Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[C:100]1([C:106]2[S:107][CH:108]=[C:109]([CH2:111][NH2:112])[N:110]=2)[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:112][CH2:111][C:109]4[N:110]=[C:106]([C:100]5[CH:101]=[CH:102][CH:103]=[CH:104][CH:105]=5)[S:107][CH:108]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NCc1csc(-c2ccccc2)n1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6csc(-c7ccccc7)n6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with C-(2-phenyl-thiazol-4-yl)-methylamine. MS (ES+) m/e 812.46 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:37]([OH:39])=O)[CH2:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[C:28]([NH2:35])=[C:27]([Cl:36])[CH:26]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:40]=1.[CH2:41]([O:43][C:44](=[O:58])[CH2:45][N:46]1[CH2:51][CH2:50][N:49]([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:48][CH2:47]1)[CH3:42]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C@H:23]([CH2:24][C:25]4[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[C:28]([NH2:35])=[C:27]([Cl:36])[CH:26]=4)[C:37]([N:55]4[CH2:56][CH2:57][CH:52]([N:49]5[CH2:50][CH2:51][N:46]([CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:58])[CH2:47][CH2:48]5)[CH2:53][CH2:54]4)=[O:39])=[O:21])[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:40]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)O)CC1)C(=O)N2
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Product: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5cc(OC)ccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 9 from 100 mg (0.17 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 49 mg (0.19 mmol) ethyl(4-piperidin-4-yl-piperazin-1-yl)-acetate.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH:20][C:21]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[C:26]([CH3:34])[CH:25]=2)=[O:22])[CH:17]([CH3:19])[CH3:18])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:16]([NH:20][C:21]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[C:26]([CH3:34])[CH:25]=2)=[O:22])[CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(=O)N[C@H](C(=O)N2CCC(Cc3ccccc3)CC2)C(C)C)c2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)N[C@H](CN2CCC(Cc3ccccc3)CC2)C(C)C)c2ccccc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-[(S)-1-(4-benzyl-piperidine-1-carbonyl)-2-methyl-propyl]-3-(2-methyl-quinolin-4-yl)-urea in THF (10 mL) is added at 0° C. LiAlH4 (40 mg, 1 mmol). The reaction mixture is stirred at room temperature for 15 h and then quenched with EtOAc (1 mL) and sat. NaHCO3 (0.2 mL). The resulting precipitate is removed by filtration and the filtercake washed with MeOH (2×5 mL). The mixture is evaporated and the residue purified by TLC (SiO2, CH2Cl2/MeOH, 5/1) to provide the title compound.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][F:32])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[F:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:16][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:18][CH:19]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(CF)cc3)cc2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(CF)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 65A. mp 153-155° C.; IR (KBr) cm−1: 3117, 3028, 1731, 1512, 1471, 1231; 400 MHz 1H NMR (DMSO-d6): δ 12.94 (br(s), 1H), 7.39-7.47 (m, 2H), 7.01-7.20 (m, 5H); 6.82-6.89 (m, 2H) 6.56 (d, 1H, J=8.4 Hz), 4.99 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J=7.5 Hz), 2.67 (t, 2H, J=7.5 Hz), 1.89 (pentet, 2H); MS m/z 437 (M−1). Anal. Calc'd for C25H23FO4S: C, 68.48; H, 5.29. found: C, 68.24; H, 5.15.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12>CN(C)C=O>[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH:68][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 46.6 %

Procedure:
DIEA (0.035 mL, 0.20 mmol) was added to 8-(trifluoromethoxy)-3-carboxy-coumarin (0.050 g, 0.18 mmol) and HATU (0.076 g, 0.20 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-imidazo[1,2-a]pyridin-2-yl-phenylamine (0.038 g, 0.18 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.039 g of 1541B in a 46% yield: LCMS (ESI) m/z 466 (MH+).
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20].O>CN(C=O)C>[C:19]([O:22][CH2:23][CH2:24][S:12][C:9]1[CH:8]=[CH:7][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:11][CH:10]=1)(=[O:21])[CH3:20]
Reactant: CCC(C)Sc1ccc(S)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Sc1ccc(SCCOC(C)=O)cc1

Procedure:
To a mixture of 4-(1-methylpropylthio)benzenethiol (53.7 g, 271.0 mmol) and potassium carbonate (49.4 g, 358.0 mmol) in DMF under N2 and with stirring is added dropwise 2-bromoethyl acetate (34.0 ml, 298.0 mmol). The mixture is stirred at RT overnight, after which water is added and the mixture is extracted with ether. The combined organic layers are washed with water and brine, dried, the solvent removed and the residue purified by distillation to give 2-[4-(1-methylpropylthio)phenylthio]ethyl acetate. To the acetate (60.9 g, 214.0 mmol) in 200 ml of ethanol is added 50% sodium hydroxide (20 ml). The reaction mixture is stirred at RT for 7 hours and is then neutralized by addition of 10% sulfuric acid and extracted with ether. The organic layer is washed with water and brine, dried and the solvent removed to give 2-[4-(1methylpropylthio)phenylthio]ethanol.
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:8]1[CH2:9][C@@H:6]([N:18]=[N+:19]=[N-:20])[CH2:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 85 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (29 g, 109 mmol) in DMF (100 mL) was added sodium azide (5.68 mL, 162 mmol) portionwise and the mixture stirred at 85° C. for 18 h. After cooling, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic was washed with water (2×100 mL) and brine, dried over Na2SO4 and evaporated in vacuo to give the desired product tert-butyl(cis-3-azidocyclobutyl)carbamate (22 g, 104 mmol, 95% yield) that was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.68 (br. s., 1 H), 3.87 (br. s., 1 H), 3.44-3.68 (m, 1 H), 2.75 (d, J=6.85 Hz, 2 H), 1.90 (q, J=9.19 Hz, 2 H), 1.44 (s, 10 H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21](=[N:27]O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]1[O:13][N:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:20]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1ccc(F)c(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2ccc(F)c(F)c2F)n1
Yield: 12 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(2,3,4-trifluorophenyl)acetic acid (0.360 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.065 g (12%) of ethyl 5-(2,3,4-trifluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: C(S[C:9]1[N:13]=[C:12]([CH3:14])[N:11]([C:15]2[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=2)[N:10]=1)C1C=CC=CC=1.O.[S:26]([Cl:30])(Cl)(=[O:28])=[O:27]>ClCCl>[CH3:22][O:21][C:19]1[N:18]=[C:17]([O:23][CH3:24])[N:16]=[C:15]([N:11]2[C:12]([CH3:14])=[N:13][C:9]([S:26]([Cl:30])(=[O:28])=[O:27])=[N:10]2)[N:20]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1nc(OC)nc(-n2nc(SCc3ccccc3)nc2C)n1
Solvent: ClCCl
Solvent: O
Product: COc1nc(OC)nc(-n2nc(S(=O)(=O)Cl)nc2C)n1
Temperature: 5 °C

Procedure:
A solution of 3-benzylthio-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)-5-methyl-1,2,4-triazole (6 g) in dichloromethane (60 ml) was treated with silica gel (14 g) 60-120 mesh and water (2.8 g). Sulphuryl chloride (10.6 ml) in dichloromethane (12 ml) was added dropwise with stirring whilst maintaining a temperature of 5° C. for 2 hours. The silica gel was filtered off, washed with dichloromethane (150 ml) and ethyl acetate (100 ml), and the combined washings were extracted with water and aqueous sodium bicarbonate. The organic layer was dried and evaporated at 40° C. in vacuo. The residue was triturated with ether and filtered to give 3 g of the desired product.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[O:15][N:14]=[C:13]([CH3:16])[N:12]=1.[Li+].[BH4-]>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[N:12]=2)=[C:4]([CH2:3][OH:2])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)ccc1-c1nc(C)no1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Cl)cc2CO)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.7 %

Procedure:
To a mixture of impure 5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzoic acid methyl ester (900 mg) in THF (10.0 mL) is added a solution of 2M LiBH4 in THF (3.6 mL, 7.2 mmol). The reaction mixture is stirred at room temperature for 16 hours and then quenched with 1M HCl aq (50 mL). The quenched reaction mixture is extracted with EtOAc (50 mL×2) and the combined organic layers are dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 35% EtOAc in heptanes as the eluent to afford [5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-phenyl]-methanol (78 mg) and the regiosiomer [4-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-phenyl]-methanol (60 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCOC(C)=O>C1COCC1.CCCCCC.CCOC(C)=O.O>[OH:25][C:19]1([CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]([OH:18])=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)C(c1ccccc1)C1(O)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a dried 250 mL round bottom flask containing 2 M lithium diisopropyl amide in THF (2 eq.) in THF (329 mL) at 0° C., was added phenyl acetic acid (6 g, 44.07 mmol). The resulting mixture was then stirred at ambient temperature for 30 minutes. The reaction mixture was cooled to −78° C. and cyclohexanone (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (5.49 mL, 52.88 mmol, 1.2 eq.) in THF (181 mL) was added dropwise. The resulting mixture was stirred at −78° C. and allowed to warm to ambient temperature over 3 hours. Reaction progress was monitored by TLC (TLC eluent: 30% EtOAc in hexane). The reaction mixture was then poured into a EtOAc/water mixture, and the aqueous layer was extracted with EtOAc. The aqueous layer was then acidified with dilute hydrochloric acid and extracted with DCM. The DCM solution was washed with brine and concentrated. The product (6.5 g) thus obtained was used without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:18]#[CH:19]>O1CCOCC1.CCN(CC)CC.[Cu](I)I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:19]#[C:18][CH2:17][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: C#CCOC1CCCCO1
Agent: I[Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCOC2CCCCO2)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (2.0 g, 5.80 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (2.44 mL, 17.4 mmol), copper iodide (55.0 mg, 0.29 mmol) and bis(triphenylphosphine)palladium (II) dichloride (407 mg, 0.58 mmol) in dioxane (15 mL) and Et3N (15 mL) was heated to reflux for 16 h under nitrogen. The mixture was then allowed to cool to r.t., filtered and the filtrate was diluted with AcOEt. This mixture was washed once with water. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 5:1) to give an orange oil, which was recrystallized in hexanes to provide 2-amino-5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-4-trifluoromethyl-benzoic acid methyl ester (1.50 g, 4.20 mmol, 72%) as a pale brown powder, m.p. 88° C., ESI-MS: m/z 358 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:10][C:11]3([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:4]=12.[BH-](O[C:44]([CH3:46])=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.ClCCCl.C(Cl)Cl>[CH2:17]([N:14]1[CH2:13][CH2:12][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][NH:1][CH:46]3[CH2:44][CH2:12][CH2:11][CH2:10]3)[N:9]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:10]2)[CH2:16][CH2:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CN)cccc43)c21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC5CCCC5)cccc43)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of cyclopentone (0.036 mL, 0.40 mmol) in THF (0.15 mL) was added to a stirred solution of (R)-tert-butyl 4-(aminomethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (30 mg, 0.067 mmol) in DCE (0.6 mL) The reaction was allowed to stir at room temperature for 15 minutes, at which point Na(OAc)3BH was added, and the reaction allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 20:1) to give (R)-N-((1′-benzyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)cyclopentanamine (34 mg, 98%) as an oil. LCMS (APCI+) m/z 518 [M+H]+; Rt=2.91 min.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:4]([CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)=[O:3]
Reactant: CCOC(=O)CCc1cn(-c2cccnc2)c2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=CCCc1cn(-c2cccnc2)c2ccccc12
Reaction time: 0.13 h

Procedure:
A solution of 2.7 g of 3-[2-(ethoxycarbonyl)ethyl]-N-(3-pyridyl)indole in 50 ml of dry methylene chloride under nitrogen is cooled to -75° and 10.6 ml of 1.75M diisobutylaluminum hydride in toluene is added dropwise. The reaction is stirred for 8 minutes and quenched with 10 ml of water at -75°. Cooling is stopped and the layers are separated. The organic phase is washed with water, dried over potassium carbonate and evaporated to a solid which is recrystallized from ether-hexane to yield 3-(2-formylethyl)-N-(3-pyridyl)indole, m.p. 44°-45°.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].[CH:24]([O-])([O-])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:10]1([C:7]2[C:6]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:5]=3[N:4]3[CH:24]=[N:2][N:1]=[C:3]3[CH2:9][N:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC([O-])[O-]
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 3.2 parts of 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine, prepared in Example 4, 8.5 parts of ethyl orthoformate and 50 parts by volume of chloroform, is added dropwise 7.6 parts of p-toluenesulfonic acid at a temperature below 10° C. The mixture is stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The chloroform layer is separated, washed with water and dried over sodium sulfate. Evaporation of the solvent yields 6-phenyl-8-trifluoromethyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as crystals. The crystals are dissolved in ethanol and the insoluble material is removed by filtration. The filtrate is concentrated and recrystallized from ethyl acetate to give colorless flakes. Melting point: 258° C to 260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C@@H:21]([C:24]2[CH:25]=[C:26]3[C:35](=[CH:36][C:37]=2Br)[O:34][CH2:33][C:32]2[N:27]3[C@H:28]([CH3:40])[C:29](=[O:39])[NH:30][N:31]=2)[C@@H:20]([CH3:41])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C@@H:21]([C:24]2[CH:25]=[C:26]3[C:35](=[CH:36][C:37]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:34][CH2:33][C:32]2[N:27]3[C@H:28]([CH3:40])[C:29](=[O:39])[NH:30][N:31]=2)[C@@H:20]([CH3:41])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: OB(O)c1ccccc1F
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cc3N21
Temperature: 90 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a mixture of (2-fluorophenyl)boronic acid (0.051 g, 0.365 mmol), (3R,4R)-4-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.243 mmol) and K2CO3 (0.067 g, 0.486 mmol) in dioxane (12 mL) and water (2 mL) was added PdCl2(dppf)-CH2Cl2 adduct (0.020 g, 0.024 mmol) and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 3-30% EtOAc in petroleum ether) to give (3R,4R)-4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.076 g, 61%) as a colorless solid. 1H NMR (CDCl3, 400 MHz) δ 8.34 (brs, 1H), 7.44-7.32 (m, 1H), 7.24-7.11 (m, 3H), 6.85 (s, 1H), 6.73 (brs, 1H), 4.80 (brs, 1H), 4.70-4.53 (m, 2H), 4.43-4.17 (m, 1H), 3.90-3.60 (m, 1H), 2.89 (brs, 1H), 2.60 (brs, 2H), 1.56 (d, J=6.8 Hz, 3H), 1.46 (m, 10H), 0.72 (m, 3H). LC/MS (Table 1, Method 25), Rt=0.948 min.; MS m/z: 509 [M+H]+& 453 [M+H−56]+. SFC (Table 1, Method 46), Rt=6.21 min.