Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=O)[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[CH3:51][O:52][CH2:53][CH2:54][CH2:55][NH2:56]>CO>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:16](=[N:56]\[CH2:55][CH2:54][CH2:53][O:52][CH3:51])/[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: COCCCN
Solvent: CO
Product: COCCC/N=C1\C=C(N[C@H]2O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]2OC)C(=O)c2cc3c(c(O)c21)C(=O)[C@]1(OC)[C@H](O)Cc2cc(C)c(C(=O)OC)c(O)c2[C@]1(O)C3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in methanol (3 mL) was added 3-methoxypropan-1-amine (127 mg, 1.43 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The reaction was quenched by adding saturated ammonium chloride solution (25 mL). Then it was extracted with chloroform (75 mL) and washed with water (2×25 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(3-methoxypropylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (53.3 mg, 48.3%) as a dark blue solid: 1H NMR (500 MHz, CDCl3) δ 11.95 (s, 1H), 7.90 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.49 (s, 1H), 6.04 (s, 1H), 5.27 (s, 1H), 5.01-4.98 (m, 1H), 4.73 (d, J=8.6 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.75-3.72 (m, 3H), 3.69-3.68 (m, 1H), 3.62 (s, 4H), 3.46 (t, J=6.1 Hz, 2H), 3.40 (s, 3H), 3.32 (s, 4H), 3.28 (s, 1H), 3.14 (t, J=9.2 Hz, 1H), 2.48 (d, J=4.9 Hz, 1H), 2.37 (s, 3H), 2.07-2.00 (m, 2H), 1.37 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 769 (M+H); HPLC 89.1% (AUC), tR=11.35 min.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=[O:9])[CH2:4][CH2:3]1.[OH-].[Na+].C(OP([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(OCC)=O)C.[O-]CC.[Na+].C(O)C.C([O-])=O.[NH4+]>C(O)C.[C].[Pd].C(O)(=O)C>[CH2:27]([O:26][C:24]([CH2:23][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][CH2:7]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Pd]
Agent: CC[O-]
Agent: O=C[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (600 ml) of ethyl 4-oxocyclohexanecarboxylate (150 g) in ethanol was added sodium hydroxide (38.8 g) with stirring at room temperature. The reaction solution was stirred for 1 hr and ethyl diethylphosphonoacetate (192 ml) was added. To this reaction solution was added dropwise 21% sodium ethoxide/ethanol solution (363 ml) with stirring under ice-cooling over 1 hr. The stirring was continued for 1 hr and acetic acid (126 ml) was added. Then ammonium formate (111 g) and palladium carbon (5%, 15 g) were added and the mixture was stirred at 60° C. for 6 hr with heating. The reaction solution was allowed to return to room temperature and insoluble materials were filtered off through celite. The filtrate was concentrated and the obtained residue was diluted with ethyl acetate. The mixture was washed successively with 2N aqueous hydrochloric acid, water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated to give a crudely purified product (180.4 g) of the title compound.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]1[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]1=[O:62].Br[C:64]1[CH:69]=[CH:68][C:67]([C:70]([F:73])([F:72])[F:71])=[CH:66][CH:65]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:71][C:70]([F:73])([F:72])[C:67]1[CH:68]=[CH:69][C:64]([C:48]2([CH3:47])[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]2=[O:62])=[CH:65][CH:66]=1
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(C=C1CCC(C)(c2ccc(C(F)(F)F)cc2)C1=O)c1ccccc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol, 10 mol % Pd), (S)-BINAP (46 mg, 0.075 mmol, 15 mol %) and 2-methyl-5-(N-methyl-anilinomethylene)cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred forI min at room temperature. 4-bromobenzotrifluoride (225 mg, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 167 mg (93%) of the title compound. The ee was determined to be 53% by chiral HPLC analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.CC1C=C(C)C=C(C)N=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C1COCC1>[C:25]1([O:24][C:22](=[O:23])[NH:11][C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[CH:8]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cn2cc(Br)ccc2n1
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: O=C(Nc1cn2cc(Br)ccc2n1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-imidazo[1,2-a]pyridin-2-ylamine (Intermediate A1)(6.2 g, 29.2 mmol) in THF (400 ml) is added 2,4,6-trimethylpyridine (5.8 ml, 43.9 mmol). The reaction mixture is cooled to 0° C. (ice-bath) and treated dropwise with a solution of phenyl chloroformate (3.85 ml, 30.7 mmol) in THF (50 ml) over 15 minutes. The reaction mixture is stirred overnight, at room temperature, quenched with water and stirred for a further 5 minutes resulting in a white precipitate. The solid is collected by filtration and dried under vacuum (40° C.) overnight to afford the title compound [MH+ 331.99 and 333.99].
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=O)=[N:4][N:3]=1.O=P(Cl)(Cl)Cl>ClCCCl>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][N:10]=[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]3)[N:4]2[N:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nnc(N)[nH]c2=O)CC1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](c2ncc3c(=O)[nH]c(N)nn32)CC1

Procedure:
A solution of methyl trans-4-{[(3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]carbamoyl}cyclohexanecarboxylate (2.00 g, 0.00646 mol) in 1,2-dichloroethane (130 mL) was charged with POCl3 (4.2 mL, 0.045 mol) and heated to reflux for 3 h. The reaction mixture was concentrated in vacuo then partitioned between EtOAc and sat. NaHCO3 and separated. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo resulting in 1.43 g, (76% yield) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (q, J=11.79 Hz, 2H), 1.61 (q, J=12.55 Hz, 2H), 1.85-2.11 (m, 4H), 2.38 (t, J=11.87 Hz, 1H), 2.98 (t, J=11.75 Hz, 1H), 3.61 (s, 3 H), 6.17 (br. s., 2 H), 7.49 (s, 1H) and 10.90 (br. s., 1H); MS (ES+): m/z 292.25 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([C:20](OCC)=[O:21])=[C:13]([C:15](OCC)=[O:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.COCCO[AlH2-]OCCOC.[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:20][OH:21])=[C:13]([CH2:15][OH:16])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1nc2c(NCc3c(C)cccc3C)cccn2c1C(=O)OCC
Agent: COCCO[AlH2-]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1CNc1cccn2c(CO)c(CO)nc12
Temperature: 0 °C

Procedure:
To an ice cooled solution of diethyl 8-(2,6-dimethylbenzylamino)imidazo[1,2-a]pyridine-2,3-dicarboxylate (2.5 g, 6.3 mmol) in toluene (100 ml) was added Red-Al (14 ml, 45 mmol)(65% in toluene) during 3 h. The temperature was allowed to rise to room temperature and a Rochell salt solution (35 g potassium sodium tartrate in 250 ml H2O) was added. The organic layer was separated dried and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using dichloromethane: isopropylalcohol (4:1) gave 0.09 g (5%) of de desired product.
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.[CH2:16]([C:18](=[C:21]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)C=O)[CH3:17].[O:36]1C[CH2:39][CH2:38][CH2:37]1>>[CH2:16]([C:18](=[C:21]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[CH:39]=[CH:38][CH:37]=[O:36])[CH3:17]
Reactant: CCC(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Product: CCC(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (25.7 mL of 2.1M solution, 54 mmol) was added to a solution of N-isopropylcyclohexylamine in 30 mL tetrahydrofuran at -10° C. After stirring for 30 minutes and cooling to -40° C., N-ethylidenecyclohexamine (27 mL of 2M solution, 54 mmol) was added and the solution stirred for 30 minutes. The solution was further cooled to -70° C. and 2-ethyl-3,3-bis(4-fluorophenyl)- 2-propenal(4.9 g, 18 mmol) in 40 mL of tetrahydrofuran was added. The mixture was stirred for 5 hours and quenched with water. The mixture was extracted with diethyl ether, the extracts dried over magnesium sulfate and concentrated in vacuo. The residue was stirred with a mixture of 100 mL of benzene, 40 mL of water and 60 mL of acetic acid for 16 hours and diluted with 1.50 mL of water. The organic layer was separated, washed with saturated sodium bicarbonate solution, dried with magnesium sulfate and concentrated in vacuo. The residue was crystallized from petroleum ether to give 3.45 g of the title compound; m.p. =98°-99.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].CCN(CC)CC>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=1)[C:10]([O:12][CH2:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionic acid (380 mg) was dissolved in ethyl acetate (5.0 mL). A commercially available reagent of 2-bromoacetophenone (164 mg) and Et3N (115.7 μL) were added and the mixture was stirred at room temperature for 2 days. To the reaction solution was added ethyl acetate and the mixture was washed with water and a saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The product was purified by recrystallization in 15% ethyl acetate/n-hexane to obtain 2-oxo-2-phenyl-ethyl (S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionate (277 mg, yield 89% over 2 steps) as colorless crystal (LCMS m/z 452 (M+1) Rt 232 min.).
Reaction SMILES: CNN(NC)CC(O)=O.Cl.[C:11]([C:13]1([NH:19][C:20]([CH:22]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[N:12].C(C1(NC(C(N[C:69]([N:71]2[CH2:76]C[O:74][CH2:73][CH2:72]2)=O)CC(C)(C)C)=O)CC(C2C=CC=CC=2)NC(C2C=CC=CC=2)C1)#N>>[C:11]([C:13]1([NH:19][C:20]([CH:22]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:21])[CH2:14][CH2:15][N:16]([C:73](=[O:74])[CH2:72][N:71]([CH3:76])[CH3:69])[CH2:17][CH2:18]1)#[N:12]
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Agent: CNN(CC(=O)O)NC
Agent: Cl
Product: CN(C)CC(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1

Procedure:
The title compound was prepared from N.N-dimethylaminoglycine and morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride using the coupling method described in Example 1-part (d). The product was purified by reverse phase preparative HPLC to give the title compound as an off-white solid; MS, m/z 477=M+1.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8](=[O:31])[C:9]3[CH:30]=[CH:29][CH:28]=[N:27][C:10]=3[N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](C#CC4C=NC=CC=4)[CH:14]=3)[N:12]=2)=[O:6])[CH2:3][CH2:2]1.[OH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1.C(OC(C1CCCC1=O)=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH:1]1([NH:4][C:5]([C:7]2[C:8](=[O:31])[C:9]3[CH:30]=[CH:29][CH:28]=[N:27][C:10]=3[N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:32][C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[CH:14]=3)[N:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: Oc1cccnc1
Reactant: O=C(NC1CC1)c1nn(-c2cccc(C#Cc3cccnc3)c2)c2ncccc2c1=O
Agent: [Cu]I
Agent: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(NC1CC1)c1nn(-c2cccc(Oc3cccnc3)c2)c2ncccc2c1=O

Procedure:
To N-cyclopropyl-4-oxo-1-[3-(pyridin-3-ylethynyl)phenyl]-1,4-dihydropyridino[2,3-c]pyridazine-3-formamide in 50 mL of DMSO was added in sequence 3-hydroxypyridine (0.48 g, 5 mmol), 2-oxocyclopentylcarboxylic acid ethyl ester (0.3 g, 2 mmol), CuI (0.4 g, 2 mmol), Cs2CO3 (2.6 g, 8 mmol), reacted in microwave reactor at 120° C. for 6 h. After reaction was complete, extraction was performed with H2O/DCM, and organic phase was separated to obtain product 26 mg.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:25]3[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:27][CH2:26]3)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCc2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 75.1 %

Procedure:
To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.15 g, 5.4 mmol) in NMP (4 mL) and TEA (0.5 mL) was added 1-Boc-piperazine (1.05 g, 5.64 mmol). The mixture was microwaved at 100° C. for 30 minutes and then diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was subject to chromatography on silica gel, eluting by hexanes/ethyl acetate (2:1-1:1) to afford the tert-butyl 4-(7-acetoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.47 g, 75%). 1H NMR (CDCl3, 400 MHz) δ 8.56 (s, 1H), 5.99-5.96 (m, 1H), 3.78-3.73 (m, 2H), 3.53-3.50 (m, 2H), 3.15-3.07 (m, 1H), 2.99-2.92 (m, 1H), 2.63-2.54 (m, 1H), 2.04-1.93 (m, 1H), 1.48 (s, 9H). MS (APCI+) [M+H] +363.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1([OH:20])[CH2:17][CH:16]2[CH2:18][CH2:19][CH:9]1[C:10]1[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:5][CH2:6][CH2:7][C:8]1([OH:20])[CH2:17][CH:16]2[CH2:18][CH2:19][CH:9]1[C:10]1[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)CC1(O)CC2CCC1c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1(O)CC2CCC1c1ccccc12
Reaction time: 4 h
Yield: 81.3 %

Procedure:
A solution of 2.6 g of rac-(1R*,8R*,9R*)-(9-hydroxy-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-yl)-acetic acid tert-butyl ester in 10 mL of THF was added to 15.3 mL of a 1M LiAlH4 solution in THF at −10° C. The mixture was stirred for 4 h while the temperature reached slowly 0° C. The reaction was quenched by addition of a 15% aq. NaOH solution. The mixture was diluted with EtOAc, washed with H2O, dried over MgSO4 and concentrated in vacuo to obtain 1.6 g of the desired compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from 2-(t-butoxycarbonylamino)-2-methylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step B) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.42 (s,12H), 1.46 (s,3H), 1.90 (m,1H), 2.5-3.0 (m,3H), 4.48 (m,1H), 5.01 (br s,1H), 6.97 (d,8 Hz,1H), 7.1-7.3 (m,3H), 7.9 (br s,1H). FAB-MS: calculated for C19H27N3O4 361; found 362 (M+H,30%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[N:27]=[CH:26][N:25]=[C:24]([C:28](O)=[O:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1.O.CCOC(C)=O.Cl>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:23]=[C:24]([CH2:28][OH:29])[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(CO)ncn3)ccc21
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 400 mg (0.9 mMol) 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidine-4-carboxylic acid (Expl. 73) in 12 ml THF are added 137 μl (0.99 mMol) Et3N and 130 μl (0.99 mMol) iso-butyl-chloroformate. After 1 h the resulting suspension is added dropwise to 75 mg (1.98 mMol) NaBH4 in 10 ml of water. After 30 min the mixture is diluted with EtOAc and 1 M HCl, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed with 1 M NaOH, water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 1:1→1:9) gives the title compound: MS: [M+1]+=431; HPLC: AtRet=13.6.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C:11]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14]>>[NH2:15][C:13]([C:12]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:11]=1[NH:10][C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1)=[O:9])=[O:14]
Reactant: Cc1ccc(C(N)=O)c(N)c1
Reactant: O=C(O)c1csc(Br)n1
Product: Cc1ccc(C(N)=O)c(NC(=O)c2csc(Br)n2)c1

Procedure:
2-Bromo-4-thiazolecarboxylic acid and 2-amino-4-methylbenzamide are reacted in analogy to the synthesis of intermediate VI.1 to give N-[2-(aminocarbonyl)-5-methylphenyl]-2-bromo-4-thiazolecarboxamide.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[C:6]([Sn:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=1)(O)=[O:2].Cl.C[N:23](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.N>C(#N)C.C1COCC1>[C:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[C:6]([Sn:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=1)(=[O:2])[NH2:23]
Reactant: C[Sn](C)(C)c1cc(C(=O)O)c2c(c1)oc1ccccc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: C[Sn](C)(C)c1cc(C(N)=O)c2c(c1)oc1ccccc12
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a stirred solution of the stannane 306 (1.1 g, 2.96 mmol) in anhydrous acetonitrile (5 mL) and THF (15 mL) under a nitrogen atmosphere was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.13 g, 5.9 mmol) and 1-hydroxybenzotriazole hydrate (1.2 g, 8.9 mmol). The solution was stirred 30 min., then 11 mL of a 2.6M ethanolic ammonia solution was added. The resulting milky white solution was stirred an additional 30 min. before being quenched with saturated aqueous ammonium chloride. The solvents were removed under vacuum and the residue taken up in ether (75 mL) and EtOAc (75 mL). The solution was washed with water (3 times) and brine (2 times), then dried with magnesium sulfate and filtered. The solution was concentrated under vacuum and the residue was purified by flash chromatography (silica gel, 35% EtOAc in hexanes) to provide 979 mg (88% yield) of stannane 307 as a white solid.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]1[C@@H:26]2[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C@H:25]2[OH:27])[CH2:16][CH2:15]1>CC(C)=O>[CH2:14]1[CH:26]2[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]2=[O:27])[CH2:16][CH2:15]1
Reactant: O[C@@H]1c2ccccc2CN2CCC[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C1c2ccccc2CN2CCCC12
Yield: 65.7 %

Procedure:
(Method B) Jones reagent (1.1 equiv., 1.77 mmol, 0.663 mL) was added to a solution of cis-1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-10-ol (1.61 mmol, 304 mg, Example 35 below) in acetone (10 mL) in 5 minutes at room temperature (Szmuszkovicz, J.; Skaletzky, L. L. J. Org. Chem. 1967, 32, 3300). The mixture was concentrated in vacuo and H2O(15 mL) was added. The mixture was cooled with ice, basified with NaOH (10 mL, 1 N) and extracted with CH2Cl2 (3×20 mL). The combined extracts were washed with H2O(15 mL) and brine (15 mL), dried over Na2SO4 and concentrated in vacuo to give 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-10-one as a yellow oil (198 mg). The 1H NMR spectrum was identical to that obtained by method (A).