Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].[H-].[Na+].Cl>O.O1CCOCC1>[C:23]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:9][C:10]=1[F:16])#[N:24]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C(C#N)C(=O)OCC)c(F)cc2c1=O

Procedure:
86.2 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 63.3 g of ethyl cyanoacetate are initially introduced into 1,000 ml of dioxane. 15.8 g of NaH are added in portions. The mixture is then heated to reflux for 4 hours. The completeness of the reaction is checked using thin-layer chromatography. After completion of the reaction, water is added dropwise. The mixture is then rendered acidic using dilute HCl and extracted using methylene chloride. The organic phase is dried and evaporated. The residue is recrystallized from isopropanol.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=S.C(N(CC)C(C)C)(C)C>C(#N)C>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:13]2[S:12][CH2:18][C:16](=[O:17])[N:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C1CSC(=S)N1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 40.8 %

Procedure:
To a suspension of (1R,2S)-2-phenyl-cyclopropylamine hydrochloride (0.85 g, 5 mmol) and rhodanine (2-thio-4-thiazolin-4-one) (0.68 g, 5 mmol) in acetonitrile (20 mL) was added DIEA (N,N-diisopropylethylamine) (2.61 mL, 15 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (1.35 g, 5 mmol) was added in two portions within a period of 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with ethyl acetate (500 mL). The filtrates were removed under the vacuum and the crude residue was diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to obtain 0.474 g (42% yield) of 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one as a white amorphous solid: EI-HRMS m/e calcd for C12H12N2OS (M+) 232.0670, found 232.0665.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH2:3]1.[H-].[Na+].[CH2:21](Br)[CH3:22].O>O1CCCC1>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:9])[CH3:10])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][O:18][CH2:21][CH3:22])[CH3:15])[CH2:3]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCO
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCN(C)CCO[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Yield: 19.3 %

Procedure:
2.57 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-hyd roxyethyl)-N-methylamine were dissolved in 100 ml of tetrahydrofuran. 0.48 g of a 50% strength sodium hydride dispersion was added at room temperature, and the reaction mixture was heated under reflux for 3 hours. A solution of 1.1 g of ethyl bromide in 20 ml of tetrahydrofuran was then added dropwise to the reaction solution at boiling temperature, and the reaction solution was heated under reflux for a further 6 hours. The reaction solution was worked up by adding 2 ml of water and concentrating the mixture under reduced pressure. The remaining residue was purified by chromatography on silica gel using n-hexane/dichloromethane/methanol as the eluent. 0.55 g of oily N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-etho xyethyl)-N-methylamine was obtained. [α]D20 =-51.20° (c=1; methanol)
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:29])([F:19])[F:28])=[CH:22][CH:23]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: I
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cn1
Temperature: 130 °C
Yield: 95 %

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.5 g, 1.93 mmol) was dissolved in anhydrous dioxane (3 mL) and 6-Trifluoromethylpyridin-3-ylamine was added (469 mg, 2.9 mmol), followed by HI/H2O (0.3 mL, 47%). The mixture was heated at 130° C. for 600 s in a Personal Chemistry microwave. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product as an orange solid (700 mg, 95% crude). The crude product was used for the subsequent step.
Reaction SMILES: CC(O)=[O:3].[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([CH:17]2[CH2:19][O:18]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1(C)C=CC=CC=1>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([C@H:17]([OH:3])[CH2:19][OH:18])[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C2CO2)C1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R,R)-(−)-N,N′-Bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexanediaminocobalt (II) (32.6 mg, 53.9 mmol) was dissolved in toluene (2.0 mL). AcOH was added (6.1 μL), and the resulting mixture was stirred at room temperature for 1 hour under air. The mixture was then concentrated and dried under high vacuum. (S)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (2.3 g, 10.8 mmol) was added, followed by water (97.1 μL), and the resulting mixture was stirred vigorously for 6 hours. Hexanes (15 mL) was added. The resulting solid was manually crushed and additional hexanes was added and stirred until the red solid became a yellowish precipitate. The precipitate was filtered and washed with 2 portions of hexanes. The precipitate was dried under vacuum to yield (S)-3-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester as an off-white solid (1.3 g). The filtrate was concentrated and purified by SiO2 flash chromatography (0-100% EtOAc in hexanes) to yield (S)—(R)-3-oxiranylpyrrolidine-1-carboxylic acid t-butyl ester as an oil (970 mg).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N+:2]=1[O-].F[B-](F)(F)F.[CH3:17][O+:18](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>ClCCl.O>[OH:18][CH2:17][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: [O-][n+]1ccc2c(c1)CCCC2
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: OCc1nccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
5,6,7,8-Tetrahydroisoquinoline-N-oxide (12.7 g, 85 mmole) is dissolved in 250 ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen. The solution is treated with trimethyloxonium tetrafluoroborate (12.6 g, 85 mmole) and the reaction is stirred 1 h at room temperature. The volatiles are removed in vacuo to a pale oily residue. The residue is dissolved in 225 ml methanol and the solution is heated to reflux. Ammonium persulfate (8 g, 34 mmole), in 34 ml water, is added rapidly dropwise to the refluxing mixture. The reaction is stirred 30 min and is treated with a second lot of ammonium persulfate (8 g, 34 mmole) in 34 ml water. The reaction is stirred an additional hour at reflux, is cooled, and the bulk of the methanol is removed in vacuo. The residue is poured into 100 ml ice containing 100 ml 10% hydrochloric acid. The mixture is washed with 2×50 ml ethyl acetate, the pH is adjusted to 9 with 45% potassium hydroxide, and the mixture is extracted with 4×50 ml dichloromethane. The haloorganics are dried over potassium carbonate and were concentrated in vacuo to a brown solid. The crude material is chromatographed over 350 g silica gel (230-400 mesh), eluting with 3 l 20% acetone/chloroform+0.6% conc. ammonium hydroxide followed by 1 l 32% acetone/chloroform+0.6% conc. ammonium hydroxide, while collecting 50 ml fractions. Fractions 19-27 are combined and concentrated to afford 4.3 g (31%) of 1-hydroxymethyl-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[OH:12][CH:13]([CH3:19])[C:14]([CH3:18])([CH3:17])[C:15]#[N:16]>>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:12][CH:13]([CH3:19])[C:14]([CH3:18])([CH3:17])[C:15]#[N:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(O)C(C)(C)C#N
Product: CC(Oc1cc(F)ccc1N)C(C)(C)C#N

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and 3-hydroxy-2,2-dimethyl-butanenitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH2:26]([NH:30][CH3:31])[CH2:27][CH2:28][CH3:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([N:30]([CH2:26][CH2:27][CH2:28][CH3:29])[CH3:31])=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CCCCNC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(C)C(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 26.7 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and n-butylmethylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was first purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a yellow solid (115 mg, yield 27%). MS calcd for (C20H26BN3O5S): 431.2. MS found (ESI negative): (M−H)−=430.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.80 (s, 1H), 9.17 (bs, 1H), 7.45 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (d, J=8, 2 Hz, 1H), 6.37 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 5.94 (bs, 2H), 4.87 (s, 2H), 3.77 (s, 2H), 3.15 (m, 2H), 2.85 (s, 3H), 1.39 (m, 2H), 1.30 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:25][O:26]C1(C2C=CC(C=O)=CC=2)CC1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][O:26][C:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Reactant: COC1(c2ccc(C=O)cc2)CC1
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: COC1(c2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2)CC1

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1-methoxy-cyclopropyl)-benzaldehyde (105 mg, 0.60 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (113 mg, 0.60 mmol) and sodium borohydride (34 mg, 0.89 mmol). The desired product was isolated without further purification as a colorless oil. MS (ISP) 350.4 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:50])[CH3:49])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35]C(OC(C)(C)C)=O)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1.C(N(C(C)C)CC)(C)C.[C:73]1([N:79]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:80](Cl)=[O:81])[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>ClCCl>[OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:49])[CH3:50])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][C:80](=[O:81])[N:79]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1
Reactant: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)N(c2ccccc2)c2ccccc2)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 110 h
Yield: 97 %

Procedure:
150 mg (0.17 mmol) of H-Ala-Ala-Pro-Val-O-MPP x TFA (Example 3) and 150 μl (0.89 mmol) of diisopropylethylamine are dissolved in 6 ml of dichloromethane, mixed with 155 mg (0.37 mmol) of diphenylcarbamoyl chloride and stirred for 110 hours at room temperature. The residue that remains after removal of the solvent i.vac. is chromatographed. Gradient chromatography (Lichroprep Si60A pre-packed column, hexane→hexane/dichloromethane/methanol 30:60:10) yields 158 mg (97%) of N-(N -(N-(N-(diphenylcarbamoyl)-L-alanyl)-L-alanyl)-L-prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna -1,4-dien-21-yl] ester, and after recrystallization, 112 mg (68%) in crystalline form from dichloromethane/diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([O:17][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Product: C=CCOc1ccc2c(N3CCCC3)cc(C)nc2c1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with allyl bromide, whereby the product was isolated as free base, 7-allyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline as a light yellow solid. EI mass spectrum, m/e: 268.2 (M calculated for C17H20N2O: 268).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[C:9]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[NH2:25].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:3]2[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([O:29][C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[C:22]([CH3:21])[CH:23]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[C:9]1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[CH3:15]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CCOCCn1c(-c2ccco2)cc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOCCn1c(-c2ccco2)cc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 140 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A mixture of 4-chloro-5-(2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (76 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (67 mg) and 1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 140° C. for 2 hrs, poured into water (8 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (20 mL×2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Diisopropyl ether-hexane was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (78 mg).
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[Na].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cn1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A slurry of diethyl malonate (42 mL) and sodium (4.71 g) was warmed slowly to 90° C. and stirred at 90° C. for 2 hours and 120° C. for 30 min. before being cooled to room temperature. Toluene (200 mL) and 2-chloro-5-nitropyridine (25.0 g) were added and the mixture was heated at 110° C. for 1.5 hours and ambient temperature for 17 h. After removal of the volatiles in vacuo, 6 N HCl (200 mL) was added and the mixture heated to reflux for 4 h and cooled to room temperature. The solution was neutralized with solid sodium carbonate, extracted with ethyl acetate (6×100 mL), dried over solid magnesium sulfate, and concentrated to a dark solid. This material was purified by flash chromatography using 20% ethyl acetate in petroleum ether as the eluent. Concentration in vacuo of the product-rich fractions afforded 2-methyl-5-nitropyridine. A mixture of 2-methyl-5-nitropyridine (13.0 g) and 10% Pd on activated carbon (0.1 g) in 1,4-dioxane (150 mL) was hydrogenated at 50 psi for 24 hours and filtered over celite. Removal of the volatiles in vacuo provided 2-methyl-5-aminopyridine. A solution of this compound (9.90 g) was dissolved in 6 N HCl (100 mL), cooled to 0° C., and vigorously stirred throughout the procedure. Sodium nitrite (6.32 g) in water (50 mL) was added. After 30 min, tin (II) chloride dihydrate (52.0 g) in 6 N HCl (100 mL) was added and the reaction slurry was stirred at 0° C. for 3 hours. The pH was adjusted to pH 14 with 40% aqueous potassium hydroxide solution and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and removal of the volatiles in vacuo provided hydrazine XC. A solution of XC (8.0 g) and 4,4-dimethyl-3-oxopentanenitrile (10.0 g) in ethanol (200 mL) and 6 N HCl (6 mL) was refluxed for 17 hours and cooled to room temperature. Solid sodium hydrogen carbonate was added to neutralize the solution. The slurry was filtered and removal of the volatiles in vacuo provided a residue which was purified by column chromatography using ethyl acetate as the eluent. Concentration in vacuo of the product-rich fractions afforded XCI, which was reacted with LXXXIX (Example 8) according to Method B to provide 9, m.p. 121-123° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([C:27](=[O:29])[CH3:28])[CH2:31][CH2:32]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: C[C@@H](c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Reactant: CC(=O)N1CCNCC1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCN(c2ccc3ncc([C@@H](C)c4c(F)cc5c(cnn5C)c4F)n3n2)CC1
Temperature: 180 °C
Reaction time: 3.5 h

Procedure:
6-Chloro-3-[(S)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate Q, 36.6 mg, 0.105 mmol), KF (30.6 mg, 0.526 mmol) and 1-acetylpiperazine (40.5 mg, 0.316 mmol) were suspended in NMP (0.4 mL). The RM was stirred at 180° C. for 3.5 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a light brown foam (tR 3.80 min (conditions 5), tR 13.31 min (conditions 3), MH+=440.3, 1H-NMR in DMSO-d6: 8.12 (s, 1H); 7.79 (d, 1H); 7.52 (s, 1H); 7.39 (d, 1H); 7.04 (d, 1H); 4.84 (m, 1H); 3.96 (s, 3H); 3.36 (m, 8H); 1.99 (s, 3H); 1.79 (d, 3H)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17]3[N:18]([N:28]=[C:29]([C:31]([OH:33])=O)[CH:30]=3)[C:19](=[O:27])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[NH2:41][C:42]1[NH:46][N:45]=[N:44][N:43]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH:43]1[C:42]([NH:41][C:31]([C:29]2[CH:30]=[C:17]3[NH:16][C:15]([C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:10][CH:11]=4)=[C:20]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[C:19](=[O:27])[N:18]3[N:28]=2)=[O:33])=[N:46][N:45]=[N:44]1
Reactant: O=C(O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Reactant: Nc1nnn[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1nnn[nH]1)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Temperature: 25 °C
Reaction time: 41 h
Yield: 35.5 %

Procedure:
To a solution of 71 mg (0.16 mmol) of 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid in 4 mL of dimethylformamide (DMF) was added 0.053 mL (0.48 mmol) of 4-methyl-morpholine, 14 mg (0.164 mmol) of 5-aminotetrazole, followed by 100 mg (0.192 mmol) of PYBOP when the solution turned yellow, and the resulting mixture was stirred at rt for 41 h. The reaction mixture was concentrated to give a residue which was purified via reverse-phase chromatography to afford 29 mg (35% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1H-tetrazol-5-yl)-amide (540) as a solid as indicated by 1H-NMR; LC-MS calcd. for C27H26N8O3 [M++H]+: 511.21; found: 511.1.