Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C:14]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([N:18]2[CH2:19][CH2:20][O:21][CH:16]([C:14]([NH:13][C@@H:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH3:12])=[O:15])[CH2:17]2)[CH:26]=[CH:27][CH:28]=1
Reactant: C[C@@H](NC(=O)C1CNCCO1)c1cccc2ccccc12
Reactant: Fc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C1CN(c2cccc(F)c2)CCO1)c1cccc2ccccc12
Temperature: 110 °C

Procedure:
A mixture solution of N-((R)-1-(naphthalen-1-yl)ethyl)morpholine-2-carboxamide (Intermediate-2) (300 mg, 1.056 mmol) in toluene (10 mL), bis(tri-tert butyl phosphine) Pd(0) (0.10, 54 mg), trisdibenzylidene acetone dipalladium(0) (48 mg, 0.0528 mmol), 1-fluoro-3-iodobenzene (0.15 ml, 1.26 mmol) and Cs2CO3 (516 mg, 1.58 mmol) were added. The reaction mass was heated to 110° C. and further maintained for 15 h under nitrogen atmosphere. The mixture was diluted with ethyl acetate, filtered through celite bed, and concentrated under vacuum. It was further purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as eluent to afford title compound as oily mass (250 mg), m/z: 379.2.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].CC([N:23]([CH:27]1[CH2:30][NH:29][CH2:28]1)C(=O)[O-])(C)C.C(N(CC)CC)C>C(#N)C>[NH2:23][CH:27]1[CH2:30][N:29]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:28]1
Reactant: CC(C)(C)N(C(=O)[O-])C1CNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(N)C3)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
A suspension of 0.81 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1.0 g (6.0 mmole) of 1,1-dimethylethyl-(3-azetidinyl)carbamate, 1.0 g (10 mmole) triethylamine and 50 ml of acetonitrile was heated at reflux 35 for four hours. The solvent was removed in vacuo and the residue was dissolved in 10 ml of trifluoroacetic acid. The solution was stirred at room temperature for one hour, the solvent was removed in vacuo and the residue dissolved in water. The turbid solution was clarified by filtration and the filtrate adjusted to pH 7.3 with 1.0N sodium hydroxide. The resulting precipitate was removed by filtration, washed successively with water, ethanol and ether. Drying in vacuo gave 0.2 g of 7-(3-amino-1-azetidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 260°-262° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[O:39][C:40](=O)[C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:43]([C:44]([O:46][CH3:47])=[O:45])[C:42]=1[CH2:53]Br>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[CH2:53][C:42]4[C:41](=[CH:50][C:49]([O:51][CH3:52])=[CH:48][C:43]=4[C:44]([O:46][CH3:47])=[O:45])[C:40]3=[O:39])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Reactant: COC(=O)c1cc(OC)cc(C(=O)OC)c1CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(OC)cc2c1CN(CC1Cc3c(sc(N)c3C(=O)OC(C)(C)C)CN1Cc1ccc(OC)cc1)C2=O
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (57.4 mg, 0.142 mmol) and diisopropyl ethylamine (49 μl, 0.28 mmol) in acetonitrile (20 ml) at room temperature was added 2-bromomethyl-5-methoxy-isophthalic acid dimethyl ester (3.00 g, 7.45 mmol). The solution was stirred for 16 hours and the solvent evaporated in vacuo. The residue was taken into ethyl acetate (50 ml) and washed with water (2×20 ml), 1 N hydrochloric acid (20 ml), brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column using a mixture of ethyl acetate/hexane (1:1) as eluent, which afforded 62 mg (71%) of 2-amino-6-(4-methoxy-benzyl)-5-(6-methoxy-4-methoxycarbonyl-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C-:13]#[N:14].[C-]#N.[Na+].C(OCC)(=O)C>O>[C:13]([C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])#[N:14]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(F)cc1C#N
Temperature: 195 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:14]=2[CH:13]=[CH:12][C:11]=1[O:26][CH2:27][C:28]#[N:29].O>C1COCC1>[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:14]=2[CH:13]=[CH:12][C:11]=1[O:26][CH2:27][C:28]1[NH:29][N:3]=[N:2][N:1]=1
Reactant: N#CCOc1ccc2c(-c3ccccc3F)noc2c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccccc1-c1noc2c(Cl)c(OCc3nnn[nH]3)ccc12

Procedure:
3.35 g NaN3 and 2.25 g of AlCl3 are stirred in 50 ml THF at reflux for 0.5 hour. A solution of 5 g {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetonitrile, of Example 50, in 50 ml THF is added and the reaction mixture is stirred at reflux for about 120 hours. To the reaction mixture is added water and the solvent is removed. The residue is treated with dilute HCl and extracted with CHCl3. Upon attempted extraction of the chloroform solution with 15% NaOH a precipitate forms which is filtered, dissolved in hot water and acidified to afford 7-chloro-3-(2-fluorophenyl)-6-{[5-tetrazolylmethyl]oxy}-1,2-benzisoxazole, mp 198°-200° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].CO[N:26](CCCCN1C2C3C=CC=CC=3N=CC=2N=C1CCC)C(=O)C>>[CH3:1][O:2][N:3]=[CH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC)C(C)=O
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC=NOC
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCC=NOC

Procedure:
The general method of Part G of Example 6 was followed using 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde O-methyloxime (17.5 g, 56.5 mmol), prepared as described in Parts A-D of Example 6, in lieu of N-methoxy-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]acetamide. Purification by flash column chromatography on silica gel afforded 11.4 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde O-methyloxime.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH:14]=O)[CH:6]=[CH:5]2.[F:16][C:17]([F:41])([F:40])[C@H:18]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]1)[C:19]1[CH:20]=[N:21][C:22]([NH:25][NH2:26])=[CH:23][CH:24]=1>C(O)C>[F:40][C:17]([F:16])([F:41])[C@H:18]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])[CH2:28]1)[C:19]1[CH:20]=[N:21][C:22]([NH:25]/[N:26]=[CH:14]/[C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([F:1])[CH:3]=3)[N:8]=2)=[CH:23][CH:24]=1
Reactant: COc1cc2nc(C=O)ccc2cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Solvent: CCO
Product: COc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 6-fluoro-7-methoxyquinoline-2-carbaldehyde (54.7 mg, 0.266 mmol) in ethanol (5 mL) was added tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (100 mg, 0.266 mmol) and the reaction was stirred for 24 hours at ambient temperature. The reaction was concentrated to dryness and used as is in the next step.
Reaction SMILES: [CH:1]1([C:5]([N:7]2[CH2:18][CH2:17][C:10]3[N:11]=[N:12][C:13]([NH:15][NH2:16])=[CH:14][C:9]=3[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:22])=O>C(O)(=O)C>[CH:1]1([C:5]([N:7]2[CH2:18][CH2:17][C:10]3[N:11]=[N:12][C:13]([NH:15][N:16]=[C:20]([CH3:22])[CH3:19])=[CH:14][C:9]=3[CH2:8]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)=O
Reactant: NNc1cc2c(nn1)CCN(C(=O)C1CCC1)C2
Solvent: CC(=O)O
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)C1CCC1)C2

Procedure:
A solution of 5.8 g of 6-cyclobutanecarbonyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 50 cc of acetone and 2 drops of glacial acetic acid is heated at reflux on a water bath for 30 minutes. The crude product obtained as a brown oil is crystallized with absolute ethanol. The title compound has a M.P. of 175°-178° (decomp., from acetone/ether).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](C=O)=[CH:3][CH:2]=1.[CH3:9][O:10][CH:11](OC)[O:12][CH3:13].S(=O)(=O)(O)O.C[O-].[Na+]>CO>[CH3:9][O:10][CH:11]([O:12][CH3:13])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=Cc1ccncc1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-pyridinecarboxaldehyde (100.00 g, 0.93 mol) and trimethylorthoformate (159.20 g, 1.50 mol) in methanol (180 mL) at 0° C., under N2 was added concentrated sulfuric acid (41 mL, 0.45 mol). The resulting white suspension was heated to reflux and stirred for 24 hours. The reaction solution became clear after 2 h. After cooling to room temperature, the reaction mixture was poured slowly into a solution of 25 wt. % sodium methoxide (360 mL) in methanol (300 mL). The mixture was then concentrated in vacuo to a light brown thick oil. To this crude oil was added t-butylmethyl ether (500 mL), followed by the slow addition of water (40 mL) (to convert the inorganics to filterable solids). After filtration through a pad of Celite, the filtrate was concentrated to yield a light brown oil. The crude oil was vacuum distilled to yield the desired product as a colorless oil
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.Br[CH2:19][C:20]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])=[O:21]>O1CCCC1>[C:1]([CH:3]([CH2:19][C:20]([C:22]1[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=1[F:28])=[O:21])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: O=C(CBr)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C#N)CC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a solution of ethyl cyanoacetate (7.24 g) and diisopropylethylamine (19.9 g) in tetrahydrofuran (30 mL) was added dropwise a solution of 2-bromo-1-(2,6-difluorophenyl)ethanone (15.16 g) in tetrahydrofuran (15 mL) at 10-15° C. The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, 1 mol/L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a pale-green oil (yield 13.8 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1([C:31](Cl)=[O:32])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][C:31]([C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][Br:13])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:32]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1OC

Procedure:
Prepared analogously to Example 1 from 3,4-dimethoxybenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[S:31]([N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:32])=[O:33]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(S(=O)(=O)n2ccc3c(CN(C)C)c(OC)ccc32)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.7 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2,5-dimethoxybenzenesulfonyl chloride (26 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a beige solid. MS (ESI+) for C20H24N2O5S m/z 405 (M+H)+.
Reaction SMILES: [C:1]1(/[C:7](/[C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])=[N:8]\[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33]>CN(C=O)C>[CH3:33][O:9]/[N:8]=[C:7](\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[C:26]([F:29])([F:27])[F:28]
Reactant: CI
Reactant: O/N=C(\c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
(E)-Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone oxime (Example 37, 0.070 g, 0.18 mmol) was taken into DMF (3 mL). Then NaH (0.014 g, 0.36 mmol) was added and stirred for 20 minutes, followed by addition of iodomethane (0.05 mL, 0.72 mmol) and stirring over the weekend. The reaction was quenched with water and extracted with ether. The combined organics were washed with water and dried over magnesium sulfate and concentrated. The resulting material was purified via column chromatography using 5% ethyl acetate in hexane as the eluent to afford 0.063 g (86%) of desired product as a white solid. MS (ESI) m/z 407 ([M+H]+); Anal. Calcd for C24H17F3N2O: C, 70.93; H, 4.22; N, 6.89. Found: C, 70.92; H, 4.19; N, 6.68.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][N:6]1[S:21]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=[O:23])=[O:22])=[O:4].[C:34]([O-:37])(=[S:36])[CH3:35].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([S:36][C:34](=[O:37])[CH3:35])[CH2:7][N:6]1[S:21]([C:24]1[CH:33]=[CH:32][C:27]2[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=1)(=[O:23])=[O:22])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](SC(C)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 100 °C
Yield: 83.2 %

Procedure:
5.42 g (11 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-(toluene-4-sulfonyloxy)-pyrrolidine-2-carboxylic acid methyl ester were suspended in 60 ml DMF and treated with 1.89 g (16.55 mmol, 1.5 eq) potassium thioacetate. The reaction mixture was heated to 100° C. for 45 min, cooled to RT and concentrated. The residue was redissolved in CH2Cl2/sat. NaHCO3 solution. The inorganic phase was extracted with EtOAc, the organic phases were washed with brine and dried over Na2SO4. After evaporation the residue was purified by column chromatography yielding 3.6 g (83%) (2S,4S)-4-Acetylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as orange oil, MS: 394 (MH+).
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])[CH:9]=[CH:8][C:7]=1[N+:26]([O-:28])=[O:27])(=[O:5])[OH:4])[CH3:2].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])[CH:9]=[CH:8][C:7]=1[N+:26]([O-:28])=[O:27])(=[O:4])[O:5][CH2:32][C:31]([O:30][CH3:29])=[O:34])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CCP(=O)(O)c1cc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Product: CCP(=O)(OCC(=O)OC)c1cc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 32, P-ethyl-2-nitro-5-(2-nitro-4-trifluoromethyl-anilino)phenylphosphinic acid is reacted with methylbromoacetate to give methoxycarbonylmethyl P-ethyl-2-nitro-5-(2-nitro-4-trifluoromethylanilino)phenylphosphinate.
Reaction SMILES: [NH2:1][C@@:2]1([CH3:27])[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14](=[O:16])[NH2:15])[C:3]1([CH3:26])[CH3:25].CCN(CC)CC.[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O>C1COCC1>[C:39]([O:38][C:36]([NH:1][C@@:2]1([CH3:27])[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14](=[O:16])[NH2:15])[C:3]1([CH3:26])[CH3:25])=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(N)C3(C)C)c(C(N)=O)cnn2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(NC(=O)OC(C)(C)C)C3(C)C)c(C(N)=O)cnn2c1
Temperature: 70 °C

Procedure:
A solution of ethyl 4-((1R,3S)-3-amino-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (8.37 g, 22.42 mmol) and Et3N (6.25 mL, 44.8 mmol) in THF (100 mL) was added BOC2O (10.41 mL, 44.8 mmol), and then the reaction mixture was heated to 70° C. for 16 hrs. The reaction mixture was concentrated to afford ethyl 4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate. LC/MS (M+H)+=474.3.
Reaction SMILES: CO[C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:4].CC(C)([O-])C.[K+].[F:19][C:20]([F:24])([F:23])[C:21]#[N:22]>C1COCC1>[CH3:12][O:11][C:9]([C:8]1[C:6]([OH:7])=[CH:5][C:3](=[O:4])[NH:22][C:21]=1[C:20]([F:24])([F:23])[F:19])=[O:10]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: N#CC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cc(=O)[nH]c1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Dimethyl 1,3-acetonedicarboxylate (34.8 g, 0.2 mol) is slowly added to a solution of potassium t-butoxide (22.4 g, 0.2 mol) in THF (300 mL) at 60° C. After addition, the reaction mixture is stirred at 60° C. for 2 hours. The reaction is allowed to cool to 40° C. and trifluoroacetonitrile gas (100 g, 1.05 mol) is slowly bubbled slowly into the above mixture. The reaction temperature is maintained at 50° C. overnight. The volatile material is removed in vacuo. The residue is dissolved in water (200 mL) and the solution is poured into hydrogen chloride solution (conc. HCl/water 80 mL: 200 mL). The white solid is collected by filtration and dried. After being triturated with chloroform (200 mL), the title product is obtained as a white solid. 1H NMR: (CDCl3) 6.29 (s, 1H), 3.76 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH:38](=O)[CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN1CCC(n2nc(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (250 mg, 0.503 mmol), acetaldehyde (44 mg, 1.007 mmol) and sodium triacetoxyborohydride (212 mg, 1.007 mmol) were mixed in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by reverse phase preparative HPLC using acetonitrile/water (50 mM ammonium acetate buffer) as mobile phase to give N2-{4-[4-amino-1-(1-ethyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (247 mg, 93%). 1H NMR (DMSO-d6) δ 1.04 ((t, J=7.15 Hz, 3H), 1.92 (m, 2H), 2.08 (m, 2H), 2.25 (m, 2H), 2.40 (q, J=7.15 Hz, 2H), 3.03 (m, 2H), 3.96 (s, 3H), 4.04 (s, 3H), 4.68 (m, 1H), 7.13 (m, 1H), 7.33 (m, 4H), 7.58 (d, J=8.00 Hz, 1H), 7.70 (d, J=7.95 Hz, 1H), 8.11 (d, J=8.15 Hz, 1H), 8.25 (s, 1H), 9.44 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 0.8 mL/min.): RT=2.08 min. MH+=525.3.