Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([CH2:13][CH:14]=[CH2:15])=[CH:8][C:7]=1[Cl:16])[CH:2]1[O:4][CH2:3]1.C(OO)(=[O:19])C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Na+]>[CH2:1]([O:5][C:6]1[C:7]([Cl:16])=[CH:8][C:9]([CH2:13][CH:14]2[O:19][CH2:15]2)=[CH:10][C:11]=1[Cl:12])[CH:2]1[O:4][CH2:3]1
Reactant: C=CCc1cc(Cl)c(OCC2CO2)c(Cl)c1
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cc(CC2CO2)cc(Cl)c1OCC1CO1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A 100 ml sulfurating flask equipped with stirrer, cooler, thermometer and drip funnel is charged with 13.0 g (0.05 mole) of 4-allyl-2,6-dichlorophenyl glycidyl ether in 40 ml of toluene and 0.5 g of sodium acetate. Over 2 hours, 14.0 g (0.07 mole) of 10% peracetic acid are then added dropwise at 30°-50° C. After the dropwise addition, the reaction mixture is diluted with 300 ml of toluene, the resultant aqueous phase is separated and the organic phase is washed with two 150 ml portions of NaHCO3 (5%) and then washed with 150 ml of water. The organic phase is dried over sodium sulfate and made peroxide-free with sodium sulfite and filtered. The filtrate is concentrated, affording 12.7 g (92.3%) of a pale yellow resin with an epoxide content of 5.62 eq/kg (77.75%) and a viscosity of 280 mPas/25° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CC)[CH:5]=[CH:6][C:7]=1[Cl:8].C([Cl:29])(=O)CCCCCCCC>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([Cl:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCCCCC(=O)Cl
Reactant: CCCCCCCCC(=O)c1ccc(Cl)c(Cl)c1
Product: CCCCCCC(Cl)c1ccc(Cl)c(Cl)c1

Procedure:
3',4'-dichlorononanophenone, b.p. 155°-157° C./0.25 mmHg, from nonanoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Sc1ccc(OC)cc1

Procedure:
To a stirred solution of 4methoxybenzenethiol (2.5 gm, 14 mmol) and anhydrous K2CO3 (4.0 gm, excess) in dry acetone (100 ml), ethyl 2-bromo-propionate (3.0 gm, 16 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, reaction was allowed to cool, filtered and the reaction mixture was concentrated to a residue. The residue was extracted with chloroform and washed with H2O and the organic layer dried over MgSO4, filtered and concentrated to afford 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester as a light yellow oil. Yield 3.6 gms (94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1S2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc2c(c1)C(=S)Nc1ccccc1S2

Procedure:
2-Amino-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.12 g was dissolved in toluene (20 ml). Phosphorus pentasulphide (0.11 g) was added to the solution and the whole was stirred under reflux for 16 hours and then cooled. Addition of water (40 ml) and separation of the phases gave, after evaporation of the dried organic layer, a yellow solid which was purified by column chromatography on silica gel and recrystallisation from ethanol to give the product as yellow needles (0.22 g, m/s. M- =258).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=5[O:23][C:22]4=[O:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc2c(c1)oc(=O)n2CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 30.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9 mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K2O3 (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours. The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2,3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31%) of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone, m.p.=152°-154° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([C:18]([OH:20])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)=[C:5]([F:21])[CH:4]=1)#[CH:2].FC(F)(F)C(O[C:27]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37])=O.N1C=CC=CC=1>CN(C=O)C>[F:33][C:32]1[C:27]([O:19][C:18]([C:11]2[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][C:5]=3[F:21])=[CH:15][C:14](=[O:16])[N:13]([CH3:17])[CH:12]=2)=[O:20])=[C:28]([F:37])[C:29]([F:36])=[C:30]([F:35])[C:31]=1[F:34]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.70 g, 2.44 mmol) was reacted with pentafluorophenyl trifluoroacetate (1.30 mL, 7.36 mmol) in the presence of pyridine (0.60 mL) in DMF. The solution was allowed to stir at room temperature for 15 hours, to afford the 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid pentafluorophenyl ester which was reacted directly with 2-aminoethanol (0.74 mL, 12.20 mmol) that is stirred at room temperature for 4 hours. The resulting precipitate was filtered and purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-hydroxy-ethyl)-amide as a yellow solid (0.24 g, 30%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.27 (s, 1H), 8.41 (t, 1H), 8.13 (s, 1 H), 7.48 (dd, J=10.2, 1.8 Hz, 1H), 7.40 (dd, J=8.6 Hz, 1H), 7.31 (dd, J=8.5 Hz, 1H), 5.73 (s, 1H), 4.76 (t, 1 H, OH), 4.24 (s, 1H), 3.51 (t, J=4.9 Hz, 2H), 3.35 (s, 3H), 3.25 (t, J=8.3 Hz, 2H). (APCI+) calcd for C17H16FN3O3 329.33 (M+1), found 330.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([CH2:16]O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:32]([CH2:16][C:14]1[CH:13]=[N:12][N:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:15]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CO)cn2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(-n2cc(CN=[N+]=[N-])cn2)cc1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of [1-(4-methanesulfonyl-phenyl)-1H-pyrazol-4-yl]-methanol (1.80 g, 7.12 mmol, 1.00 equiv) and diphenylphosphoryl azide (2.35 g, 8.54 mmol, 1.2 equiv) in THF (15 mL) at rt was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 g, 8.54 mmol, 1.2 equiv). The resulting solution was stirred overnight, concentrated and chromatographically purified (15% ethyl acetate in hexanes) to give 4-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (1.90 g, 97%). LCMS: (MH)+=278.0 (1.45 min).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.O>CN(C=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:18][CH:19]=1
Reactant: O=c1cc(O)cc[nH]1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of potassium carbonate (12.44 g, 90 mmol), 4-hydroxypyridin-2(1H)-one (10 g, 90 mmol) in DMF (500 mL) was stirred at 140° C. for 60 min prior to addition of a solution of 1-(chloromethyl)-4-fluorobenzene (13.01 g, 90 mmol) in DMF (5.0 mL). After stirring at 140° C. for 60 min, the reaction was cooled to RT prior to dilution with water (1.0 L). The resulting suspension was stirred at RT for 60 min prior to collection of precipitate by filtration. The filter cake was washed with water (250 mL), suspended with stirring in ethyl ether (500 mL) for 15 min and collected by filtration. After air-drying, 4-(4-fluorobenzyloxy)pyridin-2(1H)-one 17A was obtained as a white solid (6.67 g, 28.9 mmol, 32.1% yield). 1H NMR (400 MHz, MeOD) δ ppm 7.42-7.56 (2H, m), 7.34 (1H, d, J=7.26 Hz), 7.03-7.25 (2H, m), 6.12-6.24 (1H, m), 6.01 (1H, br. s.), 5.10 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>C(OCC)(=O)C.O>[Cl:15][C:8]1[N:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Oc1ncc2ccc(Cl)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc2cnc(Cl)nc2c1
Temperature: 110 °C

Procedure:
In a 250 mL three neck round bottom flask, 7-chloroquinazolin-2-ol (19 g, 105.55 mmol) was suspended in freshly distilled POCl3 (190 mL) at rt. The resulting suspension was heated to 110° C. for 4 h. On completion of reaction, the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate (200 mL) and cold water (200 mL). The organic layer was separated and the aqueous phase was re-extracted with ethyl acetate (500 mL×2). The combined EtOAc extract was washed with brine and concentrated under reduced pressure. The residue (pale brown) obtained was purified by silica gel (60-120 mesh) column chromatography and gradient elution with 12-20% ethyl acetate-hexanes gave 2,7-dichloroquinazoline as a pale yellow solid. Yield: 7 g (33.5%). LCMS (ESI, m/z): 199 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:30][CH2:31][CH3:32])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]([CH2:18][N:19]2C(=O)C3=CC=CC=C3C2=O)[CH2:5]1)[CH3:2].O.NN>C(O)C>[CH2:31]([O:30][C:4]1([O:3][CH2:1][CH3:2])[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C@@H:6]([CH2:18][NH2:19])[CH2:5]1)[CH3:32]
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN)C1
Yield: 107.1 %

Procedure:
A mixture of 4,4-diethoxy-1-((S)-1-phenyl-ethyl)-(R)-2-phthalimidomethyl-piperidine (5.25 g, 12.0 mmol) and hydrazine hydrate (2.92 ml, 60 mmol) was stirred overnight in ethanol (100 ml) at room temperature. The solvent was removed in vacuo and the solid residue was extracted with refluxing diethyl ether. The diethyl ether fractions were combined and evaporated in vacuo, which afforded 3.94 g (94%) of 4,4-diethoxy-1-((S)-1-phenyl-ethyl)-(R)-2-aminomethyl-piperidine as an oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.[Cl:45][C:46]1[C:51]([O:52][CH3:53])=[CH:50][C:49]([O:54][CH3:55])=[C:48]([Cl:56])[C:47]=1[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[N:63]=[C:62]([NH:67][C@H:68]1[C@H:72](O)[CH2:71][C@@H:70]([C:74]([O:76][CH3:77])=[O:75])[CH2:69]1)[N:61]=[CH:60]2>C1COCC1>[Cl:56][C:48]1[C:49]([O:54][CH3:55])=[CH:50][C:51]([O:52][CH3:53])=[C:46]([Cl:45])[C:47]=1[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[N:63]=[C:62]([NH:67][C@H:68]1[C@@H:72]([N:38]3[C:34](=[O:44])[C:35]4[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:37]3=[O:39])[CH2:71][CH:70]([C:74]([O:76][CH3:77])=[O:75])[CH2:69]1)[N:61]=[CH:60]2
Reactant: COC(=O)[C@@H]1C[C@@H](O)[C@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1C[C@@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)[C@@H](N2C(=O)c3ccccc3C2=O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Ph3P (0.213 g, 0.812 mmol) was taken up in THF (6 ml) and cooled to −78° C. under N2. DIAD (0.126 ml, 0.650 mmol) was added followed by addition of phthalimide (0.105 g, 0.711 mmol) and stirred at −78° C. for 1 hour, followed by addition of (1S,3R,4R)-methyl 3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-hydroxycyclopentanecarboxylate (0.100 g, 0.203 mmol) in 4 ml of THF at −78° C. The reaction was stirred overnight while warming to room temperature, after which the solvent was removed under reduced pressure. The residue was purified via flash chromatography (0-100% Hex/EtOAc; 12 g column) to afford methyl (3R,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(1,3-dioxoisoindolin-2-yl)cyclopentane-1-carboxylate (0.126 g, 0.203 mmol). MS (ES+) C31H26Cl2N4O6 requires: 621, found: 622 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C@@:40]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])([OH:44])[CH2:39]2)[C:34]([F:51])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C@@:40]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])([OH:44])[CH2:39]4)[C:34]([F:51])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)C[C@@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1

Procedure:
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.31 g, 0.72 mmol) in acetonitrile (6.0 mL) was added ethyl 2-((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxy-cyclohexyl)ethanoate, 60a, (0.20 g, 0.60 mmol) and degassed under N2. Na2CO3 (0.90 mL of 2 M, 1.81 mmol) was added followed by Pd(PPh3)4 (0.10 g, 0.09 mmol). The reaction was sealed and microwaved at 120° C. for 30 min. The material was concentrated under reduced pressure then diluted in EtOAc and aqueous saturated NaHCO3, then extracted with additional EtOAc (3×), dried (Na2SO4) and concentrated in vacuo. The material was diluted in DCM and silica gel chromatography (Hexanes:EtOAc) gave 217 mg of product 60c. LC MS+: 602.49 at 4.62 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([C:21](OC)=[O:22])=[C:16]([CH3:25])[C:15]=3[CH:26]=2)=[O:9])=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C1COCC1>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([CH2:21][OH:22])=[C:16]([CH3:25])[C:15]=3[CH:26]=2)=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)C1=C(C)c2cc(NC(=O)c3ccc(Cl)cn3)ccc2CCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
To a solution of methyl 2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from step 3A (345 mg, 0.930 mmol) in THF (2 mL) was slowly added 1.0 M DIBAL-H/THF (4.65 mL, 4.65 mmol) at −78° C. The mixture was stirred at −78° C. for 4 h and then allowed to warm to rt. Brine was added slowly to quench the reaction. The reaction mixture was then extracted with 3×100 mL of EtOAc and the organic layers were combined, dried over sodium sulfate, and concentrated. The residue was purified using silica gel column chromatography (hexanes-60% EtOAc) to give a clean (E)-5-chloro-N-(8-(hydroxymethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide (120 mg, 0.350 mmol, 37.6% yield). LCMS (M+H)+=343.2. 1H NMR (500 MHz, chloroform-d) δ 9.81 (s, 1H), 8.56 (dd, J=2.3, 0.6 Hz, 1H), 8.25 (dd, J=8.4, 0.6 Hz, 1H), 7.87 (dd, J=8.4, 2.3 Hz, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.55 (dd, J=8.1, 2.3 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 4.39 (s, 2H), 2.54 (t, J=7.0 Hz, 2H), 2.14 (s, 3H), 2.10 (quin, J=7.1 Hz, 2H), 2.01-1.95 (m, 2H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([S:18][CH3:19])[S:13][C:12]=2[C:20]([NH2:22])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C=O.C(O)=O>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([S:18][CH3:19])[S:13][C:12]=2[C:20]#[N:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1sc(C(N)=O)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Agent: C=O
Solvent: O=CO
Solvent: CC#N
Product: CSc1sc(C#N)c(-c2ccc(C(C)(C)C)cc2)c1C#N

Procedure:
Add 3-(4-tert-butyl-phenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid amide(0.121 mmol) to 0.5 ml of CH3CN and add 18 mg paraformaldehyde and formic acid (1.59 mmol). Heat for 6 hrs. Concentrate and purify by radial chromatography eluting with ethyl acetate/hexanes to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 7.39 (q, 4H, J=12.0 Hz), 2.80 (s, 3H) and 1.42 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([O-])=O>[Ni].CCO.N.C(Cl)Cl>[CH:9]1[C:8]2[C:13](=[C:14]([NH2:16])[N:15]=[C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]3=2)[N:12]=[CH:11][CH:10]=1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Agent: [Ni]
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc2c(c1)nc(N)c1ncccc12
Reaction time: 8 h

Procedure:
A mixture of 8-nitrobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Raney Nickel (wet, 10% wt) in EtOH/ammonia (2:1) was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The insoluble solid was filtered off through celite, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was washed with 10% MeOH/DCM and 70% EtOAc/Hexanes to give benzo[f][1,7]naphthyridine-5,8-diamine as an off white solid: 1H NMR (methanol-d4): δ 8.97 (dd, 1H), 8.90 (dd, 1H), 8.41 (d, 1H), 7.83 (dd, 1H), 7.57 (d, 1H), 7.39 (dd, 1H), 3.96 (s, 2).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].Cl.[NH:7]1[CH2:11][CH2:10][NH:9][CH:8]1[N:12]=[C:13]1[NH:17][C:16]([CH2:18]Cl)=[CH:15][S:14]1>Cl>[NH:7]1[CH2:11][CH2:10][NH:9][CH:8]1[N:12]=[C:13]1[NH:17][C:16]([CH2:18][S:5][CH2:4][CH2:3][NH2:2])=[CH:15][S:14]1
Reactant: ClCc1csc(=NC2NCCN2)[nH]1
Reactant: NCCS
Agent: Cl
Product: NCCSCc1csc(=NC2NCCN2)[nH]1
Yield: 39.9 %

Procedure:
Cysteamine hydrochloride (2.22 g; 19.5 mmoles) and 2-[(2-imidazolidinyl)imino]-4-chloromethylthiazole hydrochloride (4.94 g; 19.51 mmoles) [prepared from 1,3-dichloro-2-propanone and N-(2-imidazolidin-2-yl)thiourea which is itself prepared from 2-(cyanimino)imidazolidine] were dissolved in 20 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 100° for 5.5 hours. The reaction mixture was evaporated under reduced pressure and the residue made basic with 40% NaOH. The aqueous phase was extracted with methyl acetate, dried and evaporated to give 2.02 g of the title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:8]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 10, 39.0 g, 137.97 mmol) and 4-chloro-3-(trifluoromethyl)phenol (27.12 g, 137.97 mmol) in DMSO (197 mL) was added potassium carbonate (47.67 g, 344.92 mmol) portion wise maintaining the internal at 15-25° C. with a cold water jacket. The reaction mixture was stirred at room temperature for 2 hours, cold water charged and the resulting slurry stirred for 20 minutes. The mixture was filtered, washed with water and dried to give the title compound as a pale yellow solid (56.4 g, 90%).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1.[CH2:17]1[O:19][CH2:18]1.Cl>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([CH2:17][CH2:18][OH:19])[S:13][C:12]=2[CH:16]=1
Reactant: C1CO1
Reactant: COc1ccc2ccsc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(CCO)sc2c1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
Butyl lithium (0.27 mol of a 2.5 M solution) was added dropwise to 6-methoxybenzo[b]thiophene [prepared analogous to the procedure described in J. Med. Chem. 1989, 32(12), 2548-2554] (0.25 mol) in tetrahydrofuran (1000 ml), stirred at −30° C. The mixture was stirred for 10 minutes at −30° C. Ethylene oxide (0.38 mol in 100 ml tetrahydrofuran) was added dropwise at −30° C. The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was acidified with dilute HCl solution. The solvent was evaporated. The residue was diluted with water and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was stirred in hexane, filtered off and dried, yielding 41.3 g of 6-methoxybenzo[b]thiophene-2-ethanol (interm. 2).