Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O:17]=[C:18]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:19]=[CH:20][CH3:21]>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:20]([CH3:21])[CH2:19][C:18]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:17])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC=CC(=O)N1CCCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Product: CC(CC(=O)N1CCCC1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
Following the procedure of Example 4, 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.Og, 0.008 mole) and 1-(1-oxo-2-butenyl)pyrrolidine (1.llg, 0.008 mole) were dissolved in methanol (20ml) under an argon atmosphere and refluxed for 24 hours. The solvent was removed and the product isolated by chromatography on silica, and recrystallized from hexane to yield the product as a white solid, m.p. about 95°-99° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A solution of 4-(4-azidomethylbenzyl)-nitrobenzene (5.835 g) in tetrahydrofuran (175 mL) was treated with water (0.43 mL) and triphenylphosphine (6.45 g, 1.1 eg). The mixture was stirred at room temperature for 18 hours, and the solvent was evaporated. The residue was suspended in water, and suspension madeacidic by the dropwise addition of hydrochloric acid to about pH 1, then extracted with diethyl ether (3×). The aqueous phase was made alkaline with 50% aqueous sodium hydroxide, extracted with dichloromethane (3×) to afford a crude brown oil (5.66 g). Chromatography on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide, gave 4-(4-aminomethylbenzyl)-nitrobenzene (3.91 g, 79%) as a yellow solid.
Reaction SMILES: O(C(N[C:11]1[CH:21]=[C:20]2[C:14]([C:15](Cl)=[C:16](OCC)OC2=O)=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.O([C:33]([NH:35][C:36]1[CH:46]=[C:45]2[C:39]([C:40]([Cl:56])=[C:41]([O:47][CH2:48][CH2:49][C:50]3C=CC=CC=3)[O:42][C:43]2=[O:44])=[CH:38][CH:37]=1)=[O:34])C1C=CC=CC=1>>[C:33]([NH:35][C:36]1[CH:46]=[C:45]2[C:39]([C:40]([Cl:56])=[C:41]([O:47][CH2:48][CH2:49][CH3:50])[O:42][C:43]2=[O:44])=[CH:38][CH:37]=1)(=[O:34])[CH2:16][CH2:15][C:14]1[CH:20]=[CH:21][CH:11]=[CH:12][CH:13]=1
Reactant: CCOc1oc(=O)c2cc(NC(=O)Oc3ccccc3)ccc2c1Cl
Reactant: O=C(Nc1ccc2c(Cl)c(OCCc3ccccc3)oc(=O)c2c1)Oc1ccccc1
Product: CCCOc1oc(=O)c2cc(NC(=O)CCc3ccccc3)ccc2c1Cl

Procedure:
7-phenoxycarbonylamino-4-chloro-3-ethoxyisocoumarin and 7-phenoxycarbonylamino-4-chloro-3-(2-phenylethoxy)isocoumarin can be prepared by the same procedure.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[N:5]=1.C(=O)([O-])[O-].[Na+].[Na+].CO.O>C(=O)(O)[O-].[Na+]>[Br:1][C:7]1[C:6]([Cl:11])=[N:5][C:4]([NH2:3])=[N:9][C:8]=1[Cl:10]
Reactant: BrBr
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1nc(Cl)c(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 42 h
Yield: 83.7 %

Procedure:
Bromine (0.85 mL, 0.0166 mole) was added dropwise over 20 minutes to a stirred suspension of 2-amino-4,6-dichloropyrimidine (CAS#56-05-3, 1.70 g, 0.01037 mole) and sodium carbonate (1.00 g, 0.01244 mole) in 1:1 methanol/water (30 mL) at ambient temperature. Ten minutes after the addition was complete, more sodium carbonate (0.78 g, 0.0093 mole) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 42 hours, then it was diluted with aqueous sodium bicarbonate to provide 5-bromo-4,6-dichloropyrimidin-2-amine as a precipitate that was collected by filtration and rinsed with water. The vacuum-dried solid weighed 2.11 g (83.7% yield). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.67 (s, 1H), 7.70 (s, 1H). MS (DCl—NH3) m/z=241 (M+H)+, m/z=258 (M+NH4)+.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.C1(C)C=CC=CC=1.[OH-].[Na+]>O>[CH:1]1([C:4]2[C:5]([C:6]#[N:7])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Into a glass flask having an internal volume of 300 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 11.6 g (106.6 mmol) of 3-cyclopropyl-3-oxopropanenitrile, 31.0 g (96.9 mmol) of 2-amino-4′-fluorobenzophenone methanesulfonate having a purity of 97.3% and 121 mL of toluene were put in an atmosphere of nitrogen, and reaction was carried out under 0.04 MPa at 80° C. for 2 hours while distilling off the formed water. After completion of the reaction, the reaction liquid was cooled to room temperature, 60 mL of water and 13.3 mL (106.4 mmol) of a 8 mol/L sodium hydroxide aqueous solution were added thereto to make the reaction liquid basic, followed by liquid separation, and the obtained organic layer was analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 27.9 g (yield: 99%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([CH:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1.C(#N)C.O1CCCC1>[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([CH:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[I:20])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)cc2)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(I)c2ccc(Cl)cc2)C1
Reaction time: 0.25 h

Procedure:
Polymer supported triphenylphosphine (125 g, 370 mmol) is suspended in tetrahydrofuran: acetonitrile 9:1 (1000 ml) and treated with Iodine (95.2 g, 370 mmol) followed by stirring for 15 minutes. Imidazole (25.5 g, 370 mmol) is added followed by a solution of 3-[(4-Chloro-phenyl)-hydroxy-methyl]-azetidine-1-carboxylic acid tert-butyl ester (44.7 g, 150 mmol) in tetrahydrofuran (150 ml) and the reaction mixture stirred at ambient temperature for 20 hours. The reaction mixture is filtered through celite™ filter material and the filtrate evaporated. The residue is taken up in chloroform and washed with sodium thiosulphate solution, water and brine. The solution is dried over magnesium sulphate and evaporated to provide 3-[(4-Chlorophenyl)-iodo-methyl]-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR 400 MHz, CDCl3, δ 1.35 (9H), 3.21 (1H), 3.37 (1H), 3.60 (2H), 4.05 (1H), 5.12 (1H), 7.20 (4H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[N:3]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9]([C:8]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=3)=[CH:7][CH:6]=[N:5]2)=[CH:10][CH:11]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: Clc1ccc2c(Cl)ccnc2n1
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1

Procedure:
The product from Example 13d (200 mg, 1.0 mmol) was reacted with the product from Example 18b (215 mg, 1.0 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (200 mg, 45%).
Reaction SMILES: [C:1]([CH:5]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[OH:10])[C:6]([OH:8])=O)([CH3:4])([CH3:3])[CH3:2].[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>O1CCCC1>[C:1]([CH:5]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[O:10][C:18]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19])[C:6]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)C(C(=O)O)C(O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(C)(C)C(C(=O)n1ccnc1)C(OC(=O)n1ccnc1)c1ccc(Cl)cc1
Yield: 39 %

Procedure:
83.3 Grams (0.324 mole) of 2-tert-butyl-3-(4-chlorophenyl)-3-hydroxypropionic acid and 125 g (0.77 mole) of 1,1'-carbonyldiimidazole were mixed with 700 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 hours with stirring. After concentrating the reaction solution under reduced pressure, water and then diethyl ether were added to the residue which was then washed with water. The ether layer was separated and concentrated to form crystals with a small amount of ether left in the system. The crystal was filtered off and washed with a small amount of ether to obtain 50.6 g (38.5%) of N-{2-tert-butyl-3-(4-chlorophenyl)-3-(1-imidazolylcarbonyloxy)propanoyl}-imidazole. m.p., 69°-71° C.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[CH:3]1[CH:8]2[C:6](C(OC)=O)([C:7]2([CH3:10])[CH3:9])[C:5](=[O:15])[O:4]1.[Cl-].[Li+]>CN(C)P(=O)(N(C)C)N(C)C.CCOCC>[Cl:17][C:2]([Cl:1])([Cl:16])[CH:3]1[CH:8]2[CH:6]([C:7]2([CH3:10])[CH3:9])[C:5](=[O:15])[O:4]1
Reactant: COC(=O)C12C(=O)OC(C(Cl)(Cl)Cl)C1C2(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)C2C(=O)OC(C(Cl)(Cl)Cl)C21
Yield: 27.9 %

Procedure:
To a solution of methyl 4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (1.52 g, 0.005 mole) in 10 ml of hexamethylphosphoric triamide was added lithium chloride (0.42 g, 0.010 mole). After heating at 75° for two hours, the cooled reaction mixture was diluted with ether. The ethereal solution was washed with water, dried over magnesium sulfate, and the ether was removed by evaporation, yielding a residue which was purified by column chromatography on silica gel using 9/1 n-hexane/ethylacetate as the eluent to give 4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (0.34 g, 28% yield) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[CH2:20]([NH:21][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12)[CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Reactant: CCCCCN
Product: CCCCCNc1c(C(=O)OCC)cnc2cn[nH]c12

Procedure:
The above compound was prepared from ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate and n-amylamine in an analogous manner to the preparation of Example 2 giving a pale yellow solid, m.p. 153°-155° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)OB(c2ccc(CN3CCCC3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
A suspension of 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.18 g, 17.44 mmol), potassium carbonate (2.89 g, 20.93 mmol) and N,N-dimethylformamide (75 mL) was treated with pyrrolidine (1.875 mL, 22.67 mmol), and the reaction was heated to 80° C. for 1 hour. The reaction was cooled to ambient temperature, diluted with ether (115 mL), and filtered. The filtrate was concentrated to dryness to provide the title compound. MS ESI(+) m/z 288.2 [M+H]+.
Reaction SMILES: [CH2:1]([OH:5])[C@@H:2]([OH:4])[CH3:3].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].N1C=CN=C1>CN(C=O)C>[Si:6]([O:5][CH2:1][C@H:2]([OH:4])[CH3:3])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of (s)-(+)-1,2-propanediol (2.0 g, 26.3 mmol) in DMF (5 mL) was added TBS-Cl (5.94 g, 39.4 mmol) and imidazole (2.147 g, 31.5 mmol). The reaction was stirred at 25° C. for 18 h. The reaction mixture was partitioned between ethyl acetate and sat. ammonium chloride. The organic phase was washed with sat ammonium chloride and brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography to give 33A (4.0 g, 80% yield) as a colorless oil.
Reaction SMILES: B(F)(F)F.[Br:5][C:6]1[C:14]2[S:13][C:12]([NH2:15])=[N:11][C:10]=2[CH:9]=[C:8](N)[CH:7]=1.N(OC(C)(C)C)=O.[I:24]I>C1COCC1.CCOCC>[Br:5][C:6]1[C:14]2[S:13][C:12]([NH2:15])=[N:11][C:10]=2[CH:9]=[C:8]([I:24])[CH:7]=1
Reactant: II
Reactant: Nc1cc(Br)c2sc(N)nc2c1
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1nc2cc(I)cc(Br)c2s1
Temperature: -2.5 °C
Reaction time: 0.67 h

Procedure:
To THF (6 L) at −78° C. under N2 was added BF3-etherate (50% assay, 708 mL, 2.81 mol) followed by a slow addition of a solution of iv (275 g, 1.02 mol) in THF (500 mL) over 20 min. Tert-butyl nitrite (548 L, 4.61 mol) was then added to the solution at −78° C. and the mixture was stirred at the same temperature for 40 min and then warmed to −5-0° C. Et2O was added (at −5-0° C.) and the mixture stirred for 20 min. The solid was filtered and taken in acetone at 0° C. followed by sequential addition of KI (510 g, 3.07 mol) and iodine (519 g, 2.04 mol) and the mixture stirred at 0° C. for 30 min. The reaction was quenched with saturated solution of sodium metabisulfite and extracted with EtOAc (3×5 L). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo at 45° C. The residue was purified over basic alumina (30-35% EtOAc-hexane) to obtain v (235 g, 65%). 1H NMR (DMSO-d6, 400 MHz): δ 7.50 (d, J=1.20 Hz, 1H), 7.63 (d, J=1.20 Hz, 1H) and 7.91 (br s, 2H). MS: 354.90 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][C:8]2[O:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][CH:9]=2)[N:3]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])=[CH:19][C:18]=1[CH3:32]>>[C:13]([C:11]1[O:12][C:8]([CH2:7][N:4]2[N:3]=[C:2]([NH:1][C:29]([C:24]3[N:25]=[C:26]([CH3:28])[O:27][C:23]=3[C:20]3[CH:21]=[CH:22][C:17]([I:16])=[C:18]([CH3:32])[CH:19]=3)=[O:30])[CH:6]=[N:5]2)=[CH:9][CH:10]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc(Cn2ncc(N)n2)o1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(I)c(C)c2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccc(I)c(C)c3)n2)o1

Procedure:
Following general procedure A, starting from 1-(5-((4-amino-2H-1,2,3-triazol-2-yl)methyl)furan-2-yl)ethanone and 5-(4-iodo-3-methylphenyl)-2-methyloxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.12 min; [M+H]+=549.20.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:3][CH2:2]1.[I:15]I.S(=O)(=O)(O)O.O>CC(O)=O>[CH:1]1([C:4]2[C:13]([I:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: II
Reactant: COC(=O)c1ccc(C2CC2)cc1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(C2CC2)cc1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-methylbenzoate (compound 86.1, 2.68 g, 13.4 mmol, 95%) in AcOH (50 mL) were added NaIO4 (1.51 g, 7.08 mmol), iodine (3.58 g, 14.1 mmol), and sulfuric acid (106 μL, 2.0 mmol, 0.15 equiv). The reaction mixture was stirred overnight at 110° C. After cooling to ambient temperature, water (100 mL) was slowly added and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with Na2S2O3 (aq., sat., 3×30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50) as the eluent to yield 2.0 g (45%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])=[N:4][CH:5]=[C:6]([CH:8]=O)[CH:7]=1.[C:15]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[CH:20]=[CH:8][C:6]1[CH:5]=[N:4][C:3]([C:10]([C:11]#[N:12])([CH3:14])[CH3:13])=[C:2]([Cl:1])[CH:7]=1)[CH3:19]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C#N)c1ncc(C=O)cc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cnc(C(C)(C)C#N)c(Cl)c1
Yield: 95.5 %

Procedure:
A solution of 2-(3-chloro-5-formyl-pyridin-2-yl)-2-methyl-propionitrile (0.58 g, 2.78 mmol) from step 3 above and (carbethoxymethylene)triphenylphosphorane (1.26 g, 3.61 mmol) in dry THF (12 mL) was heated to 55° C. and maintained at this temperature overnight. The solvents were removed and the residue was purified by flash column chromatography (0-20% EtOAc in hexanes) to give the product (0.74 g, 96% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.35 (t, J=7.7 Hz, 3H), 1.87 (s, 6H), 4.29 (q, J=14, 7.7 Hz, 2H), 6.53 (d, J=16 Hz, 1H), 7.65 (d, J=16 Hz, 1H), 7.87 (d, J=2 Hz, 1H), 8.58 (d, J=2 Hz, 1H). ESIMS (MH+): 279.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C[O:29][C:30](=[O:60])[CH2:31][C@H:32]([NH2:59])[C:33]([N:35]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[NH:53][N:52]=[N:51][N:50]=2)=[CH:39][CH:38]=1)=[O:34].C([S:64][CH2:65][CH:66]([CH2:70][CH:71]([CH3:73])[CH3:72])[C:67](O)=[O:68])(=O)C.CCN(C(C)C)C(C)C>CN(C=O)C>[SH:64][CH2:65][CH:66]([CH2:70][CH:71]([CH3:73])[CH3:72])[C:67]([NH:59][C@H:32]([C:33]([N:35]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[NH:53][N:52]=[N:51][N:50]=2)=[CH:41][CH:42]=1)=[O:34])[CH2:31][C:30]([OH:29])=[O:60])=[O:68]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)[C@@H](N)CC(=O)OC
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)[C@H](CC(=O)O)NC(=O)C(CS)CC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
BOP (88 mg, 0.2 mmol) was added to a solution of (S)-3-amino-N-pentyl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]succinamic acid methyl ester (100 mg, 0.2 mmol), 2-acetylsulfanylmethyl-4-methylpentanoic acid (41 mg, 0.2 mmol) and DIPEA (34 μL) in DMF (1.5 mL) at room temperature. After 10 minutes, DIPEA (30 μL) was added. After 4 hours, the mixture was concentrate in vacuo. A solution of the concentrate in MeOH (1.0 mL), 1M aq. NaOH (1.0 mL) and 6M aq. NaOH (0.1 mL) was stirred under a nitrogen atmosphere at room temperature. After 3 hours, the mixture was neutralized with 6M aq. HCl, and was concentrated in vacuo. Reverse phase HPLC afforded the title compound (11.9 mg). MS m/z: [M+H]+ calcd for C30H40N6O4S, 581.28. found 581.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CCNCC
Product: CCOC(=O)c1c(N(CC)CC)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 37 step A from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 100 mg, 0.29 mmol) and diethyl-amine (0.06 ml, 0.58 mmol). Sticky liquid (70 mg, 63%). LC-MS: 383 (M+H)+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([O-:4])=[O:3].[N:12]1([C:17](=N)[NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.ClC1C=CC=CC=1>O>[N+:2]([C:5]1[CH:6]=[C:7]([NH:8][C:17]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[NH:18])[CH:9]=[CH:10][CH:11]=1)([O-:4])=[O:3]
Reactant: N=C(N)N1CCCC1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: Clc1ccccc1
Solvent: O
Product: N=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1

Procedure:
Samples of 3-nitroaniline hydrochloride, 15.5 g, and 1-pyrrolidinecarboximidamide, 9.6 g, were combined with 12 ml of chlorobenzene, and the mixture was warmed to reflux for three hours, and then allowed to cool. The resulting solid mass was taken up in 200 ml of hot water, and the chlorobenzene layer was separated. The aqueous layer was washed with 30 ml of chloroform and the combined organic layers were washed with 50 ml of water. The aqueous layers were combined, warmed, treated with charcoal and filtered hot. The filtrate was allowed to cool, and made strongly basic with 50% sodium hydroxide. This basic mixture was extracted with 200 ml of chloroform. The chloroform extract was concentrated on a steam bath to 150 ml, then diluted with hexanes to 300 ml, and stirred until yellow solids formed, giving 17 g of the N-(3-nitrophenyl)-1-pyrrolidinecarboximidamide, m.p. 117°-118° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18](=[O:20])[CH3:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>C(Cl)Cl.C(OCC)C>[ClH:21].[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18](=[O:20])[CH3:19])[CH2:17][CH2:16]1
Reactant: CC(=O)N(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N(C1CCNCC1)C1CC1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(acetyl-cyclopropyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.8 mmol) in DCM (9 mL) was added 2 M HCl in diethyl ether (4.5 mL). The reaction mixture was stirred (30° C., 16 h). The mixture was concentrated to an orange solid and used without additional purification. MS (ESI): mass calcd. for C10H18N2O, 182.14; m/z found, 183.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 4.07-3.95 (m, 1H), 3.48-3.40 (m, 2H), 3.11-2.98 (m, 2H), 2.77 (s, 1H), 2.49-2.36 (m, 2H), 2.22 (s, 3H), 1.97-1.89 (m, 2H), 1.00-0.94 (m, 2H), 0.90-0.82 (m, 2H).