Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[F:35][C:36]1[CH:43]=[C:42]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)[CH:41]=[CH:40][C:37]=1[CH:38]=O.O>C1COCC1>[F:35][C:36]1[CH:43]=[C:42]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)[CH:41]=[CH:40][C:37]=1[CH:38]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(-c2ccc3ccccc3c2)cc1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C=Cc2ccc(-c3ccc4ccccc4c3)cc2F)cc1
Temperature: -30 °C
Yield: 83.8 %

Procedure:
In the step, 6.30 g (15.48 mmol) of (4-fluorobenzyl)triphenylphosphonium bromide was suspended in 50 ml of THF, and the suspension was cooled to −30° C. and added with 1.74 g (=15.48 mmols) of potassium t-butoxide under stirring. After the addition was finished, the reaction solution was stirred at the same temperature for 1 hour, a 25 ml THF solution of 3.00 g (11.99 mmol) of 2-fluoro-4-naphthalene-2-yl-benzaldehyde was dropped into the same, and then the mixture was slowly heated to room temperature. After being stirred for 18 hours, the reaction mixture was added into iced water, and the mixture was extracted thrice with toluene. The extract was washed thrice with water and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellow solid of 12.73 g was purified with silica gel chromatography using heptane as the eluent to obtain 3.44 g of 2-{3-fluoro-4-[2-(4-fluorophenyl)vinyl]phenyl}naphthalene as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([N:8]=[C:9]=[O:10])[CH:5]([CH3:7])[CH3:6].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH2:23].CCN(CC)CC>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[CH2:22][NH:23][C:9](=[O:10])[NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([O:2][CH3:1])=[O:11]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Temperature: 25 °C

Procedure:
A solution of (S)-methyl-2-isocyanato-3-methylbutanoate (4.46 mL, 29.9 mmol) in CHCl3 (50 mL) was added drop-wise to a solution of (2,4-dimethoxyphenyl)-methanamine (5.00 g, 29.9 mmol) and NEt3 (8.34 mL, 59.8 mmol) in CHCl3 (100 mL) at ambient temperature. The resultant mixture was heated at 60° C. for 12 hours, then cooled to ambient temperature. The cooled reaction mixture was concentrated to provide (S)-methyl 2-(3-(2,4-dimethoxybenzyl)ureido)-3-methylbutanoate as a white solid, 1.25 g (13%). LCMS (APCI+) m/z 325 [M+H]+.
Reaction SMILES: C(OC(N1CCC[C@H](OC2C=C3C(=CC=2)C([N:25]2[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]2=[O:35])=NC=C3)C1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[C:26]1(=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33](=[O:34])[NH:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N4C(=O)c5ccccc5C4=O)nccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 293.4 %

Procedure:
A mixture of (S)-3-[1-(1,3-dioxo-1,3-dihydroisoindol-2-yl)isoquinolin-6-yloxy]piperidine-1-carboxylic acid tert-butyl ester (340 mg) in dichloromethane (14 ml) and trifluoroacetic acid (2.8 ml) was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo then flash chromatography of the residue on silica (eluent: 2-10% methanol in dichloromethane) gave (S)-2-(6-piperidin-3-yloxy)isoquinolin-1-yl]isoindole-1,3-dione (310 mg), EIMS: m/z=374.3 [M+H]+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:6]([C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To a solution of 3-trimethylsilanylethynyl-pyridin-2,6-diamine (7.0 g, 34.1 mmol) described in Manufacturing Example 13-1-2 in tetrahydrofuran (100 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 17 mL, 17 mmol) on an ice bath, which was stirred for 10 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate 3 times. The extract was dried over sodium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (3.35 g, 73.8%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]1[C@@H:17]([SH:18])[CH2:16][CH2:15][CH2:14][O:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:3]([O:10][CH2:11][C@H:12]1[C@@H:17]([S:18][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:16][CH2:15][CH2:14][O:13]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: S[C@H]1CCCO[C@H]1COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCS[C@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
0.27 g of a 55% w/w suspension of sodium hydride in mineral oil was suspended in 2 ml of dimethylformamide. To the suspension was added dropwise a solution of 1.210 g of dl-cis-2-benzyloxymethyl-3-mercaptotetrahydropyran (prepared as described in Preparation 16) in 5 ml of dimethylformamide, whilst ice-cooling the mixture. The reaction mixture was stirred at 60° C. for 1 hour, after which it was cooled to room temperature. A solution of 1.86 g of hexadecyl bromide in 3 ml of dimethylformamide was then added, and the mixture was stirred at room temperature for 1 hour. It was then poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 40 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 3:97 to 10:90 by volume was collected to give 2.284 g of the title compound as a solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([CH3:32])[C:26]=3[CH3:25])[CH2:38][CH2:37]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1C

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2,3-Dimethylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.04 (t, 1H), 6.99 (m, 2H), 5.38 (s, 2H), 3.64 (m, 4H), 2.89 (m, 2H), 2.81 (m, 2H), 2.21 (m, 9H) ppm; MS (ES) M+H expect 415.1, found 415.1.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:9]([CH:23]=[CH2:24])[C:10](N1[C@H](C(C)C)C(C)(C)OC1=O)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:27]O.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:9]([CH:23]=[CH2:24])[C:10]([OH:11])=[O:27])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: C=C[C@@H](C(=O)N1C(=O)OC(C)(C)[C@H]1C(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@@H](C(=O)O)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A cooled (0° C.) solution of (R)-3-{(R)-2-[(R)-1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-but-3-enoyl}-4-isopropyl-5,5-dimethyl-oxazolidin-2-one (400 mg, 1.04 mmol) in tetrahydrofuran/water (15 mL, 2:1) was subsequently treated with hydrogen peroxide (30% aqueous, 537 μL, 5.21 mmol) and lithium hydroxide monohydrate (87 mg, 2.09 mmol). The mixture was allowed to warm up to room temperature overnight. The reaction was quenched with sodium metabisulfite until Kl/starch paper negative. After stirring for 2 h at room temperature the volatiles were removed in vacuo. The mixture was then diluted with water and the pH was adjusted with potassium carbonate. The aqueous layer was washed with dichloromethane (2×20 mL) and acidified with hydrochloric acid (pH˜1) then extracted with ethyl acetate (3×30 mL). All ethyl acetate layers were combined and the volatiles were removed in vacuo to afford the title compound (200 mg, 79%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.09 (s, 3H), 0.11 (s, 3H), 0.89 (s, 9H), 1.22 (d, J=6.0 Hz, 3H), 3.07 (t, J=8.7 Hz, 4.11 (pentet, J=6.5 Hz, 1H), 5.20-5.35 (m, 2H), 5.70-5.90 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C=O)C>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][S:29]([CH3:28])(=[O:31])=[O:30])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 25 °C

Procedure:
To a solution of 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.19 g, 0.5 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (92 uL, 1.2 mmol) and triethylamine (0.2 mL, 1.5 mmol). The reaction mixture was stirred at 60C for 1 h, at 110° C. for 16 h, allowed to cool to room temperature and partitioned between EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography (1:1 of EtOAc/hexanes) provided the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 467 (M+1).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[I:10]N1C(=O)CCC1=O.C(#N)C>O>[I:10][C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ncc2cc[nH]c2n1
Solvent: CC#N
Solvent: O
Product: Ic1c[nH]c2ncncc12
Reaction time: 3 h
Yield: 85 %

Procedure:
In a 250 mL round-bottomed flask, 7H-pyrrolo[2,3-d]pyrimidine (4.34 g, 36.4 mmol, Eq: 1.00) and N-iodosuccinimide (8.61 g, 38.3 mmol, Eq: 1.05) were combined with acetonitrile (60 ml) to give a light brown suspension. The reaction mixture was stirred for 3 h. The reaction mixture was poured into 100 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was triturated with diethyl ether (2×25 mL) to give 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (7.58 g, 85%) as orange solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[C:31](O)=[O:32]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31]([CH:27]5[CH2:28][CH2:29][CH2:30][O:26]5)=[O:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CCCO1

Procedure:
The title compound, white solid (17.6 mg, 60.3%), MS (ISP) m/z=429.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and tetrahydrofuran-2-carboxylic acid
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18](O)=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[F:6][C:7]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: NOCCO
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)NOCCO)c(F)c1
Yield: 61 %

Procedure:
2-(Aminooxy)ethanol, 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and DMT-MM were reacted in MeOH as outlined in example 33, step D. Further purification by flash chromatography on silica gel (EtOAc followed by 10% MeOH/CH2Cl2) gave 4-(2-fluoro-4-methylanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (61%) as a cream solid; m.p. (EtOAc/Hexane) 110-115° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.62 (br s, 1H), 9.21 (br s, 1H), 8.11 (s, 1H), 7.31 (t, J=8.3 Hz, 1H), 7.17 (d, J=11.8 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 5.38 (s, 1H), 4.75 (t, J=5.3 Hz, 1H), 3.91 (t, J=4.9 Hz, 2H), 3.62 (q, J=4.9 Hz, 2H), 3.35 (s, 3 H, obscured), 2.32 (s, 3H). LCMS (ACPI−) 334 (50%). Anal. Calcd for C16H18FN3O4.0.25 H2O: C, 56.6; H, 5.5; N, 12.4. Found C, 56.5; H, 5.5; N, 12.1.
Reaction SMILES: [CH:1](/[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)=C\C1C=CC=CC=1.C(Cl)Cl.C[OH:27]>>[CH:1]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)=[O:27]
Reactant: CO
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2)c2ccccc12
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of (E)-methyl 4-styryl-1-naphthoate (Preparation 2, 1.31 g, 2.0 mmol) in 3:1 CH2Cl2/MeOH (40 mL) was cooled to −78° C. Sample was subjected to ozonylysis for 10 minutes until blue color was noted. Reaction was quenched with dimethyl sulfide (400 μL) and allowed to warm to room temperature. The residue was purified by chromatography on silica gel eluting from 100% heptane to 50:50 EtOAc:heptane to afford a solid (0.78 g, 80%). 1H NMR (CDCl3) δ ppm: 10.52 (1H), 9.28 (1H), 8.83 (1H), 8.22 (1H), 8.04 (1H), 7.79-7.70 (2H), 4.08 (3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[N:16]([CH3:41])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH2:39][CH3:40])[N:18]=3)([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:45]>C1COCC1.C1OCCOCCOCCOCCOC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[N:16]([CH3:41])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH2:39][CH3:40])[N:18]=3)([O:14][CH3:45])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 192 h

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g, 1.78 mmol) in THF (20 mL) was added NaH (86 mg, 2.14 mmol, 60% dispersion in mineral oil) and the resulting mixture allowed to stir for 5 min before the addition of iodomethane (135 μL, 2.14 mmol) and 15-Crown-5 (4 drops). The resulting mixture was stirred for 3 h before further NaH (86 mg, 2.14 mmol) and iodomethane (135 μL, 2.14 mmol) were added. The resulting mixture was allowed to stir for 8 days then partitioned between 2-methyl THF and H2O. The organic phase was washed with sat. aq. NaHCO3 and brine, then dried (Na2SO4) and concentrated in vacuo affording 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-methoxypiperidine-1-carboxylic acid tert-butyl ester. LCMS (method H): RT 3.28 min [M+H]+ 577.5
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:10]([O-:12])=[O:11].[Na+].Cl>O.CCOCC>[N+:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])N1CCc2ccccc21
Yield: 111.1 %

Procedure:
Following the procedure of Example 1, step 1, indoline (20 g, 170 mmol), sodium nitrite (14 g, 200 mmol), concentrated hydrochloric acid (30 mL) in water (70 mL) and ether (120 mL) provided 1-nitroindoline (31 g), which was reduced with zinc dust (˜50 g) in acetic acid (500 mL) to provide 1-aminoindoline (29 g). A mixture of 1-aminoindoline (17 g, 130 mmol), cycloheptanone (15 mL, 130 mmol), and concentrated sulfuric acid (20 mL) in water (180 mL) provided 8.2 g of 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole. MS (ESI) m/z 212.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28].[BH4-].[Na+].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:30][CH:27]([CH3:29])[CH3:28])[CH:18]=2)[N:6]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Reactant: CC(C)N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)NCc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Yield: 92.8 %

Procedure:
A small vial (2 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (27.9 mg, 77.6 □mol). To this was added half of a solution of isopropylamine (10 mg, 0.169 mmol) in methanol (1 ml). After stirring for two hours sodium borohydride (7.4 mg) was added, then after another 20 minutes 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 29 mg (93%) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.26 Hz, 6H) 1.63-1.68 (m, 1H) 2.59-2.63 (m, 1H) 2.93 (s, 3H) 3.57 (d, J=7.2 Hz, 2H) 6.60 (br. s., 2H) 7.05 (d, J=8.8 Hz, 2H) 7.12 (t, J=74.18 Hz, 1H) 7.15-7.18 (m, 2H) 7.22 (t, J=4.2 Hz, 1H) 7.35 (s, 1H) 7.42 (d, J=8.8 Hz, 2H); MS (ES) m/z 401.2 [M−H]−
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH2:54])[S:52][CH:53]=1)[CH3:45].C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH:54][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[S:52][CH:53]=1)[CH3:45]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (prepared as in Example 22A, 263.0 mg, 1.0 mmol) in N,N-dimethylformamide (10 mL) was treated with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (379 mg, 1.0 mmol), (2-amino-thiazol-4-yl)-acetic acid ethyl ester (279 mg, 1.5 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol). The reaction mixture was stirred at 25° C. for 5 h. The reaction mixture was then poured into a 2N aqueous hydrochloric acid solution (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (1×75 mL), a saturated aqueous sodium bicarbonate solution (1×75 mL), and a saturated aqueous sodium chloride solution (3×75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (70.0 mg, 39.4%) as a pale yellow oil: FAB-HRMS m/e calcd for C21H25N3O5S (M+H)+ 432.1593, found 432.1595.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:22]=[CH:21][C:14]([C:15](N(OC)C)=[O:16])=[CH:13][CH:12]=2)=[N:9][CH:10]=1>O1CCCC1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:22]=[CH:21][C:14]([C:15](=[O:16])[CH3:1])=[CH:13][CH:12]=2)=[N:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(-c2ccc(F)cn2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc(F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (3 M in tetrahydrofuran) (2.1 mL, 6.2 mmol) was added to a −78° C. solution of 4-(5-fluoropyridin-2-yl)-N-methoxy-N-methylbenzamide (800 mg, 3.1 mmol) in tetrahydrofuran (20 mL). After stirring at 0° C. for 30 min, the reaction mixture was quenched with methanol and saturated aqueous ammonium chloride. The organic layer was dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-15% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1NC(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-(R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-fluorobenzoyl chloride. LCMS: RT=1.57 minutes, MS: 382 (M+H).