Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[C:14](Cl)(=[O:16])[CH3:15].Cl>ClCCl>[CH3:15][C:14]([C:10]1[CH:11]=[C:6]([Br:5])[CH:7]=[CH:8][C:9]=1[O:12][CH3:13])=[O:16]
Reactant: CC(=O)Cl
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a slurry of 8.55 g (64.2 mmol) of aluminum chloride in 75 mL of dichloromethane cooled to 0° C. (under a blanket of argon) was added dropwise a solution of 10.0 g (53.5 mmol) of 4-bromoanisole and 4.6 mL (64.2 mmol) of acetyl chloride in 25 mL of dichloromethane. After the addition was complete, the clear yellow solution was stirred at 0° C. for 15 minutes, poured into 200 mL of 10% HCl (aq.) solution, cooled to 0° C. in an ice bath and then extracted with dichloromethane (3×200-mL portions). The organic phases were combined and then washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow semi-solid. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2N([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)C3C(SC=2C=1)=CC=CC=3.O1CCOCC1.O>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.CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:44]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(Cl)ccc32)CC1
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4cccnc4)ccc32)CC1

Procedure:
Using an adaptation of the method described in Procedure 16, substituting 4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 2i, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, Cp2Fe(PtBu2)2PdCl2 for Pd(PPh3)4 and a 5:1 mixture of dioxane:water for NMP, the title compound 4-(3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 3i was obtained. MS m/z (MH+) 444.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Mg+2].[C:6](=[O:9])([OH:8])[O-:7].[Nd:10]>C([O-])(=O)C.[Nd+3].C([O-])(=O)C.C([O-])(=O)C>[C:1](=[O:2])([O-:4])[O-:3].[Nd+3:10].[C:6](=[O:7])([O-:9])[O-:8].[C:1](=[O:2])([O-:4])[O-:3].[Nd+3:10]
Reactant: O=C([O-])O
Reactant: [Nd]
Agent: CC(=O)[O-]
Agent: [Mg+2]
Agent: [Nd+3]
Product: O=C([O-])[O-]

Procedure:
Adding 9 m3 of magnesium bicarbonate solution (MgO: 15 g/L, Fe: 1.1 ppm, Al: 0.5 ppm, saturated with CO2) into a reactor containing 10 m3 of neodymium acetate solution (0.2 mol/L) to react for 2 hours at 25° C., and controlling the pH value of mother liquor at 5.5, neodymium ions are precipitated and neodymium carbonate is obtained. Subsequently, the neodymium carbonate is filtered, washed, dried and finally calcined at 700° C. for 2 hours to produce neodymium oxide.
Reaction SMILES: [CH3:1][C:2]([CH3:56])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:53])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:52])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C:45]4[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:55])[CH3:54])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O.CCCCCC>ClCCl>[F:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]2[C@@H:25]2[C@@:20]([CH3:52])([CH2:21][CH2:22]3)[C@@:19]3([CH3:53])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:54])([CH3:55])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:56])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)=[CH:46][CH:47]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)Nc2ccc(F)cc2)CC1=O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)Nc2ccc(F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((4-fluorophenyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (250 mg, 0.323 mmol), TFA (1 mL, 12.98 mmol) in dichloromethane (4 mL) stirred at rt. The reaction mixture was stirred at rt for 2 h, washed with saturated NaHCO3 in water (300 mL×8); followed by 2 M HCl (300 mL), water, and then brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was solved into DCM (80 mL) and hexane (120 mL) was added. The suspension was filtered, washed with hexane to afford the crude product, and then purified by preparative-HPLC to afford the title compound (160 mg, 68%) as a light white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.56 (br. s., 3H), 7.23-6.93 (m, 3H), 5.96-5.75 (m, 1H), 4.52 (dd, J=5.1, 10.9 Hz, 1H), 3.33-3.13 (m, 1H), 2.88-2.51 (m, 3H), 2.45-0.72 (m, 47H); LC/MS: m/z calculated 717.4. Found 718.3 (M+1)+.
Reaction SMILES: [C:1]1([C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][N:9]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:38])([F:37])[C:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].O>ClCCl.[Pd]>[C:1]1([C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][NH:9][S:33]([C:29]2[CH:28]=[C:27]3[C:32](=[CH:31][CH:30]=2)[N:24]([C:22](=[O:23])[C:21]([F:38])([F:20])[F:37])[CH2:25][CH2:26]3)(=[O:34])=[O:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1ccccc1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Agent: [Pd]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CNS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C(F)(F)F)c1ccccc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-2-phenyl-2-tert-butoxycarbonylaminoethylazide (10.50 g, 0.04 mol) dissolved in 250 mL dichloromethane and 2.5 g of 10% Pd/C was hydrogenated for 5 hrs at 70 psi of H2. The catalyst was separated by filtration. To the filtrate triethylamine (8 mL) was added, the mixture was cooled to −20° C. followed by slow addition of 1-(trifluoroacetyl)indoline-5-sulfonyl chloride (12.56 g, 0.04 mol) dissolved in 150 mL dichloromethane. The reaction mixture was then stirred overnight at room temperature. Water (500 mL) was added and the mixture was shaken well, organic layer was separated, shaken with 200 mL 2% citric acid, separated and dried with MgSO4. The drying agent was separated by filtration. The filtrate was concentrated and the title product was precipitated by addition of hexane. Yield: 17.67 g, (86%); (MH)+=514; 1H NMR (DMSO-d6): 1.33 (s, 9H), 2.85-2.99 (m, 2H), 3.26-3.30 (t, J=8.0 Hz, 2H), 4.31-4.35 (t, J=8.0 Hz, 2H), 4.53-4.59 (m, 1H), 7.19-7.35 (m, 6H), 7.66-7.68 (m, 2H), 7.72-7.75 (t, J=6.0 Hz, 1H), 8.13-8.15 (d, J=8.8 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C:11]=3[C:12](=[O:30])[CH2:13][C@@H:14]2[C@H:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])[CH2:6]1)(=[O:3])[CH3:2].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C:11]=3[C:12](=[O:30])[CH2:13][C@@H:14]2[C@H:15]([CH3:20])[CH2:16][CH2:17][CH2:18][O:19][S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCCO)[C@@]4(C)CC[C@@H]32)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCCOS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]32)C1
Yield: 71.5 %

Procedure:
A solution of 3β-acetoxy-24-hydroxy-5α-chol-8(14)-en-15-one (400 mg) in dry pyridine (3 ml) and a solution of p-toluenesulfonyl chloride (300 mg) in dry pyridine (2 ml) were cooled in sealed vials in a freezer, combined, and kept at 5° C. in a sealed vial for 24 h. The reaction mixture was poured onto ice and the solid product was collected on a filter and washed with water. Reversed phase HPLC analysis on a Microsorb C18 column (solvent, methanol) indicated the following composition: 3β-acetoxy-24-tosyloxy-5α-chol-8(14)-en-15-one, 95%; unreacted 3β-acetoxy-24-hydroxy-5α-chol-8(14)-en-15-one , 3%; and 3β-acetoxy-24-chloro-5α-chol-8(14)-en-15-one, 2%. The crude tosylate (497 mg) was subjected to chromatography on a silica gel (70-230 mesh) column (250 mm×14 mm). Using 5% ethyl acetate in hexane, fractions 20 ml in volume were collected. At fractions 39 and 77, the eluting solvent was changed to 20% ethyl acetate in hexane and 50% ethyl acetate in hexane, respectively. The contents of fractions 41-74 contained 3β-acetoxy-24-tosyloxy-5α-chol-8(14)-en-15-one (392 mg, 66% yield) with a purity of 99% as judged by HPLC analysis. Additional material (62 mg) of 95% purity was recovered in fractions 75-83. The contents of fractions 41-44 (171 mg) were recrystallized from ether-hexane to give 3β-acetoxy-24-tosyloxy-5α-chol-8(14)-en-15-one (150 mg) melting at 158.0°-159.5° C. The structure was confirmed using I.R., N.M.R., and M.S. analyses.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.C([Si](C)(C)[O:44][CH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH:55]=[C:54](B3OC(C)(C)C(C)(C)O3)[CH:53]=[N:52]2)[CH2:47][CH2:46]1)(C)(C)C>>[OH:44][C@H:45]1[CH2:46][CH2:47][C@H:48]([N:51]2[CH:55]=[C:54]([C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9]4[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]5[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=5)[N:10]=4)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=3)[CH:53]=[N:52]2)[CH2:49][CH2:50]1
Reactant: CC1(C)OB(c2cnn(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn([C@H]5CC[C@H](O)CC5)c4)cc3C(=O)NC)n2)cc1)OCC
Temperature: 25 °C

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Compound 137A). After Suzuki reaction and SPE pre-purification, dried material was dissolved in DCM and 1.0 M HCl in ether was added. The mixture was stirred at room temperature for half an hour. The crude was sent to MDP for purification. MS (ES+): m/z 702.34 (100) [MH+]; HPLC: tR=0.96 min (UPLC, purity).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13](=O)[CH3:14])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11](/[C:13](=[N:22]/[S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])/[CH3:14])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnn(-c2cccc(Br)c2)c1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: C/C(=N\[S@](=O)C(C)(C)C)c1cnn(-c2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of 1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-ethanone (1.0 g, 4.53 mmol), (R)-2-methylpropane-2-sulfinic acid amide (0.66 g, 5.43 mmol) and titanium (IV) ethoxide (2.1 ml, 9.96 mmol) in tetrahydrofuran (20 ml) was refluxed for 12 hours. The reaction mixture was cooled to 25° C., quenched with brine (20 ml), and extracted with ethyl acetate (5×20 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulphate, and evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a gradient of hexane/ethyl acetate=85:15 to 80:20 as the eluent to give the (R)-2-methyl-propane-2-sulfinic acid [1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-eth-(E)-ylidene]-amide (1.0 g, 60% yield) as a yellow solid. MS (ISP): m/z=368.0 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH3:23])[C:20]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[N:19]2)=[O:17])=[CH:11][CH:10]=1.C([Li])CCC.CCCCCC.[CH3:42][N:43]([CH3:47])[C:44](Cl)=[O:45]>O1CCCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]2[CH2:22][C:21]([C:44](=[O:45])[N:43]([CH3:47])[CH3:42])([CH3:23])[C:20]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[N:19]2)=[O:17])=[CH:13][CH:14]=1
Reactant: CC1CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reactant: CN(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)C(=O)C1(C)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Into a 3000 ml three necked flask equipped with a mechanical stirrer, thermometer, and addition funnel was placed 65 ml (0.47 mole) of diisopropylamine, 155 g (0.45 mole) of N,3-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide and 1000 ml of tetrahydrofuran. The atmosphere was exchanged for nitrogen and the mixture was cooled to -20° C. internal. Then 375 ml of 2.6M n-butyllithium in hexane (0.97 mole) was added at a rate to maintain the internal temperature below -10° C. The mixture was stirred for an additional 30 minutes at -20° C. and then cooled to -60° C. whereon 45 ml of dimethylcarbamoyl chloride (0.49 mole) was added in one portion. After stirring for 15 minutes the reaction was quenched with 35 ml of acetic acid and 100 ml of water. After warming to room temperature, the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Crystallization from ethyl ether gave 125 g of N,3-bis-(4-chlorophenyl)-4-dimethylcarbamoyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. Mp 194°-197° C. NMR and IR data were consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O.C(=O)([O-])O.[Na+]>C(O)CC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:15]=[C:12]3[CH:11]=[CH:10][C:9]([B:4]4[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]4)=[CH:14][N:13]3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: CC1(C)OB(c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)OC1(C)C
Temperature: 80 °C
Yield: 93.2 %

Procedure:
2.5 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylamine and 2.65 g of 2-bromo-1-(4-chlorophenyl)ethanone in 76 ml of n-propanol are placed in a round-bottomed flask. 1.33 g of sodium hydrogen carbonate are added thereto. The mixture is heated at 80° C. for 16 h. The reaction mixture is left to cool and concentrated under reduced pressure. The residue is taken up between water and ethyl acetate, the organic phase is then separated by settling out and dried over magnesium sulphate, and the solvent is then evaporated off under reduced pressure. 3.75 g of compound are obtained.
Reaction SMILES: CN(C)C=[N:4][C:5]1[S:6][C:7]([CH:13]=[O:14])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].C(O)=O>O>[NH2:4][C:5]1[S:6][C:7]([CH:13]=[O:14])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11]
Reactant: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N
Solvent: O
Solvent: O=CO
Product: N#Cc1c(N)sc(C=O)c1Cl
Temperature: 25 °C
Yield: 90 %

Procedure:
48.3 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-formylthien-2-yl)-formamidine in a mixture of 200 parts of formic acid and 200 parts of water are heated at the boil for 3 hours. After the mixture has cooled to room temperature, the product is filtered off under suction, washed with water and dried. 33.5 parts (90% of theory) of 2-amino-4-chloro-3-cyano-5-formylthiophene are obtained. Decomposition temperature: 270° C. (from glacial acetic acid), IR (KBr): 3377, 3298, 3156 (NH2), 2216 (C≡N), 1623 cm-1 (C=0).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([C@@H:12]1[N:16]2[C:17](=O)[C@@H:18]([CH2:22][C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[NH:19][C:20](=O)[C@H:15]2[CH2:14][CH2:13]1)=[O:11])C.[OH-].[Na+].C(N(C(C)C)CC)(C)C.[F:44][C:45]([F:60])([F:59])[C:46]1[CH:47]=[C:48]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[C:49](Cl)=[O:50]>C1COCC1.C(OCC)(=O)C.O>[F:44][C:45]([F:59])([F:60])[C:46]1[CH:47]=[C:48]([C:49]([N:19]2[C@H:18]([CH2:22][C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH2:17][N:16]3[C@@H:12]([CH2:10][OH:11])[CH2:13][CH2:14][C@@H:15]3[CH2:20]2)=[O:50])[CH:52]=[C:53]([C:55]([F:56])([F:57])[F:58])[CH:54]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H]1CC[C@@H]2C(=O)N[C@H](Cc3c[nH]c4ccccc34)C(=O)N21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CO)N2C[C@H]1Cc1c[nH]c2ccccc12
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminium hydride (1.2 g) in THF (50 mL) was added a solution of (3R,6R,8aR)-3-(1H-Indol-3-ylmethyl)-1,4-dioxo-octahydro-pyrrolo[1,2-a]pyrazine-6-carboxylic acid ethyl ester (1.75 g) in THF (50 mL). The resulting mixture was heated under reflux for 3 hours, then a mixture of water (3 mL) and THF (30 mL) was added drop-wise followed by 50% sodium hydroxide (aq, 0.5 mL), and heating under reflux was continued for 2 hours. After cooling to room temperature diisopropylethylamine (4 mL) and 3,5-bis(trifluoromethyl)benzoyl chloride (2.4 mL) were added and stirring was continued overnight. Ethyl acetate was added and the mixture extracted with sodium bicarbonate (5% aq. soln.). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH4OH 95:4.5:0.5) to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,6R,8aR)-6-hydroxymethyl-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (1.49 g). MH+ 526; Rf 0.20 (EtOAc) (compound 1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[S:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.Cl.[BH4-].[Na+]>ClC1C=CC=CC=1.COCCOCCOC.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [BH4-]
Solvent: O
Solvent: COCCOCCOC
Solvent: Clc1ccccc1
Product: Cc1ccc(Cc2cccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
39 g of 4-methylbenzoyl chloride were added dropwise to a suspension of 33.8 g of aluminium chloride in 162.5 ml of chlorobenzene while stirring at 0° C. over the course of 30 minutes. The mixture was stirred at 0° C. for 90 minutes and subsequently, at 0° C., a solution of 21.8 g of thiophene in 33.8 ml of chlorobenzene was added dropwise over the course of 30 minutes. The mixture was stirred at 0° C. for 2 hours and then heated under reflux for 15 minutes until evolution of hydrogen chloride ceased. The resulting solution was added dropwise over the course of 30 minutes to a suspension of 7.2 g of sodium borohydride in 50 ml of diglyme heated to 70° C. The mixture was stirred at 70° C. for 1.5 hours and then discharged into a mixture of 250 g of ice, 200 ml of water and 62.5 g of concentrated aqueous hydrochloric acid. After addition of 100 ml of chlorobenzene and thorough stirring, the organic phase was separated off, washed with 100 ml of water and concentrated by distillation. Yield: 57.7 g of crude substance, 71.0% pure (GC), corresponding to a yield of 87.2% of theory. Distillation resulted in a 99.4% pure 2-(4-methylbenzyl)thiophene with boiling point 98° C./4 mbar.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][C@@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: CN1CCC[C@@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC[C@@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Intermediate A (245 mg, 1.50 mmol) in DMF (4 mL) was added NaH (60% dispersion in oil, 180 mg, 4.50 mmol) and the mixture stirred at RT for 0.5 h. A solution of Intermediate 60a (330 mg, 1.50 mmol) in DMF (5 mL) was added and the mixture stirred at 60° C. for 2 h. The cooled solution was diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-15% [2M NH3 in MeOH] in DCM, to give the title compound as a brown solid after freeze-drying (408 mg, 74%). LCMS (Method 3): Rt 0.44 min, m/z 364 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.CN(C(O[N:38]1N=N[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NC1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:19])=[CH:15][CH:16]=2)[NH:4][N:3]=1
Reactant: Nc1n[nH]c2cccc(-c3ccc(CC(=O)O)cc3)c12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1n[nH]c2cccc(-c3ccc(CC(=O)Nc4ccccc4)cc3)c12
Yield: 29.3 %

Procedure:
A mixture of Example 53B (40 mg, 015 mmol), diisopropylethylamine (0.078 mL, 0.45 mmol), TBTU (57 mg, 0.18 mmol), and aniline in THF (1 mL) was stirred for 18 hours at room temperature and concentrated. The residue was purified by preparative HPLC using the conditions described in Example 15H to provide 15 mg of the desired product as the trifluoroacetate salt. MS (ESI(+)) m/e 343 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 3.74 (s, 2H), 6.84 (dd, J=5.09, 3.05 Hz, 1H), 7.02-7.07 (m, 1H), 7.28-7.33 (m, 4H), 7.43-7.50 (m, 4H), 7.62 (d, J=7.80 Hz, 2H).