Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]1([CH3:29])C=CC=C[CH:24]=1.ClC(Cl)([O:33][C:34](=O)[O:35]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)CC.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34](=[O:33])[O:35][CH2:24][CH2:23][CH3:29])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 73 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-propanol (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (104 mg, yield 73%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH3:18][C:19]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1.CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.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>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:28]2[CH:27]=[N:26][C:25]([N:22]3[CH2:23][CH2:24][C:19]([CH3:18])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:20][CH2:21]3)=[N:30][CH:29]=2)[CH:3]=1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCNC(=O)Nc1nc2cc(I)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
To a solution of 1-(7-bromo-5-iodobenzo[d]thiazol-2-yl)-3-ethylurea (22.7 g, 53.20 mmol) and ethyl 4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidine-4-carboxylate (20 g, 53.2 mmol) in 1,4-dioxane:MeOH (300:180 mL) was added potassium phosphate (17 g, 79 mmol) at rt. The resulting mixture was degassed for 15-20 min by purging N2 followed by addition of tetrakis(triphenylphosphine)palladium(0) (6.1 g, 5.32 mmol). The reaction mixture was again degassed for another 15-20 min then heated up to 80° C. or 5 h. After completion of reaction (by TLC), the reaction was cooled to rt, diluted with EtOAc (500 mL) and passed through celite. The filtrate was evaporated and the crude residue purified over 100-200 M silica-gel by using 1.50% MeOH: DCM to obtain the desired product as an off-white solid (12 g, 41%). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.20 (m, 6H), 1.45 (m, 2H), 2.03 (m, 2H), 3.16 (m, 2H), 3.30 (q, J=7.20, 2H), 4.12 (q, J=6.80 Hz, 2H), 4.25 (m, 2H), 6.75 (br s, 1H), 7.69 (s, 1H), 7.86 (s, 1H); 8.75 (s, 2H) and 10.91 (br s, 1H). MS: 547.11 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[CH3:10][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH3:10]
Reactant: O=Cc1cnccc1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cnccc1Br
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-pyridine-3-carbaldehyde (400 mg, 2.15 mmol) in THF (10 mL) at −78° C. was added dropwise 3.0 M methylmagnesium bromide solution in THF (1.08 mL). After 15 min, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, then purified by flash chromatography eluted with 50% ethyl acetate in hexane to yield 1-(4-bromo-pyridin-3-yl)-ethanol as white crystals.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:4].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:4])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Product: O=C(N[C@H]1C[C@@H](C(=O)NCc2ccccc2)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O

Procedure:
(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid benzylamide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester and benzylamine in an analogous manner to example 12. MS calcd. for C30H36N3O3 [(M+H)+] 486.0, obsd. 486.4.
Reaction SMILES: C[N+]1([O-])CCOCC1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[CH2:21][OH:22]>CC#N.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[CH:21]=[O:22]
Reactant: CC(=O)NCc1ccc(Cl)c(CO)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC(=O)NCc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
NMO (1.15 g, 8.26 mmol) was added to a sol. of N-(4-chloro-3-hydroxymethyl-benzyl)-acetamide (588 mg, 2.75 mmol) in CH3CN (27 mL). The sol. was stirred for 30 min at rt, and tetrapropylammonium perruthenate (97 mg, 0.28 mmol) was added. The mixture was stirred for 1 h at rt, and was filtered over celite. The precipitate was washed with CH3CN. The filtrate was evaporated under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (382 mg, 66%). LC-MS: tR=0.71 min; ES+: 253.07.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.C(O)=O.C([NH2:16])=O.Cl>C(O)C>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:16])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: NC=O
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: CC(N)c1cccc(Br)c1
Temperature: 220 °C

Procedure:
A mixture of commercially available 3-bromoacetophenone (30 g, 0.1508 mol), formic acid (47 ml) and formamide (70 ml) was heated to 220° C. for 5 h. The brown liquid obtained was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated to provide a brown liquid. Ethanol (375 ml) and conc.HCl (75 ml) were added to the brown liquid and the reaction mixture refluxed over night. Ethanol was removed completely under reduced pressure and the aqueous layer was washed with ether and ethyl acetate to remove all non-basic impurities. The aqueous layer was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, and concentrated to provide 26 g (86.65%) of A1.13a This compound was taken to the next step with out further purification. 1H NMR (CDCl3, 300 MHz) δ 1.38 (d, 3H), 4.1 (q, 1H), 7.2 (m, 1H), 7.27 (m, 1H), 7.37 (m, 1H), 7.51 (s, 1H). LS-MS (M−H)+=200.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:5]2.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>N1C=CC=CC=1.ClCCl>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:5]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CCC(=O)NCC1Cc2ccc(N)cc2C1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCC1Cc2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2C1
Temperature: 5 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
N-(5-Amino-indan-2-ylmethyl)-propionamide (0.93 g, 4.26 mmol) was dissolved in pyridine-dichloromethane (1:2, 60 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (0.98 g, 4.48 mmol) was added and the solution stirred at 5° C. for 3 h. Solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give the product as a brown oil (1.69 g, 99%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (97 mg, 158 μmol) in dichloromethane (4 mL) was added TFA (1.48 g, 1 mL, 13.0 mmol, Eq: 82.4), the reaction mixture turned orange and was stirred at 25° C. for 2 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane (with a couple of drops of MeOH) and purified by chromatography (40 g column, 20-40 μm spherical silica, HP Gold from Teledyne/Isco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, off-white solid was separated by decantation and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62 mg, 128 μmol, 81.1%). MS (M+H)+=486 (100% purity); 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.78-7.95 (m, 2H), 7.39 (d, J=8.7 Hz, 1H), 7.19 (s, 1H), 4.55 (t, J=6.2 Hz, 2H), 2.17-2.30 (m, 2H), 2.12 (s, 7H), 1.99-2.07 (m, 2H), 1.49 (s, 10H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][CH:11]1[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:14](=[O:25])[CH2:13][S:12]1.C(Cl)(Cl)Cl>CO.O>[OH:7][CH:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:9][CH2:10][CH:11]1[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:14](=[O:25])[CH2:13][S:12]1=[O:2]
Reactant: CCCCCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CCCCCC(O)CCC1N(CCCCCCC(=O)O)C(=O)CS1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.1 %

Procedure:
Sodium metaperiodate (749 mg., 3.5 millimole) is added to a turbid solution of 7-[2-(3-hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid (1.24 g., 3.44 millimole) in methanol-water (5:4; v:v; 18 ml.) cooled in an ice bath (0° to 5° C.). After removing the cooling bath, the reaction mixture is stirred at ambient temperature for 16 hours. Precipitated solid is removed by filtration. The filtrate is diluted with cold water and extracted twice with chloroform. The combined organic extract is washed with saturated aqueous brine, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo leaves an oily residue which is applied to a silica gel column (20 g.) with chloroform. Elution with chloroform-acetic acid (25:1; v:v; 310 ml.) gives an impure forerun which is discarded. Continued elution with the same eluant (330 ml.) provides the title compound as a plae yellow oil (750 mg., 58%); pmr (CDCl3) δ 0.88 (3H, t), 4.47 (H, m) and 7.76 (2H, s, D2O exchangeable). Anal. Calcd. for C18H33NO5S: N, 3.73. Found: N, 3.37.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[N:6][CH:7]=[CH:8][CH:9]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[OH:12][CH2:11][CH:10]([C:5]1[C:4]([CH3:3])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:13][O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1cccnc1C(CO)CO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccnc1C(CO)COc1ccc([N+](=O)[O-])cc1

Procedure:
60% Oil-borne sodium hydride (2.8 g) was added little by little to a solution of 2-(3-methyl-2-pyridyl)-1,3-propylene glycol (10.0 g) and p-fluoronitrobenzene (8.45 g) in dimethylformamide (100 ml) under ice-cooling with stirring. After stirring under ice-cooling for 1 hour, the reaction solution was poured in ice-cold water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and freed of the solvent by distillation, and the residue was chromatographed on a silica-gel (200 g) column. Elution was effected with cyclohexane-ethyl acetate (3:1, V/V) to give 4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]nitrobenzene in the form of crystals. Yield of 9.6 g. Recrystallization from ethyl acetatehexane produced colorless prisms. m.p. 135°-136° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(N(CC)CC)C.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23].F[C:30](F)(F)[CH2:31][O:32]P(CC(OC)=O)(OCC(F)(F)F)=O>C1COCC1.C(Cl)Cl>[Cl:10][C:6]1[C:7]2[CH:8]=[CH:30][C:31](=[O:32])[N:23]([C:22]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:21]=3[F:20])[C:2]=2[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSc1nc(Cl)c2ccc(=O)n(-c3ccc(F)cc3F)c2n1
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (4.2 g, 18.95 mmol) and triethylamine (5.3 ml, 38 mmol) in THF (100 ml) was added 2,4-difluoroaniline (2.1 ml, 20.58 mmol). The mixture was stirred for 2 h, and methyl {bis[(2,2,2-trifluoroethyl)oxy]phosphoryl}acetate (6.0 g, 18.95 mmol) was added. The mixture was stirred for 18 h, diluted with DCM (200 ml) and washed with water (2×100 ml). The dried (Na2SO4) organic phase was filtered and evaporated. Flash chromatography (EtOAc/Hexane, 1:5) provided the title compound as a cream solid (2.5 g, 40%): LC-MS m/z 340 (M+H)+ retention 3.24 min.
Reaction SMILES: [OH:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.[BrH:20]>C(O)(=O)C>[OH2:1].[OH2:1].[BrH:20].[Br:20][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: O=C1CCc2cc(C(O)c3ccccc3)ccc2N1
Agent: Br
Solvent: CC(=O)O
Product: O
Product: O=C1CCc2cc(C(Br)c3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A mixture of 20 parts of intermediate 19, namely 3,4-dihydro-6-(hydroxyphenylmethyl)-2(1H)-quinolinone and 355 parts of a solution of hydrobromic acid in acetic acid 30% was stirred overnight at room temperature. The reaction mixture was evaporated and the residue was stirred in ethyl acetate. The product was filtered off, washed with ethyl acetate and 2,2'-oxybispropane and dried in vacuo at 35° C., yielding 23 parts (67.2%) of 6-[bromophenylmethyl]-3,4-dihydro-2(1H)-quinolinone hydrobromide dihydrate; mp. 119.5° C. (interm. 37).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([CH3:21])([CH3:20])[CH3:19])=[NH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:10][P:30]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=N)Nc2ccccc2C(C)(C)C)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: CC(C)(C)c1ccc(C(=NP(c2ccccc2)c2ccccc2)Nc2ccccc2C(C)(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.54 g of 4-tert-butyl-N1-(2-tert-butylphenyl)benzamidine (Amidine VII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow solid was collected and dried (2.31 g, 94%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[C:4]=1[CH2:13][CH2:14][OH:15])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl>[OH:24][CH2:2][CH:1]1[C:3]2[C:4](=[C:5]3[CH2:9][O:8][C:7](=[O:10])[C:6]3=[CH:11][CH:12]=2)[CH2:13][CH2:14][O:15]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1CCO)COC2=O
Solvent: ClCCl
Product: O=C1OCc2c1ccc1c2CCOC1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Ethenyl-4-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (1.2 g, 5.9 mmol) was added to a flask containing a stir bar. To the flask was then added dichloromethane (20 mL). The flask was placed in a cool bath of 0° C.; to the flask was poured mCPBA (1.5 g, 8.8 mmol) and the resulting mixture was stirred at room temperature for overnight; LC as well as TLC (hexanes/EtOAc=1/1) indicated that reaction had gone to completion. The solution was treated with dichloromethane and washed with NaHCO3, Na2S2O3, and water, the organic layer was then dried over Na2SO4, filtered and concentrated to dryness, it was then treated with AcOH (20 mL) and stirred overnight; LC indicated formation of cyclized product. The solvent was removed and the resulting residue was absorbed into silica gel and 6-(hydroxymethyl)-8,9-dihydro-1H-furo[3,4-f]isochromen-3(6H)-one was isolated with the solvent systems of hexanes/EtOAc (1/1). 1H-NMR (400 MHz, CDCl3) δ ppm 7.807 (d, J=8 Hz, 1H), 7.337 (d, J=8 Hz, 1H), 5.279 (s, 2H), 4.985 (s, 1H), 4.302-4.302 (m, 1H), 4.183-4.084 (m, 2H), 3.954-3.912 (m, 2H), 3.006-2.944 (m, 1H), 2.717-2.686 (m, 1H), 2.179-2.172 (m, 2H)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]([NH:25][C@H:26]([C:29]([OH:31])=[O:30])[CH2:27][NH2:28])=[O:24])=[CH:17][CH:16]=1>CCOCC.[OH-].[Na+]>[CH2:21]([O:22][C:23]([NH:25][C@H:26]([C:29]([OH:31])=[O:30])[CH2:27][NH:28][S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:24])[C:18]1[CH:17]=[CH:16][CH:15]=[CH:20][CH:19]=1
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(N[C@@H](CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
A solution of 21.4 g of 2-naphthylsulfonyl chloride in 200 ml of ether is added dropwise while stirring to a solution of 15 g of N-α-Z-L-2,3-diaminopropionic acid in 189 ml of 1N sodium hydroxide solution. The mixture is left to stir for a further 6 hours. Subsequently, the reaction mixture is poured into ice-cold 2N hydrochloric acid and extracted with ethyl acetate. The organic is washed with water, dried and evaporated. After chromatography of the residue on silica gel with methylene chloride/methanol/acetic acid (94:5:1) there are isolated 17.9 g of N-[(benzyloxy)carbonyl]-3-(2-naphthylsulfonamido)-L-alanine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[NH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)C(c1cccc(F)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)C(c1cccc(F)c1)CC2

Procedure:
The title compound was synthesized from methyl 6-(3-fluorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (116 mg, 0.45 mmol) and lithium hydroxide (188 mg, 4.50 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography. eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.28-2.39 (m, J=12.87, 8.60, 6.35, 6.35 Hz, 1H), 2.64-2.74 (m, 1H), 2.74-2.85 (m, 1H), 2.90-3.01 (m, J=12.83, 8.48, 8.48, 4.32 Hz, 1H), 4.23-4.31 (m, 1H), 6.80-6.87 (m, 2H), 6.89-6.97 (m, 2H), 7.23-7.32 (m, 1H), 8.74 (br. s, 1H). LCMS m/e 246 (M+H). Purity>98% (HPLC).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1)#[N:9].[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:9][CH2:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Add triethylamine (0.3 mL, 2.12 mmol) to a solution of 4-cyano-benzylamine (1.0 g, 7.58 mmol) in DCM (11 mL) and cool the mixture at 0° C. Add 2,2-dimethyl-propionyl chloride (0.93 mL, 7.58 mmol) dropwise and allow to stir the mixture at 0° C. for 15 min and at room temperature for 2 h. Add water, separate the organic phase and extract the aqueous phase twice with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (1.23 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([OH:13])=O)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([C:11]([NH2:15])=[O:13])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1c[nH]c2ncnc(Cl)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1c[nH]c2ncnc(Cl)c12
Reaction time: 2 h

Procedure:
To a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (G-1) (3.11 g, 15.7 mmol, 1.0 eq) and a catalytic amount of DMF in a mixture of DCM (40 mL) and THF (40 mL) at RT, oxalyl dichloride (2.0 mL, 23.5 mmol, 1.5 eq) is added dropwise. The resulting mixture is stirred for 2 h and then concentrated in vacuo. The residue (G2) is dissolved in DCM (50 mL) and the resulting solution is added dropwise to saturated aqueous ammonium hydroxide (200 mL) at RT. The resulting mixture is stirred for 30 min and then filtered. The filter cake is then rinsed with H2O (30 mL×2). The filtrate is acidified with con. HCl to adjust the pH to 4-5. The solid is collected by filtration, rinsed with water and dried in vacuo to afford the product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (G-3).