Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([OH:12])[CH3:11].[OH-].[Na+]>>[OH:12][CH2:10][CH2:11][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(O)Br
Agent: [Na+]
Agent: [OH-]
Product: OCCNc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of p-bromoaniline (17.2 g, 100 m mol) and bromoethanol (3.54 mL, 50 m mol) in a 50 mL round bottle was heated gradually to 70° C. and then was stirred at 70° C. overnight. The reaction mixture was then cooled, basified with aq. NaOH, and extracted with ether. The ether layers were dried over Na2SO4 and concentrated to near dryness. N-β-hydroxyethyl-p-bromoaniline was obtained as a crystalline material (5.1 g, 47%). 1H NMR (CDCl3): δ 7.28 (2H, d, J=8.8 Hz), 6.60 (2H, d, J=8.8 Hz), 3.86 (2H, t, J=5.1 Hz), 3.29 (2H, t, J=5.1 Hz), 3.00 (2H, br s) ppm.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:13])[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]1[CH:3]=[CH:2][N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[C:5]=12
Reactant: O=CCC1Cc2c(Cl)cccc2C1=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1cccc(Cl)c1C2
Reaction time: 0.75 h
Yield: 59.5 %

Procedure:
A solution of 2.08 g of (RS)-2-(2-oxoethyl)-4-chloro-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:2). 1.47 g (59%) of (RS)-1-(5-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([NH2:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([NH:20][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.7 %

Procedure:
A mixture of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (0.85 g), anhydrous potassium carbonate (430 mg), dichloromethane (40 ml), dioxane (10 ml) and ethyl chloroformate (339 mg) was stirred for 1.5 hours at room temperature. The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of chloroform and dioxane to give colorless crystals of 5-chloro-3-[(4-ethoxycarbonylamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (0.35 g).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:14](=O)([O-])[O-].[K+].[K+].CI.C(C(C)=O)C>C(OCC)(=O)C>[CH3:14][S:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CC(C)=O)cc1S
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COc1ccc(CC(C)=O)cc1SC
Yield: 84 %

Procedure:
A mixture of 10 g of 3-mercapto-4-methoxyphenylacetone, 9 g of anhydrous potassium carbonate, 42 g of methyl iodide, and 50 ml of methyl ethyl ketone was stirred under refluxing for 20 hours, and after cooling, the reaction mixture was filtered. The filtrate obtained was, then, evaporated to dryness. The residue formed was dissolved in ethyl acetate and after washing the solution obtained with water, ethyl acetate was distilled off and the crude crystals obtained were recrystallized from a mixture of n-hexane and ether to provide 9 g of 3-methylthio-4-methoxyphenylacetone having a melting point of 74°-75° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])=[CH:6][CH:7]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C(=O)CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)C(=O)CCc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A solution of 11.9 g (62 mmol) of crude 5-(4-amino-phenyl)-2-methyl-pentan-3-one (prepared in Example GGGGG) in 100 mL of acetonitrile was treated with 24.3 g (75 mmol) of cesium carbonate, and the mixture was stirred at 50° C. for 15 minutes. Benzyl chloroformate (10.7 mL, 75 mmol) was added all at once, and the mixture was stirred at room temperature for 90 minutes. The solvent was evaporated. The residue was partitioned between EtOAc and H2O; the organic layer was separated, washed with brine, dried (MgSO4), and concentrated. The product was chromatographed on silica gel, eluting with EtOAc:hexane (30:70), to give the title compound. 1H NMR (CDCl3) δ 1.01 (d, 6 H), 2.48-2.55 (m, 1 H), 2.67-2.82 (m,4 H), 5.15 (s, 2 H), 6.58 (br s, 1 H), 7.08 (d, 2 H), 7.25-7.38 (m, 7 H).
Reaction SMILES: [CH:1]([CH:3]1[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4]1)=O.C(O)(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH3:31][C:27]1[N:26]=[C:25]([NH:24][CH2:1][CH:3]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:5]3([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:4]2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cccc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cccc(NCC2CC3(CCCC3)CCN2C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
(±)tert-butyl 7-formyl-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 72, 2 g, 7.48 mmol) was dissolved in dichloroethane (25 ml), then acetic acid (5 eq) and 2-amino 6 picoline (810 mg, 7.48 mmol) were added. After 3 hours at room temperature NaBH(OAc)3 (2.53 g, 11.96 mmol) was added and the reaction was maintained under stirring at room temperature for 18 hours. The reaction was poured in aqueous NaHCO3 and extracted with ethylacetate. The organic layers were combined, dried (Na2SO4) and concentrated under vacuum; the crude was then purified by silica gel column chromatography (petroleum ether/ethyl acetate=9/1) to obtain 1.3 g of intermediate as colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=1.O1CCOCC1.C([O-])(O)=O.[Na+]>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.O>[NH2:20][C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)[CH:15]=[C:16]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:17]=1
Reactant: Nc1nc(Cl)cc(NCc2ccccc2)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(NCc3ccccc3)nc(N)n2)cc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To (4-cyano-3-fluorophenyl)boronic acid (190 mg, 1.15 mmol) and 6-chloro-N4-(phenylmethyl)-2,4-pyrimidinediamine (300 mg, 1.28 mmol) into a sealable flask were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL). The mixture was degassed with nitrogen gas for 10 minutes. Pd(Ph3P)4 (74 mg, 0.064 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto EtOAc and water. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were filtered, then washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was chromatographed on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH). The material (367 mg) was carried on as is into the next reaction.
Reaction SMILES: [C:1]1([O:7][P:8]([O:17][CH2:18][CH2:19][CH:20]([NH:24]C(=O)C[C@H](OCC2C=CC=CC=2)CCCCCCCCCCC)[C:21]([OH:23])=[O:22])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:48]([O:61][C@H:62]([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH2:63][C:64]([OH:66])=O)(=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59].C(O[C@H](CCCCCCCCCCC)CC(O)=O)C1C=CC=CC=1>>[C:1]1([O:7][P:8]([O:17][CH2:18][CH2:19][CH:20]([NH:24][C:64](=[O:66])[CH2:63][C@H:62]([O:61][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[C:21]([OH:23])=[O:22])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: CCCCCCCCCCC[C@H](CC(=O)NC(CCOP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Product: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NC(CCOP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)O

Procedure:
The 4-(diphenyloxyphosphoryloxy)-2-[(R)-3-benzyloxytetradecanoylamino]-butanoic acid can be prepared using the same reaction scheme by replacing in step 5 of example I, (R)-3-dodecanoyloxytetradecanoic acid by (R)-3-benzyloxytetradecanoic acid.
Reaction SMILES: [Zn]([CH2:4][CH3:5])[CH2:2][CH3:3].Cl[CH2:7]I.[OH:9][CH2:10][CH:11]1[CH:16]([C:17]([O-:19])=[O:18])[CH:15]=[CH:14][CH2:13][CH2:12]1>ClCCCl>[C:17]1(=[O:18])[O:19][CH2:10][CH:11]2[CH2:12][CH2:13][CH:5]3[CH2:4][CH:15]3[CH:16]12.[OH:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH:14]2[CH:15]([CH2:7]2)[CH:16]1[C:17]([O:19][CH2:2][CH3:3])=[O:18]
Reactant: CC[Zn]CC
Reactant: ClCI
Reactant: O=C([O-])C1C=CCCC1CO
Solvent: ClCCCl
Product: CCOC(=O)C1C(CO)CCC2CC21
Product: O=C1OCC2CCC3CC3C12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1,2-dichloroethane (100 mL) at 0° C. and under a dry nitrogen atmosphere was added Et2Zn (neat, 5.2 mL, 50.0 mmol) dropwise followed by chloroiodomethane (7.72 mL, 106.0 mmol) and the reaction mixture was stirred 5 min. (1R/S,6R/S)-6-(Hydroxymethyl)cyclohex-2-ene-1-carboxylate (3.67 g, 20.0 mmol) was then added and the reaction mixture was stirred 1 h at 0° C. followed by overnight stirring at room temperature. The reaction mixture was carefully quenched with water, the product extracted with ether, and dried on anhydrous sodium sulfate. The solvent was removed in vacuo and the product was purified by flash chromatography over silica gel (ethyl acetate/hexanes, 2/8) to afford the desired product (3αR/S,5αS/R,6αR/S,6βR/S)-octahydro-1H-cyclopropa[3,4]benzo[1,2-c]furan-1-one along with some of the uncyclized product ethyl(2R/S,3R/S)-3-(hydroxymethyl)bicyclo[4.1.0]heptane-2-carboxylate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:36][CH3:37])=[C:32]([CH:35]=1)[CH:33]=O)([CH3:27])[C:23]([F:26])([F:25])[F:24].C(OC(N1CCC[C@H](NCC2C=C(C(F)(F)C)C=CC=2OC(F)(F)F)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:32]2[CH:35]=[C:28]([C:22]([CH3:27])([CH3:21])[C:23]([F:26])([F:24])[F:25])[CH:29]=[CH:30][C:31]=2[O:36][CH3:37])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Reactant: COc1ccc(C(C)(C)C(F)(F)F)cc1C=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 12 and Compound 71 in the same manner of Compound 26.
Reaction SMILES: I[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][Si:10](C#C)([CH3:12])[CH3:11].[CH:15](N(CC)C(C)C)(C)[CH3:16].CN1CCCC1=O>[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:2]1[C:3]([NH:8][C:15]#[CH:16])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1I
Reactant: CCN(C(C)C)C(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: C#CNc1ncccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3-iodo-pyridin-2-ylamine described in Preparation Example 1-1-3 (40.2 g, 183 mmol), trimethylsilyl acetylene (51.7 mL, 366 mmol), copper(I) iodide (3.49 g, 18.3 mmoL), N,N-diisopropyl ethyl amine (63.7 mL, 366 mmol), N-methylpyrrolidinone (200 mL) was added tetrakis(triphenyl phosphine) palladium (0) (10.6 g, 9.15 mmol), which was stirred at room temperature for 3 hours 10 minutes under a nitrogen stream. To the reaction solution was added water and extracted four times with ethyl acetate. The solvent thereof was concentrated under a reduced pressure. The residue was purified by NH silica gel chromatography (heptane:ethyl acetate=4:1). The resulting solution was concentrated under a reduced pressure and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1 then 1:1) to obtain the title compound (28.1 g).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][CH:6]([CH3:27])[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:15]=3[O:16][C:17](=[O:18])[C:10]=2[CH2:9]1)[CH3:4].[C:28]([O-])(=O)[CH3:29].[Na+].[BH4-].[Na+].[C:35](O)(=O)[CH2:36]CC>>[CH2:3]([N:5]([CH2:28][CH3:29])[CH:6]([CH3:27])[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:15]=3[O:16][C:17](=[O:18])[C:10]=2[CH2:9]1)[CH2:4][CH2:35][CH3:36]
Reactant: CCCC(=O)O
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(OC)c(OC)cc23)C1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCCCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(OC)c(OC)cc23)C1

Procedure:
Prepared by the method described in Example 73 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one dihydrochloride (6.7 g, 0.016 moles), sodium acetate (5.2 g, 0.063 moles), sodium borohydride (3.3 g, 0.087 moles), and n-butyric acid (28.9 g, 0.33 moles) instead of acetic acid. Several recrystallizations from diisopropyl ether yielded the final product as the free base (3.0 g), mp 108°-111° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][CH:3]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:28]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[N:7]=1
Reactant: NNc1ccccc1Cl
Reactant: O=C(C=Cc1cccc(Br)n1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)n2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
1-(6-Bromo-pyridin-2-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (100.0 mg, 0.3 mmol) prepared in Step 3, 2-chlorophenylhydrazine hydrochloride (55.0 mg, 0.3 mmol), and piperidine (60.0 uL, 0.6 mmol) were added to ethanol (3.0 mL). The reaction mixture was stirred at 60° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7](C(OCC)=O)=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[C:3]=12.[OH-].[Na+].C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[Br:24][C:15]1[S:14][C:4]2[N:5]=[C:6]([CH3:13])[CH:7]=[C:2]([NH2:1])[C:3]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(C)c3)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: Cc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Temperature: 90 °C
Yield: 65.8 %

Procedure:
To a stirred solution of ethyl 4-amino-2-bromo-6-methyl-3-(3-methyl phenyl)thieno[2,3-b]pyridine-5-carboxylate (Description 58) (900 mg, 2.221 mmol) in ethanol (20 mL) at RT was added aqueous NaOH (5M) (1.0 mL, 5.0 mmol). The reaction mixture was heated to 90° C. for ca. 2 h. After cooling to RT the solvent was removed in vacuo. The residue was re-dissolved in water (ca. 80 mL) and neutralized to ca. pH 7 using aqueous HCl (5M). The solution was then extracted with 20% MeOH in DCM (ca. 50 mL×2). The combined organic layer was passed through a phase separator and the solvent removed in vacuo to give a residue which was subsequently re-dissolved in diphenyl ether (10 mL, 62.9 mmol) and heated to 200° C. for ca. 3 h. The reaction mixture was cooled to RT, passed through an SCX cartridge (eluting with MeOH/2M NH3 MeOH). The basic fractions were combined and the solvent removed in vacuo, to give the title compound (487 mg). LCMS (A) m/z: 333/335 [M+1]+, Rt 0.86 min (acidic).
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[C:14](OCC)(=[O:16])[CH3:15].O>C(O)C>[CH2:14]([O:16][C:4]1[N:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH3:15]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 5 N sodium hydroxide solution (2 mL) was added to a solution of methyl 5-chloropyrazine-2-carboxylate (150 mg) in ethanol (4 mL), and the mixture was stirred at room temperature for five hours. Ethyl acetate and water were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was made acidic with concentrated hydrochloric acid. Brine and ethyl acetate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated to obtain the title compound (135 mg).
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[I:8].O.[NH2:12][NH2:13]>C(O)CCC>[I:8][C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[C:9]([NH2:10])=[N:12][NH:13][C:2]=12
Reactant: NN
Reactant: N#Cc1nccc(I)c1F
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2c(I)ccnc12
Temperature: 105 °C

Procedure:
3-Fluoro-4-iodopicolinonitrile (25.6 g) was dissolved in n-butan-1-ol (250 mL) then hydrazine hydrate (100%, 23.3 mL) was added. The reaction was heated at 105° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, rinsed with water, and dried for 30 minutes under vacuum to give 7-iodo-1H-pyrazolo[4,3-b]pyridine-3-amine (25 g) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.35-5.55 (2H, m) 7.73-7.74 (1H, m) 7.939-7.94 (1H, m). MS [M+H] found 261.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[S:21]([CH3:24])(=[O:23])=[O:22])[C:3]=1[CH3:25].[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([NH2:38])[CH:35]=[N:36][CH:37]=2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:38][C:34]1[CH:35]=[N:36][CH:37]=[C:32]([N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH:33]=1)=[C:3]([CH3:25])[C:4]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH3:24])(=[O:23])=[O:22])=[N:5]2
Reactant: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)quinoline (60.0 mg, 0.16 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.05 (1H, d, J=8.0 Hz), 7.83-7.92 (2H, m), 7.44-7.52 (2H, m), 7.00-7.24 (3H, m), 6.54-6.59 (1H, m), 3.79 (3H, t, J=4.9 Hz), 3.09-3.25 (4H, m), 3.07 (2H, s), 2.50 (2H, s), 2.04 (1H, s), 1.89 (3H, s), 1.26 (2H, t, J=7.1 Hz). Mass Spectrum (ESI) m/e=525.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.Cl.[F:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH2:22].[O:28]1CCOCC1>>[F:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH:22][C:6]1[C:5]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:4]=2[C:3]2[C:2](=[O:28])[NH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Nc1c(F)cccc1F
Reactant: Fc1ccc2c(Cl)nc3ccnc(Cl)c3c2c1
Reactant: C1COCCO1
Agent: Cl
Product: O=c1[nH]ccc2nc(Nc3c(F)cccc3F)c3ccc(F)cc3c12
Temperature: 150 °C

Procedure:
To a solution of 1,6-dichloro-9-fluorobenzo[c]-1,6-naphthyridine (70 mg, 0.26 mmol) in dioxane (2 mL) were added HCl (0.131 mL, 4 N in dioxane) and 2,6 difluoroaniline (67.7 mg, 0.524 mmol) and heated to 150° C. for 3 hr. The reaction was cooled and purified by reverse phase HPLC. 1H NMR (600 MHz, CD3OD) δ 9.66 (dd, 1H), 8.56 (s, 1H) 7.50 (m, 1H), 7.48 (m, 2H), 7.13 (m, 2H), 6.45 (dd, 1H). LRMS (ESI) calc'd for (C18H11F3N3O) [M+H]+, 342.1; found 342.0.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.C[I:50]>C1COCC1>[CH3:16][O:15][C:13]([CH:12]1[CH2:11][CH:10]([I:50])[CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])=[O:14]
Reactant: CI
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1CC(I)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a round-bottom flask equipped with a magnetic stir bar and an addition funnel under N2 is added N-Boc-L-trans-4-hydroxy-proline methyl ester, PPh3 and anhydrous THF. The solution is cooled to 0 centigrade, DEAD in THF is added; followed by the addition of MeI. The reaction mixture is allowed to warm to ambient temperature and stirred for about 10 hours. The solvent is removed and the crude product is purified to afford 4-iodo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (31).