Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]1([CH:7]2[CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:10][CH2:11][N:12]2[C:28](=[O:30])[CH3:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(c4ccccc4)C3)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made the following manner: 55 mg of 3-phenyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine were dissolved in THF, 2 equiv. of acetylchloride and 2 equiv. of N,N-diisoproylethylamine were added. The reaction was shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentratation in vacuo afforded 43 mg of the title compound as hydrochloride salt. Yield 67%, ES MS m/z 419
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]3[CH2:19][CH2:18][CH2:17][CH:11]3[C:12](=S)[NH:13][C:14]=2[CH:15]=1.[NH3:20]>>[NH2:20][C:12]1[CH:11]2[CH2:17][CH2:18][CH2:19][CH:10]2[C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:15][C:14]=2[N:13]=1
Reactant: N
Reactant: S=C1Nc2cc(-c3ccco3)ccc2C2CCCC12
Product: NC1=Nc2cc(-c3ccco3)ccc2C2CCCC12
Yield: 82 %

Procedure:
Analogously to Example 4, 7-(2-furanyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (95 mg, 0.35 mmol) in 7N methanolic ammonia solution (30 ml) is reacted to form 72 mg (82%) of product.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C=O)C>>[C:21]1([S:27]([N:18]2[CH2:17][CH:16]=[C:15]([C:7]3[N:6]=[C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[N:9]4[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=34)[CH2:20][CH2:19]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCNCC3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(S(=O)(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-cyclobutyl-1-(1,2,3,6-tetrahydropyridin-4-yl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.0742 mmol), benzenesulfonyl chloride (9.48 uL, 0.0742 mmol), DIEA (0.0647 mL, 0.371 mmol) and DMF (1 mL, 0.01 mol) was stirred at rt for 10 min. The reaction mixture was directly given for Gilson HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=2.03 (dt, J=8.84, 2.65 Hz, 1H) 2.09-2.24 (m, 1H) 239-2.59 (m, 4H) 2.81 (d, J=1.77 Hz, 2H) 3.50 (t, J=5.68 Hz, 2H) 3.72 (quin, J=8.53 Hz, 1H) 3.85 (t, J=2.91 Hz, 2H) 5.93 (t, J=1.52 Hz, 1H) 6.82 (d, J=5.56 Hz, 1H) 6.99 (d, J=5.56 Hz, 1H) 7.55-7.69 (m, 3H) 7.86-7.90 (m, 2H). MS (ES+): m/z 409.99 (100) [MH+]. HPLC: tR=2.29 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]([F:29])([F:28])[F:27])=O)(=O)OC.O.[NH2:31][NH2:32]>>[F:25][C:21]1[C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:32][N:31]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1cccc(F)c1C(F)(F)F)OC
Reactant: NN
Solvent: O
Product: Fc1cccc(-c2cc3c(nn2)C2CCC3C2)c1C(F)(F)F

Procedure:
light-yellow gum. MS (EI): 308.1 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(3-Fluoro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(N(C)C)=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:26])[N:23]([CH3:24])[CH3:25])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)N(C)C)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CN(C)C(=O)c1cccc(NCC2CCCC2)c1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CN(C)C(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N,N-dimethyl-benzamide and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:7]1[CH:8]=[C:9]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:26])[CH:10]=[CH:11][C:12]=1[F:13])(=O)[CH3:5].CO>N1C=CC=CC=1.C(Cl)(Cl)Cl>[F:13][C:12]1[CH:11]=[CH:10][C:9]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:26])=[CH:8][C:7]=1[C:4](=[N:2][OH:3])[CH3:5]
Reactant: CC(=O)c1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=NO)c1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
LCMS purity: 99.03%, m/z=314.0 (M+1) Hydroxylamine hydrochloride (145 mg, 2.106 mmol) in pyridine (5 mL) was added to 1-(3-acetyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (220 mg, 0.702 mmol) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 18 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ethylacetate and water. The organic layer was dried over Na2SO4 and concentrated to afford 220 mg of 1-[4-Fluoro-3-(1-hydroxyimino-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (90% yield).
Reaction SMILES: I[CH3:2].[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[C:11]([CH3:14])[CH:12]=2)[N:7]=[C:6]([CH3:25])[CH:5]=1>CN(C)C=O>[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][N:16]([CH3:2])[C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[C:11]([CH3:14])[CH:12]=2)[N:7]=[C:6]([CH3:25])[CH:5]=1
Reactant: CI
Reactant: Cc1cc(Cl)c2cc(C)c(CNc3ccc(C#N)cc3)cc2n1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c2cc(C)c(CN(C)c3ccc(C#N)cc3)cc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
Iodomethane (46 mg, 0.33 mmol) was added to a solution of 4-[(4-chloro-2,6-dimethyl-quinolin-7-ylmethyl)-amino]-benzonitrile (example 101b, 70 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and 1 h at r.t., then partitioned between dichloromethane and 1 M aq. sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate 2:1, then 1:1) afforded the title compound (63 mg, 86%). White solid, ISP-MS: m/e=336.2 ([M+H]+).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:46]([CH3:48])[CH3:47])[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34][C:33]=3[O:41][C:42]([F:45])([F:44])[F:43])=[CH:28][CH:27]=2)[N:25]=1)=[O:15])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:73]([O:77][C:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]2[CH:91]=[CH:90][C:89]([NH2:92])=[CH:88][N:87]=2)[C@H:82]([CH3:93])[CH2:81]1)=[O:79])([CH3:76])([CH3:75])[CH3:74].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[C:73]([O:77][C:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]2[CH:91]=[CH:90][C:89]([NH:92][C:38]([C:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:28]=[CH:27][C:26]([C:24]5[N:25]=[C:21]([C@@H:17]6[CH2:18][CH2:19][CH2:20][N:16]6[C:14](=[O:15])[C@@H:13]([NH:12][C:10]([O:9][CH3:8])=[O:11])[CH:46]([CH3:48])[CH3:47])[NH:22][CH:23]=5)=[CH:31][CH:30]=4)=[C:33]([O:41][C:42]([F:44])([F:45])[F:43])[CH:34]=3)=[O:40])=[CH:88][N:87]=2)[C@H:82]([CH3:93])[CH2:81]1)=[O:79])([CH3:76])([CH3:74])[CH3:75]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)O)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylic acid TFA (600 mg, 0.9 mmol) and HATU (364 mg, 0.96 mmol) in DMA (8 mL) was stirred at RT for 15 min and then 0.5 M (R)-4-(5-amino-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester in DMA (1.7 mL) was added followed by N,N-diisopropylethylamine (0.76 mL, 4.36 mmol). The resulting mixture was heated at 55° C. overnight, washed with EtOAc (100 mL) and water (25 mL). The organic layer was washed again with water and then with brine, dried over sodium sulfate, filtered, and concentrated to yield a dark reddish oil which was purified by silica gel chromatography (40 g silica column, 0-80% hexane:EtOAc) to provide (R)-4-{5-[(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carbonyl)-amino]-pyridin-2-yl}-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (646 mg) as a light brownish solid.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5](SC)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1(C)C(C)=CC=CC=1.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>C(O)(=O)C.C(O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[CH2:22][CH2:23]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[CH2:22][CH2:23]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: CSC1=Nc2ccccc2N(C)c2cscc21
Reactant: OCCN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CN1c2ccccc2N=C(N2CCN(CCO)CC2)c2cscc21

Procedure:
A mixture comprising 2.6 g. of 4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine (U.S. Pat. No. 3,951,981 -- Ex. 7), 2.6 g. of hydroxyethylpiperazine, 3 drops of acetic acid and 15 ml. of xylene is stirred and refluxed overnight. The mixture is evaporated, washed with water and the residue dissolved in 50 ml. of 2N acetic acid. The solution is filtered. The filtrate is made alkaline with ammonium hydroxide and extracted with chloroform. The extract is dried over magnesium sulfate, filtered and evaporated giving a dark colored oil. This oil is dissolved in 20 ml. of ethanol. A mixture of 1.2 g. of fumaric acid in 25 ml. of ethanol is added and on standing a yellow solid separates. This solid is recrystallized from 75 ml. of ethanol giving the desired product, m.p. 192°-193° C. as the fumarate salt.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>O1CCCC1>[O:10]=[C:6]([CH3:5])[CH2:7][C:8]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:9]
Reactant: CC(C)N
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73684.2 %

Procedure:
32 ml (0.38 mmol) of isopropylamine were added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 40.36 g (0.28 mol, 79% yield) of a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][C:18](=[O:20])[CH:19]=2)=[CH:10][CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:17][C:18](=[O:20])[CH:19]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
[4-(6-Morpholine-4-yl-4-oxo-4H-pyran-2yl)-phenyl]carbamic acid tert-butyl ester (402 mg, 1.08 mmol) was dissolved in 25% trifluoroacetic acid in dichloromethane mixture (5 ml) and stirred for 1 hour at room temperature. The reaction was concentrated in vacuo, precipitated with saturated NaHCO3, filtered, washed with diethyl ether and dried to yield (4-amino-phenyl)-6-morpholin-4-yl-pyran-4-one as a yellow solid (230 mg, 79%). m/z (LC-MS, ESP): 273 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[NH2:41]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:41][C:35]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=3[F:33])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1ccc(F)c(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 51.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.250 g, 0.546 mmol) obtained in Example 145, step 2 and 2-fluoro-5-methylphenylamine (0.150 mL, 1.37 mmol), the title compound (0.155 g, 52%) was obtained.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][C:10](O)=[C:9]2O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: O=C1CC(O)=C(O)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)CCCC2=O
Temperature: 25 °C

Procedure:
3.30 ml of allyl bromide was added to a mixture consisting of 5.62 g of 6-hydroxy-3,4-dihydroxynaphthalen-1(2H)-one, 5.27 g of potassium carbonate, and 60 ml of acetone. The obtained mixture was heated to reflux under nitrogen atmosphere overnight. The reaction solution was cooled to a room temperature, and the precipitate was removed by filtration. The solvent was removed under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 6.35 g of the subject compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[CH2:17]([Li])CCC.CI>C1COCC1.CCOCC>[CH3:17][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]
Reactant: [Li]CCCC
Reactant: Nc1ccccc1-c1nc2ccccc2[nH]1
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1c(-c2ccccc2N)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(1H-benzo[d]imidazol-2-yl)benzenamine (525 mg, 2.5 mmol) in 5 mL dry THF was cooled to −78 degrees before 1 mL n-Bu-Li (2.5 mmol, 2.5 N in hexanes) was added via a syringe. The reaction was stirred at −78 degrees for 20 min and MeI (360 mg, 2.6 mmol) was added. The reaction was warmed to r.t. gradually and kept at room temperature for another hour. The reaction crude was diluted with 25 mL ether and the resulted suspension was filtered off the solid. The crude product was isolated after the solvent was removed from the collected filtrate to product 510 mg of 2-(1-methyl-1H-benzo[d]imidazol-2-yl)benzenamine in greater than 95% purity (MS, M++H=224.1).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([N:10]1C(=O)C2C(=CC=CC=2)C1=O)[C@@H:5]([CH3:9])[CH2:6][CH:7]=[CH2:8]>Cl.C(O)(=O)C>[NH2:10][C@@H:4]([C@@H:5]([CH3:9])[CH2:6][CH:7]=[CH2:8])[C:3]([OH:21])=[O:2]
Reactant: C=CC[C@H](C)[C@@H](C(=O)OC)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: C=CC[C@H](C)[C@H](N)C(=O)O
Temperature: 25 °C
Yield: 50 %

Procedure:
(2S,3S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-hex-5-enoic acid methyl ester (2.01 g, 7.00 mmol) is dissolved in a 2:1 mixture of 6 N hydrochloric acid and glacial acetic acid (62.5 mL), and the solution is heated at reflux for 4 h. The solution is cooled to room temperature and concentrated under reduced pressure. The product is taken up in water and the solution is filtered. The filtrate is concentrated under reduced pressure and the residue is dissolved in water, then the solution is applied to a column of Amberlite™ IR 120 cation exchange resin (NH4+ form.). The column is washed with water (2.5 L), then eluted with aqueous ammonia solution (2.5 L). The eluate is boiled until no ammonia can be detected, then concentrated under reduced pressure affording the title compound (0.5 g, 3.50 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([OH:18])=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19](=O)(O)[O-].[Na+].O1CCOCC1.COS(OC)(=O)=O>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([O:18][CH3:19])=[C:13]([C:14]#[N:15])[C:16]#[N:17])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOc1cc(C(O)=C(C#N)C#N)ccc1OC
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(C(OC)=C(C#N)C#N)ccc1OC
Temperature: 85 °C
Yield: 54.5 %

Procedure:
2-((3-ethoxy-4-methoxyphenyl)(hydroxy)methylene)malononitrile (25.5 mmol) and sodium bicarbonate (17 g, 204 mmol) were combined in a solution of 1,4-dioxane (48 mL) and water (8 mL). Dimethylsulphate (17 mL, 178 mmol) was slowly added and the reaction was heated to 80-90° C. for 2 hours. The reaction was cooled to RT, water was added, and the aqueous phase extracted three times with EtOAc (200 mL). The organic phases were combined, dried with MgSO4, and filtered to give a red oil. The oil was purified by silica gel chromatography (10% EtOAc/Hexanes, Rf˜0.1) to give a white solid (3.59 g, 54.5% yield over three steps). ESI-MS (M+H)+ m/z calcd 259.1, found 259.0.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH:5]([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH2:4][NH:3]1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[O:1]=[C:2]1[CH:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH2:7][S:6][CH:5]([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH2:4][N:3]1[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCC(c2ccsc2)SCC1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
To a suspension of 4.1 g of 5-oxo-6-phthalimido-2-(3-thienyl)perhydro-1,4-thiazepine [prepared as described in step (e) above] in 60 ml of dimethylformamide were added dropwise 2.2 g of t-butyl bromoacetate, followed by 593 mg of a 55% w/w suspension of sodium hydride in oil at 0° to -5° C. under a stream of nitrogen. The reaction mixture was stirred at 0° C. for 20 minutes and then poured into a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated off. The semi-solid residue was collected by filtration using ethyl acetate and diisopropyl ether, to yield 3.7 g of the title compound, melting at 157°-160° C. (with decomposition).
Reaction SMILES: [CH:1]1([C@H:6]2[C:33](=[O:34])[N:32]3[CH2:35][C@@H:29]([CH2:30][C@H:31]3[C:36]([NH:38][C@:39]3([C:44](=[O:52])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[CH2:41][C@H:40]3[CH:42]=[CH2:43])=[O:37])[O:28][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([OH:27])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:53][CH2:54][CH2:55][C@H:10]3[O:9][C:8](=[O:56])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:57](OC(=O)C)(=[O:59])[CH3:58]>N1C=CC=CC=1>[C:57]([O:27][C:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=[C:18]2[O:28][C@H:29]3[CH2:35][N:32]([C:33](=[O:34])[C@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[NH:7][C:8](=[O:56])[O:9][C@@H:10]4[CH2:55][CH2:54][CH2:53][C@H:11]4[CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][C:17]=12)[C@H:31]([C:36](=[O:37])[NH:38][C@:39]1([C:44](=[O:52])[NH:45][S:46]([CH:49]2[CH2:50][CH2:51]2)(=[O:47])=[O:48])[CH2:41][C@H:40]1[CH:42]=[CH2:43])[CH2:30]3)(=[O:59])[CH3:58]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(=O)OC(C)=O
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OC(C)=O)O2)C(=O)NS(=O)(=O)C1CC1
Solvent: c1ccncc1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OC(C)=O)O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C

Procedure:
To a solution of (3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (Example 17) (35 mg) in pyridine (0.44 mL) was added acetic anhydride (42 μl). The reaction mixture was stirred at room temperature until disappearance of the starting material. The reaction was quenched with water and extracted with ethyl acetate (3×). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40% ACN/0.05% TFA water to 100%) afforded the desired product (26 mg) after workup with NaHCO3 and ethyl acetate. LRMS (ES+) m/z 832.8 (M+H)+.