Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]([C:20](=O)[CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][S:16]([OH:19])(=[O:18])=[O:17].O.[CH2:24](O)[CH3:25]>CC#N.[Cl-].[Cl-].[Zn+2]>[CH3:10][C:11]1([CH2:12][CH2:13][CH2:14][CH2:15][S:16]([O-:19])(=[O:18])=[O:17])[C:3]2[C:4]3[CH:10]=[CH:11][CH:20]=[CH:21][C:5]=3[CH:6]=[CH:7][C:2]=2[N+:8]([C:25]2[CH:24]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:20]1[CH3:21]
Reactant: CC(=O)C(C)CCCCS(=O)(=O)O
Reactant: CCO
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC#N
Product: CC1=[N+](c2ccccc2)c2ccc3ccccc3c2C1(C)CCCCS(=O)(=O)[O-]

Procedure:
N-(2-Naphtyl), N-phenylhydrazine hydrochloride (19.51 mmol, 5.28 g), 5-methyl-6-oxoheptanesulfonic acid (17.18 mmol, 3.70 g) and anhydrous ZnCl2 (17.18 mmol, 2.34 g) in absolute ethanol (30 ml) were stirred at room temperature for 30 min, then at 80° C. for 2 h. the reaction progress was checked by TLC (10% H2O in CH3CN). After completion the reaction was cooled down and the solvent removed under vacuum. The residue was dissolved in DCM and purified by flash column on silica-gel. Yield: 3.06 g, 42%.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:2][NH2:3])[N:8]=[CH:7][N:6]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cc(Cl)ncn1

Procedure:
11.8 ml (12.1 g, 241.6 mmol) hydrazine hydrate are added dropwise to a solution of 20.0 g (134.3 mmol) 4,6-dichloropyrimidine in ethanol at RT, while stirring. If clouding of the solution occurs during metering in of the hydrazine hydrate, further ethanol (approx. 400 ml) is added. The reaction solution is subsequently stirred at RT for 12 h. For working up, the solid which has precipitated out is filtered off, the residue on the filter is washed twice with 150 ml water each time and twice with 100 ml diethyl ether each time and the product is dried in vacuo. A further crystalline product fraction is obtained from the concentrated mother liquor.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[Na+].C([O-])(=O)C.[K+]>C(O)CCC.C(Cl)(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:8][C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: OCc1cccnc1F
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cc1cccnc1F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A chloroform (10 ml) solution of (2-fluoropyridin-3-yl)methanol (49 mg, 0.385 mmol) and thionyl chloride (0.14 ml, 1.93 mmol) was stirred at 50° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in butanol (5 ml), followed by the addition of sodium 4-chlorobenzenesulfinate (92 mg, 0.462 mmol) and potassium acetate (76 mg, 0.770 mmol). The mixture was stirred at 70 to 80° C. for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure, whereby the title compound (59 mg, 54%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:41](O)=O>C=O>[CH:1]1([CH2:6][C@H:7]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)(=[O:34])=[O:33])=[CH:30][CH:31]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:14]=3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nc2ccc(N3CCOCC3)nc2s1)C(CC1CCCC1)c1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: O=CO
Agent: C=O
Product: CN1CCN(S(=O)(=O)c2ccc([C@@H](CC3CCCC3)C(=O)Nc3nc4ccc(N5CCOCC5)nc4s3)cc2)CC1
Temperature: 70 °C

Procedure:
Title compound H, 3-Cyclopentyl-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide (0.21 g, 0.354 mmol was suspended in formaldehyde (2 mL) to which 1 mL of formic acid was added. The mixture was heated to 70° C. for 7 h before being cooled and subsequently quenched into 2N NaOH and extracted with ethyl acetate. The combined organic layer was dried over MgSO4, filtered and evaporated to provide a brown foam which was purified over silica (0-20% EtOAc: methanol) to afford a white foam. This material was purified on a Chiracel column to afford pure (R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide as a white solid. 1H NMR (400 MHz, DMSO) δ 1.14 (m, 2H) 1.43 (d, J=4.80 Hz, 2H) 1.57 (d, J=8.34 Hz, 3H) 1.72 (d, J=5.05 Hz, 2H) 1.75-1.83 (m, 1H) 2.10 (s, 3H) 2.16 (m, 1H) 2.33 (d, J=4.04 Hz, 4H) 2.87 (s, 4H) 3.41-3.49 (m, 4H) 3.67-3.74 (m, 4H) 4.07 (t, J=7.58 Hz, 1H) 6.97 (d, J=9.09 Hz, 1H) 7.64-7.69 (m, 2H) 7.69-7.75 (m, 2H) 7.87 (d, J=8.84 Hz, 1H)
Reaction SMILES: [F:1][C:2]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:18]=2)[C:13](O)=[O:14])[N:8]=[N:7][N:6]=1)([F:4])[CH3:3].[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29]>>[F:1][C:2]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:18]=2)[C:13]([NH:26][C@@H:27]([CH3:30])[CH2:28][OH:29])=[O:14])[N:8]=[N:7][N:6]=1)([F:4])[CH3:3]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C(C)(F)F)c2)nc1
Reactant: C[C@@H](N)CO
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-n3nnnc3C(C)(F)F)c2)nc1

Procedure:
3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoic acid was reacted with (R)-2-amino-propan-1-ol using the procedure of step 4 of Example 5, to afford 3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-N—((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=403.
Reaction SMILES: [CH3:1][C:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[O:12][P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1([C:8]([P:13](=[O:12])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: CC1(C(=O)Cl)CCCCC1
Product: CC1(C(=O)P(=O)(c2ccccc2)c2ccccc2)CCCCC1

Procedure:
Using a method similar to that of Example 2, 80 parts of 1-methyl-1-cyclohexanecarboxylic acid chloride and 108 parts of methoxydiphenylphosphine, in the absence of a solvent, give 100 parts of 1-methyl-cyclohexylcarbonyl-diphenylphosphine oxide as an oily crude product, which is purified by chromatography over silica gel (using toluene as the eluant).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[CH3:9][Si](Cl)(C)C>CO>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1ccc[nH]1
Solvent: CO
Product: COC(=O)c1ccc[nH]1
Reaction time: 8 h

Procedure:
To a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in anh. MeOH (100 mL) under N2 at room temp. was added TMSCl (17.9 mL, 141 mmol, 2.5 equiv) in one portion. After stirring overnight, the reaction mixture was concentrated under reduced pressure, redissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated to give methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (4.62 g, 65%): 1H NMR (CDCl3) δ3.86 (s, 3H), 6.29 (br q, 1H), 6.92 (br m, 1H), 6.96 (br m, 1H), 9.30 (br s, 1H). This material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:15][C:16]1[N:20]=[CH:19][O:18][N:17]=1>C1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:15][C:16]1[N:20]=[CH:19][O:18][N:17]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1SCc1ncon1
Solvent: c1ccccc1
Product: CCOC(=O)Nc1ccccc1SCc1ncon1
Reaction time: 48 h

Procedure:
A solution of ethyl chloroformate (0.55 g) in benzene (10 ml) was added dropwise to a solution of 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole (2.07 g) in benzene (10 ml). The reaction mixture was then stirred for 2 days, filtered and the filtrate evaporated under reduced pressure to give an oil which crystallised on standing. Re-crystallisation from isopropanol gave 3-(2-ethoxycarbonylaminophenylthiomethyl)-1,2,4-oxadiazole, m.p. 55°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1([CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:28]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C(c4ccccc4)c4ccccc4)cc23)CC1
Yield: 66.1 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.0 mg (0.10 mMol) diphenylacetic acid, 14.0 mg (66%) of the title compound were recovered.
Reaction SMILES: [F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[N:10]=[N:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[N:10]=[N:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(C)c(OCC(C)(F)F)nn1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)nnc1OCC(C)(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (928 mg, yellow solid) from 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanone (860 mg, 3.74 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (679 mg, 5.60 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(Cl)Cl.[CH3:23][C:24]1[CH:41]=[CH:40][CH:39]=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:27]>C(N(CC)CC)C>[CH3:23][C:24]1[CH:41]=[CH:40][CH:39]=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:34])=[CH:31][CH:30]=1)=[O:27]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2C(=O)c1ccc(NC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
A solution of 1.2 g of ethyl 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylate in ml of methylene chloride is cooled to 0° C. and 10 ml of triethylamine added followed by 1.5 g of 4-[(2-methylbenzoyl)amino)benzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and concentrated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is dried over Na2SO4 and concentrated in vacuo to a residue. The residue is purified by column chromatography on silica gel by elution with 40% ethyl acetatehexane to give 1.0 g of the desired product as a solid; mass spectrum (M+ H)494.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH2:21])[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:21][C@H:19]([C:10]2[N:9]([C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=2)[CH3:20])[N:26]=[CH:25][N:24]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Temperature: 90 °C
Yield: 39 %

Procedure:
A mixture of (S)-1-[1-(3,5-difluorophenyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (245 mg, 0.84 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (137 mg, 0.88 mmol) and DIPEA (0.44 mL, 2.5 mmol) in IPA (1.7 mL) was heated in a sealed tube for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 25-75% EtOAc/cyclohexane) to give colourless oil. The residue was taken up in EtOAc and the product triturated with cyclohexane. The solid was filtered to afford 349 as a white solid (134 mg, 39%). LCMS (Method K): RT 4.10 min [M+H]+ 410. 1H NMR (DMSO-d6, 400 MHz): δ 7.87 (1H, s), 7.76-7.7 (2H, m), 7.36-7.31 (3H, m), 7.18 (2H, bs), 7.13 (1H, ddd, J=10.0, 8.5, 2.5 Hz), 7.05 (1H, dd, J=9.0, 2.5 Hz), 5.64 (1H, dq, J=7.0, 7.0 Hz), 1.56 (3H, d, J=7.0 Hz)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-])=O.S([O-])([O-])(=O)=O.[Mg+2].[H][H].[C:28]([O:31][CH2:32][CH3:33])(=O)[CH3:29]>[Pt]>[CH2:28]([O:31][CH2:32][C:33]1[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:29]
Reactant: [H][H]
Reactant: COCCCNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: CCOC(C)=O
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCOCc1nc2cnc3ccccc3c2n1CCCOC
Temperature: 120 °C

Procedure:
4-(3-methoxypropylamino)-3-nitroquinoline (14.6 g; 0.056 mol, Example 41) was added to a mixture of ethyl acetate (1300 mL), 5% platinum on carbon (1.0 g), and magnesium sulfate (5.0 g). The mixture was hydrogenated on a Parr apparatus at an initial hydrogen pressure of 30 psi. When the hydrogenation was complete, the solids were removed and the ethyl acetate was evaporated. The residual intermediate diamine was mixed with ethoxyacetic acid (60 mL) and heated at 120° C. for about 8 hours. The reaction mixture was cooled to room temperature, poured into water, made basic with 6N sodium hydroxide and then extracted with ether (5×100 mL). The ether extracts were combined, dried with magnesium sulfate, then evaporated. The residue was purified by silica gel chromatography (20% methanol in ethyl acetate as eluent) to give 13.3 g of a green oil. This material was used in subsequent reactions.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[S:34])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ncccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2ncccc2c1=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate [(Example 1, Step 6) 580 mg, 1.49 mmol] was suspended in toluene (5 mL) and dioxane (5 mL), placed into an oil bath preheated to 110° C. and treated in one portion with Lawesson's Reagent (603 mg, 1.49 mmol, 1 equiv). After stirring for 30 minutes, the mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 50:50; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:17]2[C:16](=[O:22])[CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:6][C:7]([CH3:10])=[CH:8][N:9]=1
Reactant: O=C1C=CCCC1
Reactant: Cc1cnc(Cl)c(C=O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)c(C(O)C2=CCCCC2=O)c1
Yield: 92 %

Procedure:
The clear solution of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 92% yield (2.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:39]2[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][O:33][CH2:32][CH2:31][OH:30])[CH2:37][CH2:38]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: OCCOCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCOCCO)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-[2-(2-hydroxyethoxy)ethyl]piperazine (35 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)(O)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.S(Cl)(Cl)=O.[OH-].[K+]>C(Cl)Cl.O>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6](/[CH:14]=[C:15](/[C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)\[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cnccn2)CCN(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyrazin-2-yl)propan-2-ol (336 mg, 1.0 mmol) in DCM (8 mL) was added at 0° C. a solution of thionyl chloride (594 mg, 5 mmol) in DCM (8 mL). The reaction mixture was stirred at RT for 30 min., volatiles were evaporated under reduced pressure and the residue was dissolved in N-methyl-2-pyrrolidone (4 mL). KOH (392 mg, 7.0 mmol) was added and the reaction mixture was stirred at RT for 5 min. and at 100° C. for 30 min. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 9.0 (d, 1H), 8.70 (s, 1H), 8.60 (d, 1H), 7.70 (s, 1H), 7.38 (s, 1H), 7.15 (m, 2H), 4.78 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.25 (m, 2H), 3.20 (s, 3H), 2.50 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.N.[F:10][C:11](I)([F:13])[F:12].C(OCC)C>O>[F:10][C:11]([F:13])([F:12])[S:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:8])=[CH:2][CH:3]=1
Reactant: FC(F)(F)I
Reactant: Cc1ccc(S)cc1
Agent: N
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(SC(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
p-Toluenethiol (8 g.) was added to liquid ammonia (60 ml.) at -30°. Trifluoromethyl iodide (18 g.) was added and the mixture was irradiated with uv light (297nm.) for 30 minutes. Dry diethyl ether (35 ml.) was added and irradiation was continued for 1 hour. The mixture was allowed to warm to 20° C. and water was added. The mixture was extracted with diethyl ether and the ethereal extracts were washed with sodium thiosulphate solution and then water. The ethereal extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. Distillation gave 4-trifluoromethylthiotoluene as a mobile yellow-brown liquid (b.p. 78°-80° C., 16 mm.).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]N1C(C)(C)CCCC1(C)C.CC1(C)CCCC(C)(C)N1.[Li]CCCC.[CH:53](=[O:56])[CH2:54][CH3:55]>C1COCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH:53]([OH:56])[CH2:54][CH3:55])[C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Reactant: CCC=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: CCC(O)c1c(F)c(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
A −40° C. solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.274 mmol) in THF (10 mL) was treated with LTMP (1.10 mmol, freshly prepared by mixing 2,2,6,6-Tetramethyl piperidine and n-BuLi at 0° C. for 30 min.). The mixture was then allowed to warm to 0° C. for 2 h. The reaction mixture was cooled to −30° C. and propionaldehyde (159 mg, 2.74 mmol) was added. The reaction was stirred at −30° C. for 2 h before it was slowly quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford 2-anilino-7-chloro-6-fluoro-5-(1-hydroxypropyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (120 mg, 97%) as a white solid: LCMS RT: 3.14 min, MH+: 424.2. Other electrophiles such as disulfide may be used to quench the anion.