Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([C:13]([OH:15])=[O:14])[C@@H:10]([OH:16])[C@H:9]([OH:17])[C@H:7]2[N:8]=1)[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH2:1]([N:3]([CH3:18])[C:4]1[S:5][C@H:6]2[O:12][C@H:11]([C:13]([OH:15])=[O:14])[C@@H:10]([OH:16])[C@H:9]([OH:17])[C@H:7]2[N:8]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(=O)O)O[C@@H]2S1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(=O)O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 5 mL sure seal vial was added (3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylic acid (53.00 mg; 0.20 mmol; 1.00 eq.) in N,N-dimethylformamide (2.00 ml) followed by dipotassium carbonate (55.85 mg; 0.40 mmol; 2.00 eq.) and iodomethane (29.69 μl; 0.40 mmol; 2.00 eq.). The mixture was stirred at room temperature for overnight before it was concentrated, purified by Yamazen C1 (40 g column, 220 nm) and dried with lyophilize to afford 7.3 mg (9.3%) monomethylated compound as white solid and two sets of peaks were found on NMR, ratio=3:1.
Reaction SMILES: [Cl:1][C:2]1[C:12]([OH:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:20]([O:13][C:12]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cnc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of ethyl 6-chloro-5-hydroxynicotinate (2 g, 0.01 mol) in Toluene (50.0 mL) were added K2CO3 (2.76 g, 0.02 mol, Rankem, India) and benzyl bromide (2 g, 0.0012 mol). The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 20% EtOAc in hexane), the reaction mixture was quenched with water (50 mL), extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and purified by column chromatography, silica gel (60-120 mesh) using 12-16% EtOAc in petroleum ether as the eluent to give the title compound. MS (ESI, positive ion) m/z: 292.2 (M+H).
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([F:22])[CH:21]=1)[O:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(OCC)C>N1C=CC=CC=1>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:16][CH2:15][CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:7]3[CH:6]=[C:5]([F:4])[CH:21]=[C:20]([F:22])[CH:19]=3)=[CH:18][CH:17]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Oc3cc(F)cc(F)c3)cc2)cc1
Temperature: -20 °C
Yield: 92.8 %

Procedure:
To a solution of 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol ethanol (2.66 g, 10.0 mmol) in pyridine (2.8 g), p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) was gradually added with stirring while cooling at -20° C., and the resultant mixture was allowed to stand in a refrigerator overnight. Diethyl ether was added to the reaction mixture, which was washed with dilute hydrochloric acid until the aqueous layer became acidic, followed by washing with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The obtained ether layer was dried over anhydrous magnesium sulfate, and the solvent was removed to give 2-[4-(3,5-difluorophenoxy)phenoxy]ethyl p-toluenesulfonate (3.90 g).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:32]([OH:34])=[O:33])=[C:19]([CH:22]([S:26][C:27]4[NH:31][N:30]=[N:29][N:28]=4)[CH2:23][CH2:24][OH:25])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.C([O-])(=O)C.[Na+].O>O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:32]([OH:34])=[O:33])=[C:19]([CH:22]([S:26][C:27]4[NH:31][N:30]=[N:29][N:28]=4)[CH2:23][CH2:24][OH:25])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: O=C(O)C1=C(C(CCO)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)C(=NOC3CCCC3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C(=NOC2CCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=C(C(CCO)Sc4nnn[nH]4)CS[C@H]23)cs1
Yield: 71.5 %

Procedure:
A solution of 7-[2-[2-(2,2,2-trifluoroacetamido)-thiazol-4-yl]-2-cyclopentyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 2.5 g.), sodium acetate 3 hydrate (4.9 g.), water (30 ml.) and tetrahydrofuran (14.0 ml.) was stirred at room temperature for 18 hours. After removing tetrahydrofuran from the resultant solution in vacuo, water (20 ml.) was added to the residue and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-cyclopentyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 1.54 g.), mp. 150°-156° C. (dec.).
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([CH:4]1[N:8]([C:18](=[O:21])[CH:19]=[CH2:20])[C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: C=CCC1CCC(C)(C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1CCC(C)(C)N1C(=O)C=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 5-allyl-2,2-dimethylpyrrolidine (1.5 g, 10.5 mmol) in 50 ml of anhydrous CH2Cl2, triethylamine (3 ml, 21 mmol) and acryloyl chloride (0.94 ml, 11.6 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature and stirred for overnight. Analysis of the reaction mixture by LCMS indicated the completion of the reaction. Saturated aqueous NaHCO3 was added to the reaction mixture and the layers were separated. Aqueous layer was worked up twice with CH2Cl2 and the combined organic layers were dried over Na2SO4. Removal of the volatiles and purification of the crude by column chromatography gave the product in 80% yield (1.60 g) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1cccnc1)N1CCOCC1
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1cccc(C(=O)NCC(c2cccnc2)N2CCOCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]3[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O.C(O)C>[CH:18]1([CH:9]2[CH2:10][CH2:11][C:12]3[C:17]4=[C:16]([C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]24)[CH:15]=[CH:14][CH:13]=3)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1cn2c3c(cccc13)CCC2C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c3c(cccc13)CCC2C1CCCC1
Yield: 85.7 %

Procedure:
To a solution of 4-cyclopentyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (1.45 g, 4.9 mmol) in water (10 ml) and ethanol (15 ml) was added sodium hydroxide (1.96 g, 49 mmol) and the reaction mixture heated at reflux overnight (˜14 h). The reaction was cooled and acidifed with 5 M HCl. The resulting white precipitate was filtered and dried in vacuo to give 4-cyclopentyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (1.13 g, 4.2 mmol) as a white solid.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8]1[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=[CH:11][C:12]=1[C:13](OC)=[O:14])[C:4]([O:6][CH3:7])=[O:5].CC(C)([O-])C.[Na+].O>CN(C=O)C>[CH:17]1([N:9]2[C:8]3[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:2][NH:1][C:13](=[O:14])[C:12]=3[CH:11]=[CH:10]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)C(=CN)c1c(C(=O)OC)ccn1C1CCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c[nH]c(=O)c2ccn(C3CCCC3)c12
Temperature: 160 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of methyl 2-(1-amino-3-methoxy-3-oxoprop-1-en-2-yl)-1-cyclopentyl-1H-pyrrole-3-carboxylate (20.45 g) in DMF (205 mL) was added sodium tert-butoxide (6.72 g), and the mixture was stirred at 160° C. for 1 hr. The reaction mixture was allowed to be cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate and hexane to give the title compound (7.83 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[CH2:1]([N:8]1[C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=2[N:16]=[CH:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc(Br)cc1NCc1ccccc1
Solvent: O
Solvent: COC(OC)OC
Product: Brc1ccc2ncn(Cc3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of N1-benzyl-5-bromobenzene-1,2-diamine (450 mg, 1.63 mmol) in HC(OMe)3 (15 mL) was added TsOH.H2O (30 mg, 0.16 mmol). The mixture was stirred at 100° C. for 4 h. The reaction solution was concentrated, and the residue was washed with water and extracted with EtOAc. The organic layer was concentrated to give the crude 1-benzyl-6-bromo-1H-benzo[d]imidazole. The crude product was used in next step without further purification. LCMS (m/z): 287.1/288.1 [M+H]+/[M+2H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20]Br>CN(C=O)C>[F:1][C:2]1[C:9]2[O:10][CH2:19][CH2:20][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: BrCCBr
Reactant: O=Cc1cc(O)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c2c(c1)OCCO2
Yield: 95.4 %

Procedure:
To a solution of 3-fluoro-4,5-dihydroxybenzaldehyde (0.66 g, 4.2 mmol) in DMF (30 ml) was added potassium carbonate (1.15 g, 8.3 mmol) and 1,2-dibromoethane (0.72 ml, 8.3 mmol) and the resultant mixture was heated to 80° C. for 18 h before the solvent was removed under reduced pressure. The reaction mixture was then treated with dichloromethane and water. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried and the solvent was removed under reduced pressure to give the desired compound as a cream solid (0.73 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]3[S:16][CH:17]=[CH:18][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][C:29]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[O:15]=[C:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:29]=3[CH3:28])=[CH:20][CH:19]=2)=[O:7])[C:9]2[CH:18]=[CH:17][S:16][C:10]1=2
Reactant: Nc1ccc(C(=O)N2CCCC(=O)c3sccc32)cc1
Reactant: Cc1c(F)cccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3sccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a mixture of 287 mg of 4,5,6,7-tetrahydro-4-(4-aminobenzoyl)-8H-thieno[3,2-b]azepin-8-one in 3 ml of methylene chloride is added 209 μl of triethylamine which is cooled to 0° C. is added 207.1 mg of 2-methyl-3-fluorobenzoyl chloride. The cooling bath is removed and the reaction mixture stirred at room temperature under argon for 18 hours. An additional 50 ml of methylene chloride and 20 ml of water is added and the separated organic layer washed with 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate and the filtrate evaporated in vacuo to a white foam which is crystallized from ethyl acetate-hexane to give 305 mg of the desired product as a white solid, 200°-202° C.
Reaction SMILES: Cl[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH3:14].[CH2:22]([SH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>CO>[CH2:22]([S:29][C:2]1([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH3:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: SCc1ccccc1
Reactant: CCCN1C(=O)c2ccccc2C1(Cl)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1C(=O)c2ccccc2C1(SCc1ccccc1)c1ccc(Cl)cc1

Procedure:
Distilled THF was added to 3-chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one (1.06 g, 3.31 mmol) followed by benzyl mercaptan (0.855 mL, 7.29 mmol) as for general procedure C. On addition of the benzyl mercaptan, a pale pink precipitate formed which turned white over time. The ethyl acetate was mostly removed under vacuum. On leaving overnight in the fridge, clear crystals formed. The crude product was purified by flash column chromatography (20:80, EtOAc:petrol) and recrystallised in the minimum amount of hot ethyl acetate giving large colourless crystals of 3-benzylsulfanyl-3-(4-chlorophenyl)-2-propyl-2,3-dihydroisoindolin-1-one (918 mg, 2.25 mmol, 68%). Rf 0.68 (40:60 EtOAc:petrol). Mp. 131.5-133.4° C. λmax (CH3OH)/nm 223.0, Abs 0.964. IR: 3161, 2968, 1665, 1608, 1467, 1435, 1402 cm−1. 1H NMR (300 Hz, CDCl3); δ 0.72 (t, 3H, J=7.5 Hz, N(CH2)2—CH3), 1.37 (m, 1H, N—CH2—CH2—CH3), 1.57 (m, 1H, N—CH2—CH2—CH3), 2.80 (d, 1H, J=12 Hz, S—CH2), 3.10 (d, 1H, J=12 Hz, S—CH2), 3.17 (m, 1H, N—CH2), 3.36 (m, 1H, N—CH2), 6.92-7.81 (m, 13H, Ar). 13C NMR (75 Hz, CDCl3); 111.8 (N—(CH2)2—CH3), 21.5 (N—CH2—CH2), 33.4 (S—CH2), 42.6 (N—CH2), 78.2 (S—C—N), 123.2, 123.4, 127.3, 128.0, 128.5, 128.9, 128.9, 131.0, 132.8, 134.9, 135.8, 137.1, 148.3 (Ar), 167.9 (C═O). LC/MS-ES+ m/z 410.6, 408.7, 286.1, 287.1. Anal. Calcd. for C24H22ClNOS: C, 70.66; H, 5.44; N, 3.43%. Found C, 70.60; H, 5.51; N, 3.51%.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][NH2:35]>>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:35]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and 2-fluoro-phenylhydrazine according to the method described for example 43. MS: M=431.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.C([O:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])[C:30](Cl)=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:12][C:11]1[C:2]2[N:1]=[C:30]([CH:29]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[Cl:40])[OH:28])[N:13]([CH2:14][CH2:15][CH2:16][OH:17])[C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: CC(=O)OC(C(=O)Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
To a stirred solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.01 g, 3.90 mmol) and triethylamine (1.20 mL, 8.58 mmol) in tetrahydrofuran (20 mL) was added a solution of 2-chloro-1-(2,4-dichlorophenyl)-2-oxoethyl acetate (2.20 g, 7.80 mmol) in tetrahydrofuran (10 mL) at 0° C. After 30 min, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was dissolved in acetic acid (20 mL), and the mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was dissolved in methanol (20 mL) and potassium carbonate (539 mg, 3.90 mmol) was added at room temperature. After 30 min, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by column chromatography on NH-silica gel eluting with a 0-10% methanol/ethyl acetate gradient mixture to afford the desired product as pale yellow solid (745 mg, 1.61 mmol, 41%).
Reaction SMILES: Br[C:2]1[C:3]2[C:28]([CH3:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:27](=[O:36])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.[CH3:37][NH2:38]>C1COCC1>[CH3:35][C:28]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:3]2[C:2]([NH:38][CH3:37])=[N:7][C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])[N:9]=3)=[N:5][C:4]=2[NH:26][C:27]1=[O:36]
Reactant: CC1(c2ccccc2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(Br)c21
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncccc23)nc2c1C(C)(c1ccccc1)C(=O)N2

Procedure:
The intermediate from Step A above (100 mg, 0.176 mmol), methylamine (0.881 mL, 1.763 mmo, 2 M in THF) and THF (2 mL) were sealed in a microwave tube and subject to microwave irradiation at 140° C. for 2 h. The reaction mixture was partitioned between brine and EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title product, as a solid. 1H NMR (500 MHz, CD3OD) δ 9.01 (dd, J=8.1, 1.6 Hz, 1H); 8.6 (dd, J=4.5, 1.6 Hz, 1H); 7.39-7.32 (m, 5H); 7.32-7.27 (m, 1H); 4.96 (t, J=7.3 Hz, 3H); 3.07 (s, 3H); 3.05-2.91 (m, 2H); 1.88 (s, 3H). m/z=518.1 (M+H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2C=[CH:14][C:13]([NH:16][C:17]3[C:18]4[N:19]([N:31]=[CH:32][N:33]=4)[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][OH:30])[CH:24]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].BrC1N2N=CN=C2C(NC2C=NC(N3CCN(C(C)C)CC3)=CC=2)=[N:37]C=1>>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:37]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[N:19]([N:31]=[CH:32][N:33]=4)[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][OH:30])[CH:24]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cn2)CC1
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccnc(CO)c4)n4ncnc34)cc2)CC1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4ccnc(CO)c4)n4ncnc34)cn2)CC1

Procedure:
This compound may be prepared using the methods as described for Compound 83, using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[6-(4-isopropylpiperazin-1-yl)pyridin-3-yl]amine in Step 4. LCMS: Rt=0.71 min (95%), m/z (ESI) 446 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.[CH:11]1[CH:16]=[N:15][C:14]2N(O)N=N[C:13]=2C=1.C(Cl)CCl.N(CC)CC>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:15]([CH2:16][CH3:11])[CH2:14][CH3:13])=[O:10])[N:6]=1
Reactant: On1nnc2cccnc21
Reactant: Nc1nc(CC(=O)O)cs1
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)Cc1csc(N)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(2-aminothiazol-4-yl)acetic acid (1 eq), HOAT (1 eq), EDC (1.1 eq), TEA (1 eq) and HNEt2 (1 eq) in DMA was stirred at room temperature for 6 hours. The reaction mixture was then quenched with H2O and concentrated. The residue was dissolved in a stirred 4:1 mixture of EtOAc and NaHCO3(sat.). The two phases were separated and the organic solution was washed with brine, dried over Na2SO4 and concentrated to dryness. The resulting solid was washed twice with Et2O and dried to yield the desired product as a white solid. LC/MS (m/z): 214.0 (MH+), Rt 1.13 minutes.
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH2:33][O:34][CH3:35])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[C:11]([O:24][CH3:25])[CH:10]=2)[N:5]1C(OC(C)(C)C)=O)=[O:3].C([Cl:39])(C)=O>C(OCC)(=O)C.CO>[ClH:39].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C@@H:6]2[NH:5][C@:4]([CH2:33][O:34][CH3:35])([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7]2)=[CH:10][C:11]=1[O:24][CH3:25]
Reactant: CC(=O)Cl
Reactant: COC[C@@]1(C(N)=O)CC[C@H](c2ccc(OCc3ccccc3F)c(OC)c2)N1C(=O)OC(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC[C@@]1(C(N)=O)CC[C@H](c2ccc(OCc3ccccc3F)c(OC)c2)N1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5R)-2-(aminocarbonyl)-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-2-[(methyloxy)methyl]-1-pyrrolidinecarboxylate (D65, 70 mg, 0.14 mmol) in a mixture of ethyl acetate (1.8 ml) and methanol (0.2 ml) at 0° C. was added AcCl (170 μl, 2.38 mmol). The mixture was stirred for 4 hours at room temperature. The solvent was evaporated and the residue was triturated with Et2O to afford the title compound as a white solid (49 mg, 82%); Rt (HPLC) 3.62 min; MS: (ES/+) m/z: 389 [MH]+ C21H25FN2O4 requires 388; 1H NMR (500 MHz, DMSO-d6) δ (ppm): 9.91-10.02 (br.s, 1H); 8.07-8.25 (br.s, 2H); 7.94-8.03 (br.s, 1H); 7.50 (t, 1H); 7.35-7.43 (m, 1H); 7.17-7.25 (m, 2H); 7.13 (s, 1H); 7.06 (d, 1H); 6.95 (dd, 1H); 5.08 (s, 2H); 4.51-4.66 (m, 1H); 3.92 (d, 1H); 3.74 (s, 3H); 3.69 (d, 1H); 3.26 (s, 3H); 2.17-2.35 (m, 2H); 1.97-2.12 (m, 1H); 1.79-1.96 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.BrC1C=CC=C2C=1NC=C2.C([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:27]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: c1ccc2[nH]ccc2c1
Agent: Brc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(N2CCNCC2)c2[nH]ccc2c1
Temperature: 25 °C
Yield: 54 %

Procedure:
The Boc protected indole (200 mg, 1.5 mmol) prepared from 7-bromoindole and N-Boc piperazine as described in Step 1 of Preparation 54A is dissolved in DCM (1 mL). TFA (1 mL) is added and the mixture is stirred at r.t. for about an hour. The mixture is then concentrated to oil, which is taken up in methanol and freebased via SCX purification to afford about 164 mg (54%) of the final compound.