Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]2[N:26]=[CH:25][CH:24]=[N:23]2)=[N:6][CH:7]=1.ClC1N=CC(N[C@H]2CCC[C@@H]2N[C:42](=O)[C:43]2[CH:48]=CC=CC=2N2N=CC=N2)=NC=1.C1(B(O)O)CC1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH:48]1([C:2]2[N:3]=[CH:4][C:5]([NH:8][C@H:9]3[CH2:13][CH2:12][CH2:11][C@@H:10]3[NH:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]3[N:26]=[CH:25][CH:24]=[N:23]3)=[N:6][CH:7]=2)[CH2:43][CH2:42]1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(Cl)cn1)c1ccccc1-n1nccn1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(Br)cn1)c1ccccc1-n1nccn1
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: OB(O)C1CC1
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C2CC2)cn1)c1ccccc1-n1nccn1

Procedure:
A mixture of N-[(1S,2S)-2-[(5-bromopyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide and N-[(1S,2S)-2-[(5-chloropyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30a and 30b; 100 mg, 0.23 mmol), cyclopropylboronic acid (CAS number 411235-57-9; 60 mg, 0.70 mmol), sodium carbonate (aq. 2 M, 350 μl, 0.70 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol) in 1,4-dioxane (778 μl) was sealed, purged and evacuated with nitrogen and then subjected to microwave irradiation at 100° C. for 1 hour. To this was then added further cyclopropylboronic acid (CAS number 411235-57-9; 60 mg, 0.70 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol). The reaction was sealed, purged and evacuated with nitrogen and again subjected to microwave irradiation at 140° C. for 20 minutes. The reaction was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) and further purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:26]>>[CH3:26][N:25]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:30][CH:29]=1)[CH3:24]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccc(CN(C)C)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(dimethylaminomethyl)-aniline
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[F:22])=[C:8]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:7]=1>C(Cl)Cl>[Cl:3][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2[C:8]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:7][C:6]([NH2:5])=[N:11][C:10]=2[CH3:12])=[C:15]([F:22])[CH:16]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.224 mL) was added to a solution of the product from step (v) (0.85 g) in DCM (15 mL) under nitrogen. The resulting mixture was stirred at rt for 2 h. The reaction mixture was evaporated to dryness under reduced pressure to give the subtitle compound as a yellow solid 0.85 g that was used without purification.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)[CH3:3].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:1][CH:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:8][CH2:9]1)[CH3:3])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of (±)-phenylmethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (0.64 g, 2.43 mmol), Et3N (1.03 mL, 7.29 mmol) in CH2Cl2 (50 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (0.38 mL, 4.86 mmol). The reaction mixture was stirred at 0° C. for 1 h, then at ambient temperature for 1.5 h, diluted with CH2Cl2 (100 mL) and washed with 1M NaH2PO4 (50 mL×2) and brine (25 mL). The CH2Cl2 layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown oil. The crude product was purified by flash chromatography on an ISCO silica gel column using 0 to 45% EtOAc/hexanes to give 0.73 g (88%) of (±)-phenylmethyl 4-{1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.25 (m, 5H), 5.12 (s, 2H), 4.70-4.60 (m, 1H), 4.25 (bs, 2H), 2.99 (s, 3H), 2.80-2.65 (m, 2H), 1.85-1.60 (m, 3H), 1.40 (d, 3H, J=6.4 Hz), 1.35-1.20 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=O)=[CH:4][CH:3]=1.[OH-].[K+].C(O)CO.NN>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:20][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)c1nccs1)n2Cc1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)cc(Cc1nccs1)n2Cc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 45.9 %

Procedure:
To a mixture of the compound obtained in Example 27 (6) (88 mg), potassium hydroxide (25 mg) and ethylene glycol (2.5 ml), hydrazine (65 mg) was added and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was poured into water, extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was separated and purified twice with silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) and (chloroform:methanol=15:1) to obtain 39 mg of the desired product as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1
Reactant: CN1CCN(S(=O)(=O)Nc2ccc(CO)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)Nc2ccc(C=O)cc2)CC1
Reaction time: 0.42 h
Yield: 33.6 %

Procedure:
To a solution of oxalyl chloride (1.06 mL, 12.1 mmol) in CH2Cl2 (20 mL) was added DMSO (1.8 mL, 25.4 mmol.) at −60° C. and the mixture was stirred for 25 min. A solution of 4-(4-methyl piperazinyl)sulfonamido benzyl alcohol (3.0 g, 10.5 mmol) in CH2Cl2 (25 mL) and DMSO (5 mL) was added. and the mixture was stirred for 1.5 h at −60° C. Triethylamine (7.4 mL) was added and the mixture was partitioned between brine and EtOAc. The organic extract was concentrated, then purified by flash chromatography to yield the title compound (1.0 g, 33%).
Reaction SMILES: [CH:1](O)=O.Cl[C:5]1[CH:6]=[C:7]([N:12]2[CH2:16][CH:15](C)[C:14]([NH:18][CH:19]=[O:20])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].CCCCCC>ClCCl>[Cl:11][C:10]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]([CH3:1])[CH2:15][C:14]([NH:18][CH:19]=[O:20])=[N:13]2)=[CH:8][CH:9]=1
Reactant: O=CO
Reactant: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1CC(NC=O)=NN1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 4.8 g. amount of the above compound is dissolved in 25.0 ml. of a mixture of formic acid and acetic anhydride (Example 15). The reaction mixture is allowed to remain at room temperature for 3 hours, then ice water is added to separate a gum. The aqueous phase is decanted and the gum is dissolved in dichloromethane. The solution is dried over magnesium sulfate and passed through a hydrous magnesium silicate. The effluent is evaporated leaving a gum. The gum is dissolved in dichloromethane. The solution is heated and hexane is added until turbidity results. The mixture is cooled and filtered to yield 3.6 g. of the desired product as off-white crystals, m.p. 112°-113° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:14][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OC1CCCC1
Product: Brc1ccc(OC2CCCC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and cyclopentanol by the method of Example 10 (b).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]([O:27][C:28](=[O:35])[C@@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH2:30])[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[CH2:25]([O:27][C:28](=[O:35])[C@@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH:30][C:21](=[O:22])[C@@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH3:26]
Reactant: CCOC(=O)[C@H](N)CCSC
Reactant: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCSC)NC(=O)[C@@H](Cc1cn(C)c2ccccc12)NC(=O)OC(C)(C)C
Yield: 101.2 %

Procedure:
To a suspension of N-tert-butoxycarbonyl-1-methyl-D-tryptophan (1.60 g) and hydrochloric acid salt of D-methionine ethyl ester (1.06 g) in dry methylene chloride (30 ml) which was cooled on an ice bath and stirred was added a solution of triethylamine (0.50 g) in dry methylene chloride (10 ml). The mixture was stirred for 30 minutes, and to the mixture was added a solution of N,N'-dicyclohexylcarbodiimide (1.04 g) in dry methylene chloride (10 ml). The resulting mixture was stirred overnight. After removal of the solvent, crude residue was taken up with a mixture of ethyl acetate and water, filtered, and organic layer was washed with 10% hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to give crystalline N-tert-butoxycarbonyl-1-methyl-D-tryptophyl-D-methionine ethyl ester (2.43 g).
Reaction SMILES: C[O-].[Na+].Br[C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[N:25][N:24]=4)=[CH:18][CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[N:7][CH:6]=1>CN(C=O)C.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>[N:12]1[C:13]2[C:8](=[N:7][CH:6]=[CH:5][CH:14]=2)[C:9]([O:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[N:25][N:24]=3)=[CH:20][CH:21]=2)=[CH:10][CH:11]=1
Reactant: Brc1cnc2c(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cccnc45)cc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of tetrakis(triphenylphosphine)palladium (9 mg, 0.0079 mmol) and sodium methoxide (9 mg, 0.16 mmol) was added a solution of N-(4-(7-bromo-1,5-naphthyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (0.041 g, 0.079 mmol) in DMF (2 mL). The mixture was heated to 100° C. in an Argon purged, resealable tube. After 3 hrs, the solvent was removed in vacuo and the residue was purified by silica gel chromatography using 1-10% MeOH:CH2Cl2 containing 1% NH4OH to afford N-(4-(1,5-naphthyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine as a tan solid. MH+=442.1@1.51 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:26]=[CH:25][C:14]2[O:15][C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18](=O)[NH:19][C:13]=2[CH:12]=1)=O>C1COCC1>[OH:8][CH2:9][C:11]1[CH:26]=[CH:25][C:14]2[O:15][C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[CH:18]=[N:19][C:13]=2[CH:12]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccccc1O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)N=Cc1ccccc1O2
Reaction time: 0.75 h
Yield: 46 %

Procedure:
Lithium aluminum hydride (11 mL, 11 mmole) was slowly added to the solution of 11-Oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepine-8-carboxylic acid methyl ester (1.346 g, 5 mmole) in THF under N2 at room temperature. The reaction mixture was stirred for 1 hour and 45 minutes then quenched with 2N of HCl until the pH value reaches 2–3. Removed all the THF by rotary evaporation, and extracted the reaction mixture with ethyl acetate for five times, dried the organic layer with sodium sulfate and filtered and concentrated. Obtained the desired compound (white solid) in 46% yield.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)=O)[CH2:3][CH2:2]1.[BH3-]C#[N:13].[Na+].[OH-].[Na+]>CO>[CH:1]1([CH:4]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[NH2:13])[CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: O=C(c1nccs1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(c1nccs1)C1CC1
Yield: 54 %

Procedure:
The title compound was synthesized according to General Method F, utilizing cyclopropyl(thiazol-2-yl)methanone (0.28 g, 1.8 mmol), NH4OAc (1.7 g, 22 mmol), NaCNBH3 (0.46 g, 7.3 mmol), and MeOH (30 mL). Aq. NaOH (2 M, 15 mL) was added and the product was extracted into EtOAc (3×40 mL). The combined EtOAc layer was dried (MgSO4), filtered, concentrated to dryness. Purification by flash chromatography (Biotage Isolera, 25 g HP-SIL, 60-100% EtOAc in hexanes) gave the title compound as a yellow oil (0.15 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.63 (d, J=2.8 Hz, 1H), 7.18 (d, J=2.8 Hz, 1H), 3.50 (d, J=8.5 Hz, 1H), 2.35 (br. s., 2H), 1.03-1.16 (m, 1H), 0.48-0.63 (m, 2H), 0.26-0.47 (m, 2H); MS ESI 138.0 [M-NH2]+, calcd for [C7H10N2S—NH2]+138.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH:10]([CH:12]1[CH2:14][C:13]1([F:16])[F:15])C.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:12]2[CH2:14][C:13]2([F:16])[F:15])=[CH:4][N:3]=1
Reactant: CC(Br)C1CC1(F)F
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC1(F)CC1COc1ccc(Br)nc1
Temperature: 70 °C

Procedure:
The mixture of 0.30 g (1.7 mmol) of 2-bromo-5-hydroxypyridine, 0.59 g (3.5 mmol) of 1-bromoethyl-2,2-difluorocyclopropane and 0.60 g (4.3 mmol) of K2CO3 in 10 ml ACN is stirred at 70° C. over night. The reaction mixture is filtered over alumina/activated carbon. The solvent is removed in vacuo.
Reaction SMILES: [P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].[CH:11]([NH2:14])([CH3:13])[CH3:12]>C(O)C>[CH:11]([NH3+:14])([CH3:13])[CH3:12].[P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2]
Reactant: CC(C)N
Agent: O=C(O)CNCP(=O)(O)O
Solvent: CCO
Product: CC(C)[NH3+]

Procedure:
50 g (0.3 moles) of N-(phosphonomethyl)-glycine are reacted with 17.5 g (0.3 moles) of isopropylamine in 200 ml of 96% ethanol at room temperature. The mixture is refluxed for half an hour, filtered, concentrated by evaporation and crystallized. 69 g (0.3 moles) of crystalline, dried mono-isopropylammonium salt of N-(phosphonomethyl)-glycine are obtained. The product is not hygroscopic, readily soluble in water. Melting range 161°-163° C. It contains 73.9% N-(phosphonomethyl)-glycine Yield 99.95%. Characteristic absorption bands (FT-IR spectroscopy, cm-1) 1660, 1600, 1553, 1545, 1075, 513, 475, characteristic values of crystal-lattice-planes measured with X-ray diffraction: 11.0, 9.06, 5.94, 5.54, 4.13, 3.71. (α type crystals).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[O:9][C:10]([CH3:14])=[CH:11][C:12]=1[SH:13].[Cl-].C([NH+](CC)CC)C.Cl>C(C(C)=O)C.C(N(CC)CC)C.O>[C:2](=[O:3])([S:13][C:12]1[CH:11]=[C:10]([CH3:14])[O:9][C:8]=1[CH3:7])[O:4][CH2:5][CH3:6]
Reactant: Cc1cc(S)c(C)o1
Reactant: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Sc1cc(C)oc1C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a mixture of ethyl chloroformate (0.86 g, 7.9 mmol) and 2,5-dimethyl-furan-3-thiol (1 g, 7.8 mmol) in methyl ethyl ketone (10 ml) was added triethylamine (0.8 g, 7.9 mmol). The mixture was cooled in ice and stirred for 3 hours. After reaching room temperature water (10 g) was added to the mixture to dissolve the triethylammonium chloride which was formed during the reaction. Concentrated hydrochloric acid (2 g) was added to neutralise the excess triethylamine. The organic layer was separated and washed with a saturated sodium hydrogen carbonate solution (10 g), water (10 g) and finally a sodium sulphate solution (10 g). After evaporation of the solvent the residue was analysed and confined by NMR spectroscopy as O-ethyl S-(2,5-dimethyl-3-furyl) thiocarbonate yield 89% (1.4 g, 7 mmol) purity 91%.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][O:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[CH:21][CH:20]=1.[OH-].[Na+]>CN(C)C=O>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][O:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][C:24]2[CH:25]=[C:26]([C:27]3[NH:28][N:3]=[N:2][N:1]=3)[CH:29]=[CH:30][CH:31]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc(-c2nnn[nH]2)c1
Temperature: 100 °C

Procedure:
A mixture of sodium azide (0.03 mol), ammonium chloride (0.03 mol) and 3-(4-(2-quinolinylmethyloxy)benzyl)benzonitrile (0.01 mol) in dimethylformamide (20 ml) are heated at 100° C. for 18 hours. The reaction is poured into aqueous 10% sodium hydroxide solution and washed with ethyl acetate. The crystalline product is isolated by acidification and filtration to obtain 5-(3-(4-(2-quinolinylmethyloxy)benzyl)phenyl)tetrazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[CH2:30]([O:37][C:38](ON1C(=O)CCC1=O)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>O1CCOCC1.O>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH2:19][CH2:20][O:21][CH3:22])[C:38](=[O:39])[O:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COCCNC1CCC(C(=O)NCc2nccnc2Cl)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COCCN(C(=O)OCc1ccccc1)C1CCC(C(=O)NCc2nccnc2Cl)CC1
Yield: 99.9 %

Procedure:
To a solution of N-((3-chloropyrazin-2-yl)methyl)-4-(2-methoxyethylamino)cyclohexane-carboxamide (3.15 mmol, 1.03 g) in dioxane (10 ml) and water (10 ml) were added triethylamine (3.36 mmol, 0.47 ml) and N-(benzyloxycarbonyloxy)succinimide (3.31 mmol, 825 mg). After stirring for two hours at room temperature water and 2N hydrochloric acid (1.5 ml) were added and this mixture extracted twice with dichloromethane. The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution, dried (sodium sulfate) and concentrated in vacuo to give benzyl 4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl(2-methoxyethyl)carbamate (1.45 g).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:8](=[O:20])[NH:7][C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>CCO>[CH2:32]([NH:36][C:2]1[N:10]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:8](=[O:20])[NH:7][C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1)[CH2:33][CH2:34][CH3:35]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2CC(=O)c1ccccc1
Reactant: CCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCCNc1nc2c(c(=O)[nH]c(=O)n2C)n1CC(=O)c1ccccc1
Temperature: 120 °C
Yield: 44.9 %

Procedure:
A mixture of commercially available 8-bromo-3,7-dihydro-3-methyl-7-(2-oxo-2-phenylethyl)-1H-purine-2,6-dione (42, 50 mg, 0.138 mmol), diisopropylethylamine (47 μL, 0.275 mmol) and butylamine (27 μL, 0.275 mmol) in EtOH (1 mL) was heated at 120° C. for 12 h. The reaction was cooled to room temperature, the solid was filtered off, washed with water, affording the desired product as a white solid (22 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ=11.57 (s, 1H), 8.04 (d, J=7.8 Hz, 2H), 7.72 (t, J=7.8 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 6.99 (t, J=5.5 Hz, 1H), 5.62 (s, 2H), 3.32 (s, 3H), 3.32 (m, 2H), 1.51 (quint, J=7.4 Hz, 2H), 1.31 (sext, J=7.4 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, DMSO-d6): δ=192.2, 154.6, 153.0, 150.7, 150.0, 134.1, 133.8, 128.7, 127.9, 101.7, 49.5, 41.8, 31.0, 28.2, 19.2, 13.5; IR (film): ν=3361, 3008, 2827, 1681, 1485, 1425, 1230, 746 cm−1; HRMS (ESI): m/z: calcd for C18H21N5O3Na+: 378.1542, found: 378.1545.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:25])[NH:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][C:28]=2[O:36][CH3:37])=[CH:7]1)=[O:5])[CH3:2].ClCCCl.[C:44]1([CH3:54])[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([NH2:53])(=[O:52])=[O:51]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:25])[NH:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:53][S:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH3:54])(=[O:51])=[O:52])=[O:33])=[CH:29][C:28]=2[O:36][CH3:37])=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)n1cc(Cc2ccc(C(=O)O)cc2OC)c2cc(C(=O)NCC(C)CC(F)(F)F)ccc21
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)C(=O)n1cc(Cc2ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc2OC)c2cc(C(=O)NCC(C)CC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a solution of 4-[1-diethylcarbamoyl-5-(4,4,4-trifluoro-2-methylbutylcarbamoyl)-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.12 grams, 0.22 mmol), 4-dimethylaminopyridine (0.040 grams, 0.33 mmol) and 1,2-dichloroethane (0.063 grams, 0.33 mmol) in methylene chloride (15 mL) was added o-tolylsulfonamide (0.038 grams, 0.22 mmol). The resulting solution was stirred, at room temperature, for 12 hours. The reaction mixture was then diluted with methylene chloride and washed with 1 M hydrochloric acid (aq). The organics were dried over magnesium sulfate and concentrated in vacuo. Recrystallization from wet ether gave the titled compound (0.115 grams, 75% yield), m.p.=153-154° C. Anal calcd. for C35H39H4O6SF3 : C, 59.92; H, 5.60; N, 7.99. Found: C, 60.18; H, 5.68; N, 8.41.