Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH3:47][CH2:48][CH:49]([C:52]1[S:53][CH:54]=[C:55]([C:57](O)=[O:58])[N:56]=1)[CH2:50][CH3:51].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:57]([C:55]3[N:56]=[C:52]([CH:49]([CH2:50][CH3:51])[CH2:48][CH3:47])[S:53][CH:54]=3)=[O:58])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CCC(CC)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CC)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 2-(pentan-3-yl)thiazole-4-carboxylic acid (example 71, step d) (0.081 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and then evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound a as clear gum. Yield 0.25 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[C:22]([Br:35])[CH:21]=1>>[Br:35][C:22]1[CH:21]=[C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([CH2:10][OH:11])[CH2:12][CH3:13])[C:5]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][N:3]=2)[CH:25]=[CH:24][C:23]=1[S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27]
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1Br
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1Br
Yield: 47 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-thiophen-2-yl-pyrimidine-4-ylamino)-butan-1-ol (425 mg, 1.5 mmol) with (RS)—S-(4-amino-2-bromphenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide (404 mg, 1.3 mmol) according to procedure 5b, the desired product is obtained in 47% yield (340 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:31]1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@H]2CC)=N[C:36]=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[CH2:31][CH3:36])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@H]2CC)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@H]1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (+/−)-5-bromo-3,6-diethyl-N-[trans-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a light yellow semi-solid. IR (liq.) 3443, 2965, 2934, 2874, 1588, 1566, 1551, 1497, 1470, 1390, 1203, 1186, 1173, 1101, 747 cm−1; OAMS supporting ions at: ESI+ 440.0; MS (EI) m/z 439 (M+); Anal. Calcd for C25H27Cl2N3: C, 68.18; H, 6.18; N, 9.54. Found: C, 68.11; H, 6.17; N, 9.29.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH:18]([CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][C:15]=3[CH:24]=2)=[O:9])=[CH:6][CH:5]=1.[ClH:27].[CH3:28]O>>[ClH:27].[NH2:1][N:2]=[CH:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH:18]([CH2:20][C:21]([O:23][CH3:28])=[O:22])[CH2:17][CH2:16][C:15]=3[CH:24]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: CO
Reactant: NN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1
Agent: Cl
Product: COC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3)ccc2O1
Reaction time: 2 h

Procedure:
A suspension of 0.35 g (1.0 mmol) of the acid from Example 48 in 20 ml methanol was cooled to 0° C. and saturated with gaseous hydrogen chloride. After 2 hours stirring it was concentrated under reduced pressure, and the remaining compound (343) was recrystallized from methanol/ether. Yield: 0.29 g (72%) of yellow crystals, m.p. 235-237° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]([O:29][CH3:30])=[C:9]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:28])=[C:18]([N:20]3[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]3)[CH:19]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:36]([NH2:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>>[CH3:38][C:37]([CH3:40])([CH3:39])[CH2:36][NH:41][C:25]([C:23]1[N:22]=[CH:21][N:20]([C:18]2[CH:19]=[C:14]([C:12](=[O:13])[NH:11][C:9]3[CH:10]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=[C:7]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:8]=3[O:29][CH3:30])[CH:15]=[CH:16][C:17]=2[CH3:28])[CH:24]=1)=[O:26]
Reactant: CC(C)(C)CN
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cnc(C(=O)O)c3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cnc(C(=O)NCC(C)(C)C)c3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
The above carboxylic acid was then coupled with neopentylamine using the coupling procedure described in Example 4 to provide the title compound. 134-136° C.; ESI MS m/z 570 [C29H39N5O5S +H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:21](=[O:23])[CH3:22]>C1COCC1>[C:21]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C)(C)C#N)cc1
Temperature: -100 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
2-(4-bromophenyl)-2-methylpropanenitrile (1 g, 4.46 mmol) is dissolved in anhydrous THF (75 ml) the solution is cooled down to −100° C. with a diethyl ether-liquid nitrogen bath, n-butyl lithium 2M in c-hexane (4.0 ml, 8.0 mmol) is added and this reaction mixture stirred for 10 min., then N-methoxy-N-methyl acetamide (1.6 g, 15.6 mmol) is added and the reaction is then left to slowly warm-up to room temperature. After work-up (washing with acidic brine) and concentration the crude mixture is purified on silica gel using a 0 to 50% ethyl acetate in hexane gradient, to give the desired compound (660 mg, 78%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.C(O[C:19](OCC)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:20])C>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[CH2:20][C:4](=[O:6])[C:3]2[C:2](=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[CH:9][CH:8]=2)[N:1]=1
Reactant: COC(=O)c1cccc(C(=O)OC)c1N
Reactant: CCOC(C)(OCC)c1ccccc1Cl
Product: COC(=O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
Alternatively, to 8 grams of dimethyl 2-aminoisophthalate was added 9.2 grams of o-chloroacetophenone diethylacetal, the mixture was heated at 140° C. for 30 minutes, then at 200° C. for additional 20 minutes, and finally heated to reflux for 18 hours. The reaction mixture was cooled, crystals separated out were collected by filtration, and recrystallized from acetone to give 2.8 grams of the title product, melting point 166°-168° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:44]=[CH:43][C:10]2[NH:11][C:12]([CH2:14][CH2:15][CH:16]3[CH2:19][CH:18]([N:20]([CH2:22][C@@H:23]4[C@H:27]5[O:28]C(C)(C)[O:30][C@H:26]5[C@H:25]([N:33]5[CH:41]=[N:40][C:39]6[C:34]5=[N:35][CH:36]=[N:37][C:38]=6[NH2:42])[O:24]4)[CH3:21])[CH2:17]3)=[N:13][C:9]=2[CH:8]=1)([CH3:6])[CH3:5].Cl.[CH3:46]O>>[NH2:42][C:38]1[N:37]=[CH:36][N:35]=[C:34]2[C:39]=1[N:40]=[CH:41][N:33]2[C@H:25]1[C@H:26]([OH:30])[C@H:27]([OH:28])[C@@H:23]([CH2:22][N:20]([CH:18]2[CH2:19][CH:16]([CH2:15][CH2:14][C:12]3[NH:11][C:10]4[CH:43]=[CH:44][C:7]([C:4]([CH2:5][CH3:46])([CH3:6])[CH2:3][O:2][CH3:1])=[CH:8][C:9]=4[N:13]=3)[CH2:17]2)[CH3:21])[O:24]1
Reactant: CO
Reactant: COCC(C)(C)c1ccc2[nH]c(CCC3CC(N(C)C[C@H]4O[C@@H](n5cnc6c(N)ncnc65)[C@@H]5OC(C)(C)O[C@@H]54)C3)nc2c1
Agent: Cl
Product: CCC(C)(COC)c1ccc2[nH]c(CCC3CC(N(C)C[C@H]4O[C@@H](n5cnc6c(N)ncnc65)[C@H](O)[C@@H]4O)C3)nc2c1
Reaction time: 2.5 h
Yield: 53 %

Procedure:
9-[(3aR,4R,6R,6aR)-6-{[(3-{2-[5-(1-Methoxy-2-methylpropan-2-yl)-1H-1,3-benzodiazol-2-yl]ethyl}cyclobutyl)(methyl)amino]methyl}-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-amine (0.485 g, 0.706 mmol, 88% pure) was dissolved in MeOH (20 ml) and conc. HCl (4.9 ml, 10 vol) was added at r.t. and the reaction left for 2.5 h. The reaction was concentrated in vacuo and the residue dissolved in the minimum amount of MeOH (˜2 ml). The reaction was quenched by addition of sat. NaHCO3 solution (10 ml) and EtOAc (30 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% DCM and 20% 2M NH3 in MeOH:80% DCM as eluent to give the product as a white foam (0.213 g, 53%): MS (ESI+) for C29H40N8O4 m/z 565.4 [M+H]+; LC purity 100% (ret. time, 2.11 min) (7 min); 1H NMR (500 MHz, d4-MeOD) δH 8.28 (d, J=4.1 Hz, 1H), 8.22 (d, J=3.2 Hz, 1H), 7.51 (s, 1H), 7.42 (dd, J=8.5, 2.1 Hz, 1H), 7.29 (dd, J=8.5, 1.5 Hz, 1H), 6.01 (t, J=3.9 Hz, 1H), 4.84-4.74 (m, 1H), 4.41-4.29 (m, 1H), 4.29-4.19 (m, 1H), 3.48 (s, 2H), 3.30 (s, 3H), 3.14-2.98 (m, 1H), 2.99-2.89 (m, 1H), 2.90-2.73 (m, 2H), 2.39 (s, 3H), 2.37-2.30 (m, 1H), 2.28-2.10 (m, 2H), 2.08-1.86 (m, 4H), 1.70-1.51 (m, 1H), 1.38 (s, 6H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[C:31]=2[CH3:37])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[C:31]=4[CH3:37])[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)c1C

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M128) (0.31 g, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (130 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[F:20][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.O>[F:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: Cc1ccc(F)cc1-c1ccc2c(F)c(N)ncc2c1
Reaction time: 16 h
Yield: 49.1 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (203 mg, 806 μmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (313 mg, 883 μmol) were dissolved together in acetonitrile (2.0 mL) at ambient temperature and the mixture stirred for 16 h, at which time LCMS indicated approx 40% conversion. The mixture was diluted with water, extracted three times into dichloromethane and the combined organic phases washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 0-6% methanol in dichloromethane) to yield the impure title compound as a pale solid (107 mg), used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:15])[CH2:13][CH:12]2[NH:14][CH:9]([CH2:10][CH2:11]2)[CH2:8]1.[CH3:16][O:17][C:18]1[C:23]2[O:24][C@H:25]([CH2:28]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][O:27][C:22]=2[CH:21]=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[C:23]2[O:24][C@@H:25]([CH2:28][N:14]3[CH:12]4[CH2:11][CH2:10][CH:9]3[CH2:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)([OH:15])[CH2:13]4)[CH2:26][O:27][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: OC1(c2ccccn2)CC2CCC(C1)N2
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Product: COc1cccc2c1O[C@@H](CN1C3CCC1CC(O)(c1ccccn1)C3)CO2
Yield: 70 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-(2-pyridinyl)-8-azabicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 70%, white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9]>[Ru].C(O)(C)C>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: [Ru]
Solvent: CC(C)O
Product: CC1(C)C(O)C(C)(C)C1O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A 2 liter Parr autoclave was charged with 100 grams of 2,2,4,4-tetramethylcyclobutane-1,3-dione, 300 grams of isopropyl alcohol, and 50 grams of 2% ruthenium on alumina (surface area=10 m2/g, purchased from BASF Catalysts). The autoclave was pressure purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 3.5 MPa (500 psig) with hydrogen. The autoclave was heated to 100° C. with stirring and held for 6 hours at 3.5 MPa (500 psig). Analysis of the product by gas chromatography indicated that 99.8% conversion of the 2,2,4,4-tetramethylcyclobutane-1,3-dione was obtained with 99.9% selectivity to 2,2,4,4-tetramethycyclobutane-1,3-diol with a cis:trans ratio of 1.54:1.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.Br[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([F:33])[CH:32]=1)[C:28]#[N:29]>>[C:28]([C:27]1[CH:26]=[C:25]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9]([CH3:22])([CH3:23])[CH:10]=[C:11]3[CH3:21])[CH:32]=[C:31]([F:33])[CH:30]=1)#[N:29]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Product: CC1=CC(C)(C)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Yield: 38.6 %

Procedure:
This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (46.4 mg, 0.14 mmol) and 3-bromo-5-fluorobenzonitrile (29.1 mg, 0.14 mmol). The crude material was purified to recrystallization from hexane to afford 15.8 mg (37%) of Compound 271. Data for Compound 271: 1H NMR (400 MHz, acetone-d6) 7.83 (app t, J=1.3, 1 H), 7.68 (dd, J=10.6, 4.0, 1 H), 7.43 (d, J=2.0, 1 H), 7.41 (dd, J=2.2, 1.2 1H) 7.35 (dd, J=8.3, 2.2, 1 H), 6.59 (d, J=8.4, 1 H), 5.35 (br s, 1 H), 5.39 (s, 1 H), 2.04 (s, 3 H), 1.28 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2>CN(C)C=O.C(N(CC)CC)C.[Pd]>[NH2:15][C:3]1[C:2]([NH2:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([OH:14])[C:7]([OH:13])=[N:8]2
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Yield: 72.3 %

Procedure:
A solution of 3 g (11,9 mmol) 6-amino-7-chloro-5-nitro-2,3-dihydroxyquinoxaline in a mixture of 80 ml dimethyl-formamide and 7,5 ml triethylamine was hydrogenated at atm. pressure using 5% Pd-C (0,5 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with 100 ml water, added 4N hydrochloric acid to pH 5-6, and the precipitate was filtered off to give 2,1 g of a crude product. Recrystallization (dimethylformamide-methanol) gave 1,95 g (74%) 5,6-diamino-7-chloro-2,3-dihydroxy-quinoxaline, m.p. >300° C. NMR (DMSO-d6): 11.6 (lH, broad s), 11.0 (lH, broad m), 6.47 (lH,s), 5.1 (2H, broad s), 4.6 (2H, broad s).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=12.C([Sn](CCCC)(CCCC)[C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)CCC>C1(C)C=CC=CC=1.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>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:2]1[C:11]2[O:10][CH2:9][C:8]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:3]=12
Reactant: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc2c(c1)COc1c-2cc2ccc(O)cc2c1-c1ccco1
Temperature: 110 °C
Reaction time: 23 h
Yield: 64.2 %

Procedure:
A mixture of 7-bromo-5H-dibenzo[c,g]chromene-3,9-diol (450 mg, 1.32 mmol), 2-(tributylstannyl)furan (0.622 ml, 1.97 mmols) and tetrakis(triphenylphosphine)palladium(0) (153 mg, 0.132 mmoles) in toluene (26 ml) is heated at 110° C. with stirring for 23 h. The mixture was filtered through celite, concentrated and purified by reverse-phase preparative HPLC to yield 280 mg (64%) of the title compound as a light brown solid. It is further purified by triturating with CH2Cl2 to yield a gray solid: mp 158–163° C.; 1H NMR (DMSO-d6): δ 5.04 (2H, s), 6.61 (1H, d, J=3.11 Hz), 6.67–6.69 (2H, m), 6.85 (1H, dd, J=8.47 Hz, J=2.33 Hz), 6.95 (1H, dd, J=8.72 Hz, J=2.27 Hz), 6.99 (1H, d, J=1.98 Hz), 7.77 (1H, d, J=8.77 Hz), 7.82 (1H, d, J=8.53 Hz), 7.85 (1H, d, J=1.32 Hz), 8.24 (1H, s), 9.70 (1H, s), 9.75 (1H, s); MS (ESI) m/z 329 (M−H)−, 331(M+H)+.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C:23](=[O:24])[N:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([CH2:17]Cl)[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[C:1]([NH:9][C@@H:10]1[C:23](=[O:24])[N:12]2[CH:13]([C:19]([O:21][CH3:22])=[O:20])[C:14](=[CH2:17])[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(CCl)CS[C@@H]2[C@H](NC(=O)c3ccccc3)C(=O)N12
Solvent: C1CCOC1
Solvent: O
Product: C=C1CS[C@@H]2[C@H](NC(=O)c3ccccc3)C(=O)N2C1C(=O)OC
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 96 %

Procedure:
To a solution of 48 ml of SmI2 in THF (0.1M), a solution of 0.8 g of methyl 7β-benzoylamino-3chloromethyl-3-cephem -4-carboxylate in 100 ml of dry THF, was added by dropping at -78° C. The resulting mixture was allowed to warm to room temperature in 0.5 hours. Water was added, and the mixture stirred for further 0.2 hours at room temperature. After the usual work-up and column chromatography, the title product was isolated in 96% yield.
Reaction SMILES: CCN(CC)CC.[CH3:8][C:9](OC(C)=O)=[O:10].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]4[N:35]=[CH:36][CH:37]=[CH:38][C:26]=4[N:25]3[C:39]=2[C:40]2[CH:45]=[CH:44][C:43]([C:46]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:49][CH2:48][CH2:47]3)=[CH:42][CH:41]=2)=[CH:18][CH:17]=1>C(Cl)Cl>[C:9]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]4[N:35]=[CH:36][CH:37]=[CH:38][C:26]=4[N:25]3[C:39]=2[C:40]2[CH:45]=[CH:44][C:43]([C:46]3([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:56])[CH3:55])[CH2:47][CH2:48][CH2:49]3)=[CH:42][CH:41]=2)=[CH:20][CH:21]=1)(=[O:10])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Yield: 59.5 %

Procedure:
Et3N (25.9 μL, 0.186 mmol) and Ac2O (6.45 μL, 0.0682 mmol) were added to a solution of tert-butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (35.4 mg, 0.0620 mmol) in DCM (1 mL) at 0° C. After stiffing the mixture for 17.5 hours at room temperature, the mixture was concentrated. The residue was diluted with sat. NaHCO3 aq. and extracted with CHCl3 (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1) to afford desired product (22.6 mg, 59.5%) as a white solid. 1HNMR (CDCl3) 400 MHz δ: 8.18-8.13 (m, 1H), 8.03-7.97 (m, 1H), 7.60-7.49 (m, 2H), 7.45-7.25 (m, 8H), 7.19-7.10 (m, 3H), 6.95 (d, J=7.8 Hz, 1H), 6.85-6.73 (m, 1H), 6.59 (dd, J=8.0, 4.8 Hz, 1H), 6.46-6.37 (m, 1H), 5.27-5.17 (m, 1H), 2.64-2.25 (m, 4H), 2.20-2.01 (m, 1H), 2.14 (s, 3H), 1.98-1.83 (m, 1H), 1.38 (br s, 9H); LCMS: 613 [M+H].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:37])[CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=2[CH2:25][CH2:26][CH3:27])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:37])[CH:15]([C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][C:18]=2[CH2:25][CH2:26][CH3:27])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCc1cc(CO)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCc1cc(C=O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.1 %

Procedure:
To a solution of 0.573 g (1.09 mmol) of the product of Example 65 dissolved in 5.0 mL of dichloromethane was added 2.86 g (32.9 mmol) of manganese dioxide and 1.15 g of finely powdered 3A molecular sieves and the reaction mixture was magnetically stirred at room temperature for 14 hours. The reaction mixture was then filtered through a bed of celite and MgSO4 and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane and applied to a silica gel flash chromatography column and then eluted with 3% MeOH--CH2Cl2. Evaporation of the purified fractions and drying in vacuo afforded 0.149 g (26%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH:16]=O.[OH-].[K+]>>[Cl:12][C:13]1[CH:14]=[C:15](/[CH:16]=[CH:2]/[C:1]([C:4]2[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)=[O:3])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: COc1ccc(C(C)=O)cn1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)cn1

Procedure:
In analogy to example 170, step 1, 5-acetyl-2-methoxypyridine was reacted with 3,5-dichlorobenzaldehyde in the presence of potassium hydroxide to give the title compound as a colourless solid.