.33 (1H, s), 7.20-7.36 (9H, m), 7.65 (1H, d, J 9.9), 8.32 (1H, d, J 1.7).
Reaction SMILES: Cl([O-])(=O)(=O)=[O:2].[Cl:6][C:7]([C:13]([C:18]#N)=[CH:14][N:15](C)C)=[N:8][CH:9]=[N+:10]([CH3:12])[CH3:11]>C(#N)C.O>[Cl:6][C:7]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[C:13]([CH:18]=[O:2])[C:14]#[N:15]
Reactant: CN(C)C=C(C#N)C(Cl)=NC=[N+](C)C
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CN(C)C=NC(Cl)=C(C#N)C=O
Reaction time: 6 h
Yield: 60.7 %

Procedure:
100 g of N-(3-chloro-4-cyano-5-dimethylamino-2-aza-2,4-pentadienylidene)N,N-dimethylammonium perchlorate are dissolved in a mixture of 400 ml of acetonitrile and 400 ml of water. Stirring is carried out for 6 hours at 20° to 22°C and is followed by double extraction with two 400 ml portions of trichloromethane. Following this the combined trichloromethane phases are extracted twice with two 1000 ml portions of water. The organic phase is dried with Na2SO4 or MgSO4 and reduced in volume by distilling off of the solvent at 30° to 35°C to a quarter of the original volume. After allowing the resultant to stand for one hour in an ice-box at about 0°C, the precipitate is vacuum filtered to yield yellowish crystals. 36 g (61%) of 3-chloro-5-dimethylamino-2-formyl-4-aza-2,4-pentadienenitrile, with a melting point of 144°C (with decomposition), are thus obtained.