Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: CCOc1cnc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCOc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-ethoxy-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.46 min; Mass spectrum (ESI+): m/z=434 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH3:14])[CH:10]([N:15](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:15][CH:10]1[CH:11]([O:13][CH3:14])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC1CN(C(=O)OC(C)(C)C)CC1N
Yield: 81.4 %

Procedure:
0.13 g of 20% w/w palladium-on-carbon was added to a solution of 0.99 g (0.0025 mole) of 1-t-butoxycarbonyl-3-dibenzylamino-4-methoxypyrrolidine dissolved in 15 ml of ethanol, and the mixture was stirred vigorously at 50° C. for 4 hours in an atmosphere of hydrogen. The catalyst was filtered off from the reaction mixture, after which the filtrate was concentrated by evaporation under reduced pressure, to give 0.44 g of 3-amino-1-t-butoxycarbonyl-4-methoxypyrrolidine as a colorless oil.
Reaction SMILES: BrC[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1>C1COCC1.O.[Zn+2].[Br-].[Br-]>[CH2:3]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([O:8][CH3:7])=[O:17])[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC(C)CCBr
Agent: [Br-]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
In an oven-dried round bottom flask Mg turnings (1.13 g, 46.6 mmol) are suspended in THF (1 mL). 1-Bromo-3-methylbutane (6.37 g, 46.5 mmol) is carefully added while the mixture is initially heated to reflux. The mixture is stirred for approximately 30 min until the Mg has dissolved. The mixture is then added to a cold (5° C.) solution of ZnBr2 (10.47 g, 46.5 mmol) in THF (80 mL). The thick suspension is stirred at 0° C. for 20 min before it is cooled to −75° C. 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (184 mg, 0.225 mmol) followed by methyl-3-bromobenzoate (5.0 g, 23.3 mmo) is then added. The mixture is warmed to rt and stirred for 24 h. The reaction mixture is diluted with water and extracted with EA. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 20:1 to give methyl 3-isobutyl-benzoate (4.34 g) as a colourless oil. This material is dissolved in methanol (50 mL) and 2 N aq. LiOH (10 mL) and stirred at rt for 16 h. The mixture is acidified by adding 1 N aq. HCl and extracted with EA. The org. extracts are dried over MgSO4, filtered and evaporated to give 3-isobutyl-benzoic acid (3.84 g) as a colourless oil; LC-MS: tR=0.91 min; 1H NMR (CDCl3): δ 0.87 (d, J=6.7 Hz, 6H), 1.77-1.94 (m, 1H), 2.48 (d, J=7.0 Hz, 2H), 7.29-7.35 (m, 2H), 7.86 (s, 1H), 7.88-7.94 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]2=[O:31])=[CH:8][CH:7]=1)C.[OH-].[Na+]>CO>[C:27]([O:26][C:24]([CH2:23][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[CH:11][CH:10]=2)[C:13]1=[O:31])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)Cc1ccc(-n2c(=O)c3ccccc3n(CC(=O)OC(C)(C)C)c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccc(CC(=O)O)cc2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of [4-(1-tert-butoxycarbonylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-acetic acid ethyl ester (Intermediate G) (1.4 g, 3.2 mmol) in MeOH (25 ml) is treated with aqueous sodium hydroxide (0.5 M, 10 ml). After stirring at RT for 30 minutes, the MeOH is removed in vacuo and the resulting mixture is diluted with distilled water and washed with EtOAc (2×) to remove impurities. The separated aqueous phase is acidified with dilute HCl (0.1 M) to pH 3 and extracted with EtOAc (2×). The combined organic portions are dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an off-white solid.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[CH3:18][N:19]([CH2:21][C:22](Cl)=[O:23])[CH3:20].CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:11][C:7]1[C:6]2[N:5]([C:4]([CH:12]3[CH2:17][CH2:16][N:15]([C:22](=[O:23])[CH2:21][N:19]([CH3:20])[CH3:18])[CH2:14][CH2:13]3)=[N:3][C:2]=2[I:1])[CH:10]=[CH:9][N:8]=1
Reactant: CN(C)CC(=O)Cl
Reactant: Nc1nccn2c(C3CCNCC3)nc(I)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2nc(I)c3c(N)nccn23)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of 1-iodo-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamine (1.000 g, 2.91 mmol) and dimethylamino-acetyl chloride (0.38967 g, 3.20 mmol) in DMF (10.00 mL) was added DIEA (2.58 mL, 14.57 mmol) at 0° C. The resulting mixture was stirred at rt. overnight. The mixture was diluted with sat. aq. NaHCO3 and extracted with DCM (50 ml×3). The extracts were combined, dried (Na2SO4). Solvent was then removed under reduced pressure and the resulting residue was used for next step without further purifications. MS (ES+): m/z 428.74 [MH+].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:26]([O:33][CH2:34][CH2:35]I)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(OCC)(=O)C.CCCCCC>[Si:26]([O:33][CH2:34][CH2:35][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]#[N:10])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: N#CCCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Combine 3-phenylpropionitrile (2.0 g, 15.25 mmol) and tetrahydrofuran (15 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of lithium bis(trimethylsilyl)amide (16.0 mL, 1 M in THF, 16.0 mmol). After 1 hour, add 2-(t-butyldimethylsilyloxy)ethyl iodide (4.58 g, 16.0 mmol). After the addition of 2-(t-butyldimethylsilyloxy)ethyl iodide is complete, warm slowly to ambient temperature over about 7 hours. Add water and extract twice with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give the title compound: Rf=0.50 (silica gel, 10% ethyl acetate/hexane).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.[OH-].[Cs+].[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>O1CCOCC1.O.C(OCC)(=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>[Cl:15][C:13]1[CH:12]=[CH:11][C:4]2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:42][CH:41]=4)=[CH:31][CH:30]=3)[C:3]=2[CH:14]=1
Reactant: COc1ccc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc(C3=NCC(=O)N(C)c4ccc(Cl)cc43)cc2)cc1
Temperature: 90 °C

Procedure:
(E)-5,7-Dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (5.00 g, 20.57 mmol), cesium hydroxide (6.91 g, 41.1 mmol), and 2-(4-(4-methoxybenzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.10 g, 26.7 mmol) were dissolved in dioxane/water (100 mL/30 mL), and the mixture was subjected to vacuum followed by nitrogen gas. The de-gassing was repeated twice, and then tetrakis(triphenylphosphine)palladium (0) (475 mg, 0.41 mmol) was added. The reaction was then heated to 90° C. for 18 hours, and then cooled to room temperature. The crude mixture was diluted with ethyl acetate, and the organic solution was washed with water, then brine, and then dried over sodium sulfate, and concentrated. The crude product was vacuum pulled through a silica plug eluting with 6:4 ethyl acetate:hexanes. The filtrate was concentrated and then washed with methyl-tert-butyl ether. The product was collected as a light yellow solid by filtration (5.13 g, 59%). 1H NMR (300 MHz, CDCl3) δ 3.36 (s, 3H), 3.73 (d, 1H), 3.81 (s, 3H), 4.77 (d, 1H), 5.03 (s, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.27 (d, 1H), 7.32 (d, 1H), 7.36 (d, 2H), 7.49 (dd, 1H), 7.55 (d, 2H).
Reaction SMILES: [O:1]=[C:2]([CH2:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:17]/[C@@H:18]([O:25]C2CCCCO2)[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:14]([O:32]C2CCCCO2)[CH2:13][C:12]1=[O:39])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]>C(O)(=O)C.O.O1CCCC1>[O:1]=[C:2]([CH2:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:25])[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:14]([OH:32])[CH2:13][C:12]1=[O:39])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC#CCC(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CC(=O)CCCCC(=O)O)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC#CCC(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(=O)O
Yield: 97.5 %

Procedure:
160 mg of (13E)-(11R,15S,16RS)-6,9-Di-oxo-11,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18,19,19-tetradehydro-13-prostenoic acid was mixed with 88 ml of a mixture of acetic acid:water:tetrahydrofuran (65:35:10) and allowed to react for 15 h at room temperature. It was concentrated by evaporation in a vacuum and the residue portions of acetic acid and water were removed by addition of toluene by azeotropic vacuum distillations repeated several times. The resulting raw oil was purified by chromatography on glass plates coated with silica gel. A mixture of dichloromethane and methanol was used as mobile solvent. 108 mg (98%) the title compound was isolated as colorless oil.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:11]([N:13]1[CH2:34][CH2:33][CH2:32][C@H:14]1[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[C:30](Cl)=[N:29][S:28][N:27]=1)=[O:16])=[O:12])=O)(C)(C)C>C(Cl)Cl>[ClH:25].[NH2:9][C@H:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:11]([N:13]1[CH2:34][CH2:33][CH2:32][C@H:14]1[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[CH:30]=[N:29][S:28][N:27]=1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1nsnc1Cl)C1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1cnsn1)C1CCCCC1

Procedure:
HCl gas was bubbled through a stirred 0° C. solution of 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)benzyl]-L-prolinamide (41.1 mg, 0.07 mmol) in CH2Cl2 (1.0 mL) for 15 min. The solution was reduced in vacuo. The resulting solid was triturated with EtOAc and filtered. 1-[(2R)-2-Amino-2-cyclohexylethanoyl]-N-[5-chloro-2-(1,2,5-thiadiazol-3-yl)benzyl]-L-prolinamide hydrochloride was isolated as a solid. 1H NMR (CD3OD 400 MHz) δ 1.30 (m, 6H), 1.74 (m, 2H), 1.86 (m, 4H), 2.02 (m, 2H), 2.23 (m, 1H), 3.62 (m, 1H), 3.75 (m,1H), 3.98 (d, J=6.0 Hz, 1H), 4.42 (m, 1H), 4.64 (s, 2H), 7.46 (dd, J=2.2, 8.2 Hz, 1H), 7.62 (s, 1H), 7.74 (d, J=8.2 Hz, 1H), 8.99 (s, 1H): MS m/z=462.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]=1[O:13][CH3:14].C([Li])CCC.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>O1CCCC1.CCCCCC>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:8]1[CH:7]=[CH:6][C:5]([C:9]([CH3:11])([CH3:10])[CH3:12])=[C:4]([O:13][CH3:14])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C(C)(C)C)c1OC
Reactant: BrCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(CCCCCCBr)ccc(C(C)(C)C)c1OC
Reaction time: 3 h
Yield: 15 %

Procedure:
To 27.0 g (0.139 mole) of 1,2-dimethoxy-3-(1,1-dimethylethyl)benzene in 350 mL of anhydrous tetrahydrofuran cooled in an ice-brine bath at -5° was added. 87 mL (0.139 mole) of 1.6M butyl lithium in hexane over 30 minutes. The reaction mixture was stirred at -5° for 3 hours and then at reflux for 1 hour. After cooling in an ice bath, 21.5 mL (0.139 mole) of 1,6-dibromohexane in 75 mL of tetrahydrofuran was added dropwise. The reaction mixture was then stirred at reflux for 17 hours. The solvent was removed under reduced pressure, 50 mL of 3N hydrochloric acid was added and the product was extracted with ether. The extract was washed with sodium bicarbonate solution, dried and concentrated at reduced pressure to an oil. Purification by HPLC using 20% toluene-hexane gave 7.6 g ((15% yield) of 1-(6-bromohexyl)-2,3-dimethoxy-4-(1,1-dimethylethyl)benzene.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40](=[O:49])[NH:41][CH2:42][CH:43]1[O:48][CH2:47][CH2:46][NH:45][CH2:44]1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40](=[O:49])[NH:41][CH2:42][CH:43]1[O:48][CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:31])([F:32])[F:30])=[CH:28][C:3]=3[C:2]([F:1])([F:34])[F:33])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Product: CC(C)(C)OC(=O)NCC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
(4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-morpholin-2-ylmethyl)-carbamic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Morpholin-2-ylmethyl-carbamic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:21]=1.[Br:39][C:40]1[S:41][C:42]([C:45](O)=[O:46])=[CH:43][N:44]=1>CN(C=O)C.CCOC(C)=O>[Br:39][C:40]1[S:41][C:42]([C:45]([NH:19][C:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:21]=2)=[O:46])=[CH:43][N:44]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1-c1ccc(F)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2cnc(Br)s2)cc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
2-Chloro-1-methylpyridinium iodide (0.84 g, 3.3 mmol), DIPEA (0.78 mL, 4.4 mmol) and tert-butyl 3-amino-5-(4-fluorophenyl)-1H-pyrazole-1-carboxylate (0.5 g, 2.2 mmol) were added to a solution of 2-bromothiazole-5-carboxylic acid (0.45 g, 2.2 mmol) in DMF (6 mL). The resulting solution was stirred at RT till completion of the reaction. Then the mixture was diluted with AcOEt, washed with water, dried with Na2SO4 and concentrated. The crude product was purified by column (50%-100% AcOEt/PE gradient), yielding tert-butyl 3-(2-bromothiazole-5-carboxamido)-5-(4-fluorophenyl)-1H-pyrazole-1-carboxylate (160 mg, 20%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)c3ccncc3)sc2-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 31.6 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.07 g, 0.56 mmol) in N,N-dimethylacetamide (10 mL) was added isonicotinoyl chloride hydrochloride (0.48 g, 2.72 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.22 g, yield 32%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].OCC[CH2:18][CH2:19][NH:20][C:21](=[O:56])[C@H:22]([CH3:55])[CH2:23][C@H:24]([OH:54])[C@@H:25]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:26][C@@H:27]([CH:43]([CH3:45])[CH3:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1>CN(C1C=CN=CC=1)C.O1CCCC1>[C:12]([O:11][CH2:8][CH2:9][CH2:18][CH2:19][NH:20][C:21](=[O:56])[C@H:22]([CH3:55])[CH2:23][C@H:24]([OH:54])[C@@H:25]([NH:46][C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:26][C@@H:27]([CH:43]([CH3:45])[CH3:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCCO)C(C)C)ccc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCCOC(C)=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
30 ml of triethylamine, 2 mg of 4-(N,N'-dimethylamino)pyridine (DMAP) and 20 ml of acetic anhydride are added at 0° C. to 116 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid [N-(4-hydroxybutyl)]amide (Example 93) in 5 ml of tetrahydrofuran. The reaction solution is stirred for 18 hours at room temperature. The reaction mixture is partitioned between diethyl ether and water/saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by FC (40 g of silica gel, eluant: dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.60.
Reaction SMILES: C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.[N:15]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=N1.[C:35]([O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([OH:44])=O)(=[O:37])[CH3:36].NCC1C=CC=CN=1>ClCCl>[C:35]([O:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:41]([C:42]([NH:17][CH2:18][C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][N:15]=2)=[O:44])[CH:40]=1)(=[O:37])[CH3:36]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C(=O)NCc2ccccn2)c1
Reaction time: 0.17 h

Procedure:
93 ml (0.66 mol) of triethylamine and 160 g (0.36 mol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) are added, at ambient temperature under argon, to 65.0 g (0.36 mol) of 3-acetoxybenzoic acid in solution in 600 ml of dichloromethane. After 10 minutes, 32.5 g (0.30 mol) of 2-(aminomethyl)pyridine in solution in 200 ml of dichloromethane are added dropwise at 0° C. The reaction medium is allowed to return to ambient temperature and then stirred for 3 hours.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][CH:7]=1.C([O-])(=[O:18])C.[Na+]>CN(C)C=O>[C:10]1(/[CH:9]=[CH:8]/[C:5]2[O:6][CH:7]=[C:3]([CH2:2][OH:18])[N:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCc1coc(/C=C/c2ccccc2)n1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 91.3 %

Procedure:
A mixture of 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole (5.0 g), sodium acetate (7.48 g) and N,N-dimethylformamide (50 ml) was stirred at 90° C. for 4.5 hours. The reaction mixture was poured onto ice-water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water dried (MgSO4), and concentrated under reduced pressure. To the residue was added potassium carbonate (4.73 g), water (25 ml) and methanol (50 ml) and then the resultant was stirred for 2 hours at room temperature. The reaction mixture was concentrated, to which was added brine, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give 2-[(E)-2-phenylethenyl]-4-oxazolylmethanol (4.18 g, 91%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 94-95° C.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12](=[CH:16]N(C)C)[C:11](=O)[C:10]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)[C:27]([NH2:29])=[NH:28]>>[CH2:1]([N:8]1[C:14](=[O:15])[CH2:13][C:12]2[CH:16]=[N:28][C:27]([NH:26][C:30]3[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)=[N:29][C:11]=2[C:10]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CN(C)C=C1CC(=O)N(Cc2ccccc2)c2cc(Cl)ccc2C1=O
Product: O=C(O)c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2N(Cc2ccccc2)C(=O)C3)cc1

Procedure:
In a manner similar to that described for method I, 1-benzyl-8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-N) and 4-guanidinobenzoic acid were converted to I-6 (26%): MS m/z═471 (M+H)HRMS Calcd. for C26H19ClN4O3: 471.1223, Found 471.1310.