Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.[CH:24]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:24]1([C:28]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)C1CCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NC(=O)C1CCC1)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (80 mg, 0.26 mmol, 1.0 eq.), cyclobutanecarboxylic acid (36 mg, 0.34 mmol, 1.5 eq.), N,N-diisopropylethylamine (63 mg, 0.51 mmol, 2.0 eq.) in dichloromethane (4 mL) was added a solution of phosphorus oxychloride (45 mg, 0.31 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 30 min. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water and extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=2:1) to afford 54 mg of methyl 2-(2-(cyclobutanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 53%. MS (ESI+APCI) M+1=393.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@:15]([F:17])([CH3:16])[CH2:14][N:13]([C:18]([C:20]4([C:23]#[N:24])[CH2:22][CH2:21]4)=[O:19])[CH2:12]3)=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([C:20]1([C:18]([N:13]2[CH2:14][C@@:15]([F:17])([CH3:16])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:33]5[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:27])=[O:26])[CH2:12]2)=[O:19])[CH2:21][CH2:22]1)#[N:24]
Reactant: C[C@]1(F)CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(N[C@@H]4CN(C(=O)C5(C#N)CC5)C[C@]4(C)F)c(C(N)=O)cnn3c2)cn1
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 51.2 %

Procedure:
A mixture of 6-bromo-4-(((3R,4S)-1-(1-cyanocyclopropanecarbonyl)-4-fluoro-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (16 mg, 0.036 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14.82 mg, 0.071 mmol), PdCl2(dppf) (2.61 mg, 3.56 mmol) and 2.0 M aqueous solution of potassium phosphate tribasic (0.071 mL, 0.142 mmol) in N,N-dimethylformamide (1 mL) was deoxygenated by bubbling N2 through the mixture for 5 min and heated to 90° C. under N2 for 1 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (8.3 mg, 51% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.16 (d, J=8.4 Hz, 1H), 7.90-7.74 (m, 3H), 7.06 (d, J=19.3 Hz, 1H), 5.03-4.87 (m, 1H), 4.38-4.20 (m, 2H), 4.01-3.93 (m, 3H), 3.88-3.54 (m, 2H), 1.99-1.47 (m, 7H); MS (ES+) m/z: 451.2 (M+H); LC retention time: 1.09 min (analytical LCMS Method I).
Reaction SMILES: O1C(C2C=C(N[C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)C=CC=2)=CN=C1.[NH2:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[CH2:49][CH:48]([NH:53][C:54](=[O:59])[C:55]([F:58])([F:57])[F:56])[CH2:47]2.Cl.C(OCC)C>CC(O)C>[F:58][C:55]([F:56])([F:57])[C:54]([NH:53][CH:48]1[CH2:47][C:46]2[C:50](=[CH:51][CH:52]=[C:44]([NH:43][C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:29]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)[CH:45]=2)[CH2:49]1)=[O:59]
Reactant: Nc1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CC(NC(=O)C(F)(F)F)C4)n2)c1
Yield: 37.3 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (109 mg, 0.25 mmol) (see Example 2, step B) and N-(5-amino-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (72 mg, 0.30 mmol) were combined in i-PrOH (2 mL) and 1M hydrochloric acid in diethyl ether (25 μL, 0.025 mmol) and heated at 180° C. in the microwave reactor for 20 min. The reaction product was concentrated and purified directly by silica gel flash column chromatography (30-100% EtOAc in hexanes). Purification yielded 61 mg (38%) of a brown oil. ES-LC/MS m/z=654 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].CC(=CC)C.O.P([O-])(O)(O)=[O:36].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.C1COCC1.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[C:4]([OH:36])=[O:5]
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=O)c3)nc(OC)n2)cc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCNc2cc(-c3ccc(F)c(C(=O)O)c3)nc(OC)n2)cc1
Reaction time: 15 h

Procedure:
A solution of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [120 mg, 0.31 mmol, Example 35(j)] and 2-methyl-2-butene (2.93 mL, 28 mmol) in t-butanol (4 mL) and THF (2 mL), is treated with a solution of sodium dihydrogen phosphate monohydrate (303 mg, 2.2 mmol) and sodium chlorite (0.28 g, 3.2 mmol) in water (2 mL) at room temperature. After 15 hours at 20° C., the mixture is concentrated and diluted with water. The mixture is adjusted to pH 3 and the resulting solid is filtered and dried to afford 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid. [118 mg, 96%, Example 20(a)]. LCMS: RT=2.38 minutes, MS: 398 (M+H). IC50=0.4 nM
Reaction SMILES: C(O[CH:5]([CH2:11][CH3:12])[CH:6]([N+]([O-])=O)[CH3:7])(=O)C.[N+:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[C-:14]>>[CH2:11]([C:5]1[C:6]([CH3:7])=[CH:14][NH:13][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]
Reactant: CCC(OC(C)=O)C(C)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1[nH]cc(C)c1CC

Procedure:
reacting 3-acetoxy-2-nitropentane with ethyl isocyanoacetate in the presence of a nonnucleophilic base to form ethyl 3-ethyl-4-methylpyrrole-2-carboxylate;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([OH:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)nc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(O)nc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 5,6-dimethylpyridin-2-ol (9.57 g, 0.078 mol) and concentrated sulfuric acid (116 mL) cooled in an ice bath was treated with 70% nitric acid (6.5 mL) in a dropwise manner so that the reaction temperature remains below 15° C., after which the reaction was stirred for a further 1 hour. The mixture was poured into ice-water (300 ml), stirred for 5 minutes then filtered, washed with water (60 mL) and dried under vacuum at 60° C. to yield 5,6-dimethyl-3-nitropyridin-2-ol (7.09 g, 54%). 400 M Hz 1H NMR (DMSO-d6) δ: 12.74 (s, 1H), 8.32 (s, 1H), 2.26 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]CC2C=CC=CC=2)[CH:5]=[CH:4][C:3]=1[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:18]1>CO.ClCCl.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=2[F:30])=[N:18]1
Reactant: O=C(Nc1ccn(Cc2ccc(OCc3ccccc3)cc2Cl)n1)c1c(F)cccc1F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccn(Cc2ccc(O)cc2Cl)n1)c1c(F)cccc1F

Procedure:
A solution of {N-[1-({2-chloro-4-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]-2,6-difluorobenzamide (for a preparation see Example 30)(0.731 g, 1.61 mmol) in methanol (35 ml) was hydrogenated using the H-cube (settings: ambient, 1 bar, 1 ml/min flow rate) and 10% Pd/C CatCart 30 as the catalyst. The solvent was removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (0.331 g); LCMS: (System 4) MH+=364, tRET=2.36 min.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([NH2:11])=[CH:10][C:3]=12.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][C:3]=12
Reactant: Nc1cc2c(O)nc[nH]c-2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cc2c(O)nc[nH]c-2n1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A mixture of 3.0 g (0.02 mole) of 4-hydroxy-6-aminopyrrolo[2,3-d]pyrimidine and 8.4 g (0.07 mol) of pivaloyl chloride in 40 mL of pyridine is stirred for 30 minutes at from 80° to 90° C., the mixture then evaporated to dryness, and the residue dissolved in 30 mL of methanol. Addition of 10% aqueous ammonia yields 4.2 g (89%) of 4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine which can be further purified by chromatography through silica gel, eluting with 8% methanol in methylene p chloride. mp 295° C. 1NMR (d6 -DMSO) δ1.20(s, 9H), 6.37(d, J=3.4Hz, 1H), 6.92(d, J=3.4Hz, 1H), 10.78 (s, 1H), 11.56 (s, 1H), 11.82 (s, 1H). Anal. Calc. for C11H14N4O2C, 56.40; H, 6.02; N, 23.92. Found: C, 56.16; H, 6.01; N, 23.67.
Reaction SMILES: [Cl: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[CH:8]=[C:7]([C:16]#[C:17][CH2:18][OH:19])[C:6]=2[CH:20]=1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].Cl>CCOCC>[S:28]([O:19][CH2:18][C:17]#[C:16][C:7]1[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1)(=[O:30])(=[O:29])[CH3:27]
Reactant: OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21

Procedure:
A solution of 6 g. of 3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol in 50 ml. of pyridine is treated dropwise at -10° C. to 0° C. with 1.7 ml. of methanesulfonyl chloride in 10 ml. of pyridine and stirred at this temperature for 2 hours. After pouring onto ice, acidification with hydrochloric acid and extraction with ether, there is obtained 3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol mesylate which melts at 100°-102° C. after recrystallizatin from ether.
Reaction SMILES: [CH3:1][C:2]12[C:7]([CH2:9]CC=C(C)CO)([CH3:8])[CH:6]3[CH2:16][CH:3]1[CH:4]2[CH2:5]3.CN/C(/NCCSCC1OC(CN(C)C)=CC=1)=C\[N+]([O-])=[O:22].Cl>>[CH3:1][C:2]1[C:7]([CH3:8])([CH3:9])[CH:6]([CH2:16][CH2:3][OH:22])[CH2:5][CH:4]=1
Reactant: CN/C(=C\[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reactant: CC(=CCCC1(C)C2CC3C(C2)C31C)CO
Agent: Cl
Product: CC1=CCC(CCO)C1(C)C

Procedure:
5-(2,3-dimethyl-tricyclo-[2.2.1.02.6]-hept-3-yl)-2-methyl-2-penten-1-ol, or santanol.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]3[C:12]([NH:13][C:14](=[O:24])[CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:16]3)=[CH:11][C:10]=2[Cl:25])[CH:5]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=1)=[C:34]=[O:35].O>CN(C)C=O>[Cl:25][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:34]([NH:33][C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:45][CH:46]=3)=[O:35])=[CH:5]1)[N:16]=[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](=[O:24])[NH:13]2
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: CCOC(=O)C1Nc2cc(-n3ccc(CN)c3)c(Cl)cc2NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)NCc2ccn(-c3cc4nc(C(=O)OCC)c(=O)[nH]c4cc3Cl)c2)cc1
Reaction time: 3 h
Yield: 31.6 %

Procedure:
To a solution of the compound of Example 5 (61.2 mg, 159 μmol) in N,N-dimethylformamide (1.6 ml) were added triethylamine (33.3 μl, 239 μmol) and successively ethyl 4-isocyanatobenzoate (36.5 mg, 191 μmol) at room temperature, and the mixture was stirred for 3 hours at the same temperature. Water was added to the reaction mixture and the precipitated crystals were collected by filtration. After washed with water and then with ethyl acetate, these were air-dried, thereby obtaining 27.0 mg of title compound as yellowish brown powder. Yield 32%.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:16]([CH3:17])[CH:15]=[C:14]([CH:18]=O)[CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([C:22]1[CH:23]=[C:24]([C:28](O)=O)[N:25](C)[CH:26]=1)=O.[Li].Cl.Cl.C(N1CCNCC1)(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:16]([CH3:17])[CH:15]=[C:14]([CH2:18][N:25]3[CH2:26][CH2:22][CH2:23][CH2:28][CH2:24]3)[CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cn1cc(C=O)cc1C(=O)O
Reactant: CC(C)N1CCN(C(=O)c2cc(C=O)cn2C)CC1
Agent: CC(C)N1CCNCC1
Agent: Cl
Agent: [Li]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2cc(CN3CCCCC3)cn2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(4-Isopropyl-piperazine-1-carbonyl)-1-methyl-1H-pyrrole-3-carbaldehyde. 4-Formyl-1-methyl-1H-pyrrole-2-carboxylic acid, lithium salt, (1.08 g.) was diluted with thionyl chloride (20 mL) and heated at reflux under nitrogen for 1.5 h. The reaction mixture was carefully concentrated. The residue was co-evaporated with toluene (3×) to remove residual HCl, and then was kept under vacuum for 2 h. Separately, a solution of 1-isopropyl-piperazine dihydrochloride (1.21 g, 6.00 mmol) in DCM (50 mL) was cooled to 0-5° C. TEA (2.23 mL, 24.0 mmol) was added slowly, followed by the above acid chloride solution in DCM (50 mL). The resulting mixture was allowed to stir overnight at rt. The mixture was concentrated to yield the crude product (3.78 g), which was purified on silica gel column using 2-6% 2 M NH3 in MeOH/DCM to yield the title compound (0.20 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9](I)([F:14])[C:10]([F:13])([F:12])[F:11].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>O.COC(C)(C)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:8][C:9]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)([F:14])[C:10]([F:13])([F:12])[F:11]
Reactant: FC(F)(F)C(F)(F)I
Reactant: Nc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: COC(C)(C)C
Product: Nc1ccc(C(F)(F)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
To a solution of 2-aminopyridine (25.0 g, 263 mmol) in a mixture of water (250 ml) and tert-butyl methyl ether (25 ml) was added, successively perfluoroethyl iodide (80 g, 38 ml, 315 mmol), sodium hydrosulfite (64.6 g, 26 ml, 315 mmol), sodium hydrogen carbonate (26.5 g, 315.6 mmol) and tetrabutyl ammonium hydrogen sulfate (“TBAHS”) (0.11 equiv., 9.92 g, 28.9 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The mixture was filtered and the filtrate was extracted twice with tert-butyl methyl ether. The combined organic phases were washed successively with water, aqueous hydrochloric acid (1N) and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (AcOEt/cyclohexane) to give 5-(1,1,2,2,2-pentafluoroethyl)pyridin-2-amine in 7% yield. 1H NMR (400 MHz, CDCl3) 8.23 (d, 1H), 7.61 (d, 1H), 6.72 (m, 1H), 5.04 (sb, 2H, NH2) ppm. The major by-product was 3,5-bis(1,1,2,2,2-pentafluoroethyl)pyridin-2-amine.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2[CH2:13][S:14][CH2:15][C:3]1=2.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2=[CH:13][S:14][CH:15]=[C:3]12
Reactant: Cn1c2c(c(=O)c3ccccc31)CSC2
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: Cn1c2ccccc2c(=O)c2cscc21
Yield: 70 %

Procedure:
2.17 Parts of 1,4-dihydro-4-methylthieno-[3,4-b]-quinolin-9(3H)-one are reacted with 0.88 part by volume of sulfuryl chloride in 25 parts by volume of methylene chloride at 0° C. for 0.5 hour. The end product is isolated from the reaction mixture by the method described in Example 5c. 1.50 parts (70% of theory) of 4-methyl-thieno-[3,4-b]-quinolin-9(4H)-one of the melting point 188°-190° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([SH:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCc2cccnc2)nc1
Yield: 75.8 %

Procedure:
5-nitro-2-pyridinethiol (5.0 g) was dissolved in an aqueous methanol solution (125 ml), and to this solution was added sodium hydroxide (3.84 g) and then, 3-(chloromethyl)pyridine hydrochloride (6.30 g), and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure, and the obtained residue was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[(3-pyridinylmethyl)sulfanyl]pyridine (6.0 g).
Reaction SMILES: O[N:2]=[C:3]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4]1.[OH-].[Na+]>CCO.O.[Ni]>[CH2:5]1[C:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH:3]([NH2:2])[CH2:4]1
Reactant: ON=C1CCc2c1[nH]c1ccccc21
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC1CCc2c1[nH]c1ccccc21
Yield: 90.1 %

Procedure:
To a stirred solution of 3-hydroxyimino-1,2,3,4-tetrahydrocyclopent[b]indole (6 g) in 150 ml of 95% EtOH at 0° C. was added a nickel alloy (Harshaw, Ni-100P, 10 g) followed by 12.9 grams of sodium hydroxide in 150 ml water. The ice bath was removed after 0.5 hour and the mixture was stirred an additional hour and filtered. The EtOH was removed in vacuo and the product crystallized to provide 5.0 grams of solid. A sample was recrystallized from toluene to provide analytically pure material.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[CH2:6][C@H:7](OC)[B:8]([OH:10])[O:9][C:4]=2[C:3]=1[C:15]([OH:17])=[O:16].[NH2:18][C:19]1[S:20][C:21]([SH:24])=[N:22][N:23]=1>>[NH2:18][C:19]1[S:20][C:21]([S:24][C@H:7]2[CH2:6][C:5]3[CH:13]=[CH:14][C:2]([F:1])=[C:3]([C:15]([OH:17])=[O:16])[C:4]=3[O:9][B:8]2[OH:10])=[N:22][N:23]=1
Reactant: CO[C@H]1Cc2ccc(F)c(C(=O)O)c2OB1O
Reactant: Nc1nnc(S)s1
Product: Nc1nnc(S[C@H]2Cc3ccc(F)c(C(=O)O)c3OB2O)s1

Procedure:
Compound 23 was prepared from Compound 19G (example 19) following methods described in steps 5 and 6 of Example 1 utilizing 2-amino-5-mercapto-1,3,4-thiadiazole.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.I[C:44]1[C:45]([O:59][CH3:60])=[CH:46][C:47]([N:50]([CH3:58])[C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[N:48][CH:49]=1.[C:61]1([C:67]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[NH:68])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:61]1([C:67](=[N:68][C:44]2[C:45]([O:59][CH3:60])=[CH:46][C:47]([N:50]([CH3:58])[C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[N:48][CH:49]=2)[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1cc(N(C)C(=O)OC(C)(C)C)ncc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(N(C)C(=O)OC(C)(C)C)ncc1N=C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 69.3 %

Procedure:
Pd2(dba)3 (33.70 mg, 0.03680 mmol) and Xantphos (42.58 mg, 0.07359 mmol) were added to a sealed tube containing tert-butyl N-(5-iodo-4-methoxy-2-pyridyl)-N-methyl-carbamate (268 mg, 0.7359 mmol), diphenylmethanimine (173.4 mg, 160.6 μL, 0.9567 mmol) and Cs2CO3 (719.4 mg, 2.208 mmol) in dioxane (2.5 mL). The reaction was placed under an atmosphere of nitrogen and heated at 100° C. for 4 hours. At RT, the reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 30% EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl (5-((diphenylmethylene)amino)-4-methoxypyridin-2-yl)(methyl)carbamate as a yellow solid (213 mg, 69% Yield). MS (ES+) 418.2.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CN(C)C=O.[BH4-].[Na+].[Cl:21][CH2:22][CH2:23]CBr>O.CC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][CH2:23][CH2:22][Cl:21])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: ClCCCBr
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Nc1ccc(SCCCCl)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
6 G. of 2-nitro-4-thiocyanatoaniline in 30 ml. of dimethylformamide is treated under nitrogen with 1.2 g. of sodium borohydride at 20° to 30°. After 11/2 hours 15 ml. of acetone is added, followed 2 hours later by 10 g. of 3-chloropropylbromide. The mixture is left at 20°-25° for 16 hours, then diluted with water. The oily product is extracted into chloroform and passed through a silica column. 2-Nitro-4-(3-chloropropylthio)aniline is isolated by evaporation of the solvent.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].C(OC)=O.[S:8](=[O:11])([OH:10])[O-:9].[Na+:12].[OH-].[Na+].[CH2:15]1[CH2:20][CH2:19]C[CH2:17][CH2:16]1>O>[CH:2]1([CH:1]=[O:3])[CH2:19][CH2:20][CH2:15][CH2:16][CH2:17]1.[S:8](=[O:9])([OH:11])[O-:10].[Na+:12]
Reactant: CC=O
Reactant: C1CCCCC1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC=O
Product: O=CC1CCCCC1

Procedure:
A solution of cyclohexane with 1000 ppm acetaldehyde and 500 ppm methyl formate impurities was prepared and a partitioning run was carried out in a 500 mL separatory funnel, reacting this mixture with aqueous sodium bisulfite as the reducing agent and aqueous sodium hydroxide as the base. The cyclohexane-aldehyde solution was prepared by mixing 1000 g cyclohexane, 1.0 g acetaldehyde, and 0.5 g methyl formate in a large flask. After mixing, a portion was decanted into a labeled vial for analysis. Sodium bisulfite solution was prepared by mixing 9.66 g water and 2.16 g Na2S2O5 in a flask with shaking until complete dissolution had occurred. Sodium hydroxide solution was drawn from 0.2 N sodium hydroxide laboratory stock solution.