Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([F:20])[CH:12]=1.CCN(CC)CC.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][OH:16])=[C:13]([F:20])[CH:12]=1
Reactant: O=C(O)c1ccc(Oc2nc3ccccc3s2)cc1F
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Oc2nc3ccccc3s2)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of 4-(benzothiazol-2-yloxy)-2-fluoro-benzoic acid (4.7 g, 16.1 mmol) in THF (100 mL) was added Et3N (2.5 mL, 17.7 mmol). The mixture was cooled to 0° C., and isobutylchloroformate (2.1 mL, 16.1 mmol) was added. The reaction mixture was stirred for 2 h, filtered, and concentrated. The residue was dissolved in THF (50 mL) and cooled to 0° C. Sodium borohydride (1.2 g, 32.2 mmol) was added and immediately followed by water (10 mL). The reaction mixture was then partitioned between EtOAc (50 mL) and brine (20 mL). The organic layer was separated, dried (Mg2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 60% EtOAc in hexanes) afforded the title compound as a colorless solid (3.3 g, 75%). MS (ESI): mass calcd. for C14H10FNO2S, 275.0; m/z found, 276.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.77 (d, J=8.1 Hz, 1H), 7.72 (dd, J=5.3, 2.7 Hz, 1H), 7.54 (t, J=8.4 Hz, 1H), 7.43 (td, J=7.6, 1.3 Hz, 1H), 7.32 (td, J=7.5, 1.2 Hz, 1H), 7.24-7.16 (m, 2H), 4.81 (d, J=5.8 Hz, 2H), 1.79 (t, J=6.1 Hz, 1H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([NH:14][C:15](=[O:35])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:18][C:17]=3[N+:32]([O-])=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.O.Cl[Sn]Cl>CO>[CH:10]1[C:11]2[CH:12]([NH:14][C:15](=[O:35])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:18][C:17]=3[NH2:32])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(C(=O)NC2c3ccccc3-c3ccccc32)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)NC2c3ccccc3-c3ccccc32)c(N)cc1OCc1ccccc1
Yield: 84 %

Procedure:
N1-(9H-9-fluorenyl)-4-(benzyloxy)-5-methoxy-2-nitrobenzamide of formula (7e) (500 mg, 1.07 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (839 mg, 3.2 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude N1-(9H-9-fluorenyl)-2-amino-4-(benzyloxy)-5-methoxybenzamide (450 mg, 95% yield). This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (8e) (610 mg, 84% yield). 1H NMR (CDCl3) δ 3.95 (s, 3H), 5.20 (s, 2H), 5.70 (s, 1H), 6.70 (s, 1H), 7.00-7.41 (m, 5H), 7.45-7.706 (m, 9H); FABMS: 436 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:10]1[N:11]([CH:15]([CH3:21])[C:16](OCC)=[O:17])[CH:12]=[CH:13][N:14]=1)[CH2:8][CH3:9].O.[OH-].[Na+]>O1CCCC1>[CH2:7]([C:10]1[N:11]([CH:15]([CH3:21])[CH2:16][OH:17])[CH:12]=[CH:13][N:14]=1)[CH2:8][CH3:9]
Reactant: CCCc1nccn1C(C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nccn1C(C)CO
Temperature: 0 °C
Yield: 73.4 %

Procedure:
Lithium aluminum hydride (2.5 g) was suspended in tetrahydrofuran (40 ml). Ethyl 2-(2-propylimidazol-1-yl)propanate [9.2 g] in tetrahydrofuran (40 ml) was added with stirring at 0° C. The reaction was refluxed for 3 hours, cooled to 0° C., water (3 ml) was added dropwise followed by 15% sodium hydroxide (3 ml) and a further portion of water (9 ml). The suspension was filtered through solka-flok and the solvent removed under reduced pressure. Dichloromethane (50 ml) was added, the organic phase washed with brine (25 ml) dried over magnesium sulphate and the solvent removed under reduced pressure yielding the title compound as a white foam 5.4 g (67%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][N:13]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=O)=O)=CC=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K].O.C(OCC)(=O)C>CN(C)C=O>[C:25]([O:24][C:22]([N:13]1[CH2:14][C@H:15]([O:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:16][C@H:12]1[CH2:11][N:34]1[C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]2[C:30]1=[O:40])=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OC(C)(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (20.78 g) in dimethylformamide (200 ml), potassium phthalimide (9.61 g) is added. The mixture is stirred at 70° C. for 3 hours. The reaction mixture is poured into a mixture of water and ethyl acetate. The organic layer is taken, successively washed with dilute aqueous sodium hydroxide and water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by 5% wet silica gel column chromatography to give (2S,4R)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (11.17 g). Yield: 60%. Colorless foam. NMR δ(CDCl3) ppm: 1.33, 1.42(2×s, 9H), 2.0 to 2.55(m, 2H), 3.02(s, 3H), 3.4 to 4.6(m, 5H), 5.15 to 5.3(m, 1H), 7.6 to 7.95(m, 4H). IR ν (CHCl3) cm-1 : 1775, 1716, 1693.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>>[CH2:24]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[CH3:19])=[N:8]1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2C)c2cccc(Cl)c21
Yield: 62.7 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and allyl bromide (0.07 mL, 0.7 mmol) to give the title compound (0.102 g) as a white solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:8][CH2:9][C@@H:10]([CH3:23])[O:11][CH2:12][P:13](=[O:22])([O:18][CH:19]([CH3:21])[CH3:20])[O:14][CH:15]([CH3:17])[CH3:16])C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)O)C=CC=CC=1>C(O)(=O)C>[OH:8][CH2:9][C@@H:10]([CH3:23])[O:11][CH2:12][P:13](=[O:22])([O:14][CH:15]([CH3:17])[CH3:16])[O:18][CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)OP(=O)(CO[C@H](C)COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(C)C
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: CC(C)OP(=O)(CO[C@H](C)CO)OC(C)C
Reaction time: 0.33 h

Procedure:
The 90.6 g (0.182 mol) of diisopropyl (R)-[(2-triphenylmethoxy-1-methylethyloxy)methyl]phosphonate as a transparent yellow oil and 80% acetic acid solution (380 mL) were stirred to form a homogeneous solution, which was placed in 85° C. oil-bath and heated. The reaction was performed under stirring for 20 min, and then placed in an ice-bath for overnight to allow the side-product triphenylmethanol sufficiently to precipitate. After filtration, the filter cake was washed with 80% acetic acid solution (3×15 ml), and the filtrates were combined, and distilled at a reduced pressure to remove acetic acid and water. The residue was added to ethyl acetate (250 ml), and the mixture was washed with saturated brine (2×50 ml) to obtain an oil layer, which was dried over anhydrous sodium sulfate, and filtered. The filtrate was distilled at a reduced pressure to remove the solvent, and the residue was separated by a column chromatography (column chromatography conditions: silica gel 200-300 mesh; eluting agent was dichloromethane:methanol=50:1 to 10:1), to obtain diisopropyl (R)-[(2-hydroxy-1-methylethyloxy)methyl]phosphonate as a transparent light yellow oil product, 24.1 g.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:23]1([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:23]5[CH:27]=[N:26][CH:25]=[N:24]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1ncn(C2CCNC2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Cc1c(F)c(N2CCC(n3cncn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 28.9 %

Procedure:
1-Cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg, 0.1 mmol) was reacted with 40 mg (0.2 mmol) of 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride in 2 ml of pyridine in the presence of 70 mg (0.45 mmol) of DBU at 95° C. overnight. The orange solution was evaporated to dryness and to the residue water was added. The orange solid was collected and washed with methanol to yield 19 mg of the crude product, which upon further purification from methanol yielded 12 mg of the desired product. m.p. 207°-210° C. 1H NMR (TFA) δ: 9.81 (s, 1H), 9.27 (s, 1H), 8.78 (s, 1H), 5.75-5.55 (m, 1H), 4.83-4.12 (m, 5H), 3.0-2.7 (m, 5H), 1.7-1.2 (m, 4H). Anal. calcd. for C20H19F2N5O3H2O: C, 55.43; H, 4.88; N, 16.16. Found: C, 55.72; H, 4.73; N, 15.65.
Reaction SMILES: C(O)(C)(C)C.N.[C:7]([O:11][C:12]([N:14]1[C@H:23]([CH2:24][OH:25])[CH2:22][C:21]2[C:16](=[CH:17][C:18]([OH:26])=[CH:19][CH:20]=2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Li].[NH4+].[Cl-]>CCOCC>[C:7]([O:11][C:12]([N:14]1[C@H:23]([CH2:24][OH:25])[CH2:22][CH:21]2[CH:16]([CH2:17][CH:18]([OH:26])[CH2:19][CH2:20]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1CO
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC2CC(O)CCC2C[C@H]1CO
Reaction time: 6 h

Procedure:
To a solution of t-butyl alcohol (9.1 g, 123 mmol), 50 ml ether, and ammonia (150 mL) is added (S)-2-t-butoxycarbonyl-1,2,3,4-tetrahydro-3-hydroxymethyl-7-hydroxyisoquinoline (5 mmol). The solution is brought to reflux, and lithium shot (0.51 g, 82 mmol) is added over 30 minutes. The solution is allowed to reflux for 3 hours, and solid NH4Cl added until the color disappears. The ammonia is allowed to evaporate overnight, ice-water is added, and the organic layer separated. The aqueous layer is extracted with chloroform and the combined organic phases are washed with brine, dried and evaporated. The crude product is redissolved in methanol, 5% Pt/C added and the solution shaken under 3 atm H2 for 6 hours to complete the reduction. The catalyst is filtered and the solvent evaporated. The resulting residue is purified by silica gel flash column chromatography to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([O:16]CC)=[O:15])[N:11]=[C:10]3[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([NH:27][C:28]([NH:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:29])[C:24]=4[C:25](=[O:26])[C:9]=23)=[CH:4][CH:3]=1.O1CCOCC1.C(O)C.[OH-].[Na+]>CCOC(C)=O.CS(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([OH:16])=[O:15])[N:11]=[C:10]3[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([NH:27][C:28]([NH:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:29])[C:24]=4[C:25](=[O:26])[C:9]=23)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1nc2c(c1-c1ccc(O)cc1)C(=O)c1c(NC(=O)NN3CCOCC3)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)Cn1nc2c(c1-c1ccc(O)cc1)C(=O)c1c(NC(=O)NN3CCOCC3)cccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 37 (1.2 g, 2.4 mmol)was dissolved in 60 ml 3:2:1; dioxane:ethanol:DMSO and 12 ml 0.5 N NaOH added and the reaction became red. The reaction mixture was stirred at room temperature for one hour, diluted with EtOAc and washed with 1 N HCl. The aqueous layer was back extracted once with ethyl acetate and the combined organic layers dried over MgSO4 and concentrated to an orange solid. The solid was triturated with 10 ml MeOH/100 ml Et2O, filtered off and dried to a solid (1.1 g, 2.4 mmol, 100%, compound 38: designated G7).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([CH2:33][CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[C:25]([O:26][C:27](=[O:35])[CH2:28][CH2:29]1)=[CH:24][CH2:23]3)=[O:15]>C1COCC1.[Rh]>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=1[NH:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([CH2:33][CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[CH:25]([O:26][C:27](=[O:35])[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)=[O:15]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4OC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: [Rh]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CCC4OC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of N-(2',5'-bistrifluoromethylphenyl)-4-oxa-androst-5-en-3-one-17β-carboxamide (230 mg, 0.433 mml, prepared according to the procedures of Example 7) in THF (5 mL) was added 5% Rh/C (200 mg). After stirring the reaction mixture for overnight under hydrogen atmosphere, the reaction mixture was flushed with nitrogen, filtered, concentrated and purified by preparative tlc (50% EtOAc/hexane) to give pure product. Mass spec. M+ 532 (m+1, observed).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Br:14])=[CH:9][C:8]=1[F:15].[C:16](=[O:18])=[O:17].Cl>C(OCC)C>[Br:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([C:16]([OH:18])=[O:17])=[C:8]([F:15])[CH:9]=1
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1cc(F)c(Br)cc1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Freshly titrated n-butyl lithium (27.0 ml, 1.39 M in hexanes) is added slowly (over about 30 minutes) to a −78° C. solution of diethyl ether (90 ml) containing 1,4-dibromo-2,5-difluorobenzene (1, 10.22 g, 0.038 mol). The resulting yellow solution is stirred at −78° C. for 2 hours to give a yellow suspension. Several pellets (˜10) of dry ice are added to the suspension, which is then allowed to warm slowly to room temperature as it degasses (approximately 40 minutes). The resulting suspension is acidified with a 1 M aqueous solution of hydrochloric acid (500 ml), and the product extracted with diethyl ether (5×200 ml). The combined organics are washed with water (4×100 ml) and filtered. The ether solution is concentrated to approximately 200 ml under reduced pressure, and the product extracted into a saturated aqueous solution of sodium bicarbonate (3×200 ml). The combined aqueous extracts are washed with methylene chloride (3×100 ml) and acidified with hydrochloric acid. The product is extracted with diethyl ether (3×200 ml), and the combined organic extracts washed with water (2×200 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give (2) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.74 (dd, JH-F=8.5 Hz, 6.5 Hz, 1H), 7.84 (dd, JH-F=10.0 Hz, 5.5 Hz, 1H), 13.7 (br, 1H, CO2H). 19F{1H} NMR (282 MHz, DMSO-d6): δ −114.0 (d, JF-F=17.0 Hz, 1F), −113.6 (d, JF-F=17.0 Hz, 1F). 13C{1H} NMR (75 MHz, DMSO-d6): δ 113.6 (dd, JC-F=23.5 Hz, 10.0 Hz), 118.4 (dd, JC-F=26.5 Hz, 2.5 Hz, CH), 120.0 (dd, JC-F=19.0 Hz, 12.0 Hz), 122.2 (d, JC-F=28.0 Hz, CH), 154.4 (dd, JC-F=245.0 Hz, 5.5 Hz, CF), 156.8 (dd, JC-F=251.5 Hz, 4.0 Hz, CF), 163.4 (m, CO2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:18])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Cl:18])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1c[nH]c2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A mixture of 6-bromo-1H-indole (850 mg, 4.34 mmol) and NCS (593 mg, 4.44 mmol) in DCM (17 mL) was stirred at 0° C. for 1.5 hour. The mixture was partitioned between saturated aqueous ammonium chloride (25 mL) and ethyl acetate (150 mL). The organic phase was separated, washed with brine (25 mL), dried with anhydrous magnesium sulfate, filtered and evaporated to dryness to give the title compound (894 mg). LCMS (A): m/z (M+H)+ 230/232, C8H5BrClN requires 229/231 (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([NH:16][CH3:17])=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:28][C:29]([F:47])([F:46])[C:30]1[CH:31]=[C:32]([C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.[OH-].[Na+]>CN(C)C=O.C1COCC1.C(OCC)(=O)C>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:32]([C:40]([CH3:45])([CH3:44])[C:41]([N:16]([C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:13][N:12]=[C:11]([S:14][CH3:15])[N:10]=2)[CH3:17])=[O:42])[CH:31]=[C:30]([C:29]([F:46])([F:28])[F:47])[CH:35]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1nc(SC)ncc1-c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc(-c2ccccc2Cl)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 0.70 g (2.6 mmol) [5-(2-Chloro-phenyl)-2-methylsulfanyl-pyrimidin-4-yl]-methyl-amine in 4 ml N,N-dimethylformamide 2.6 ml of a 1M solution potassiumhexamethyldisilazide (2.6 mmol) in THF were added at 0°. After 1 h, 0.92 g (2.6 mmol) (2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 2 ml THF were added and the reaction mixture stirred for 24 hrs. at RT. The reaction mixture was poured onto 50 ml 0.5 N NaOH-solution. After addition of ethyl acetate the phases were separated, the aqueous layer washed twice with 50 ml ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 0.85 g (58%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-4-yl]-N-methyl-isobutyramide as a white foam, MS (EI): 547 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([O:28]C)=[O:27])[CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1>Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:21][CH2:22][C@H:23]([C:26]([OH:28])=[O:27])[CH2:24][CH2:25]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Agent: Cl
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 37% HCl (30 mL) and methyl trans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (500.0 mg, 1.28 mmol) was stirred for 18 h at rt. The reaction mixture was then concentrated in vacuo, and the residue washed with diethyl ether (3×10 mL) and ethyl acetate (2×10 mL), then with ice-cold acetonitrile (10 mL) to afford 0.3 g of the desired product. 1H NMR (d6-DMSO, 400 MHz): δ 12.15 (br s, 1H), 11.69 (s, 1H), 8.45 (br s, 2H), 7.97 (d, J=6.4 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.50 (dd, J=8.0, 0.4 Hz, 1H), 7.19 (m, 1H), 7.13 (d, J=6.0 Hz, 1H), 7.06 (m, 1H), 6.83 (d, J=1.6 Hz, 1H), 3.27 (td, J=11.6, 3.2, 3.2 Hz, 1H), 2.33 (td, J=10.8, 3.2, 3.2 Hz, 1H), 2.05 (m, 4H), 1.73 (m, 2H) and 1.58 (m/z, 2H). MS (ES+): m/z 376.05 [MH+].
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[O:21]1[CH2:24][C:23](=[O:25])[CH2:22]1>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[C:23]1([OH:25])[CH2:24][O:21][CH2:22]1
Reactant: Fc1cncc(Br)c1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC1(c2c(F)cncc2Br)COC1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
n-BuLi (1.6 M in hexane, 4.26 mL, 6.82 mmol) was added dropwise to a solution of diisopropylamine (1.05 mL, 7.39 mmol) in THF (14 mL) at −78° C. under Nitrogen atmosphere. The resulting mixture was warmed up to −40° C. and stirred for 10 min and recooled to −78° C. A solution of 3-bromo-5-fluoropyridine (1000 mg, 5.68 mmol) in THF (5 mL) was added dropwise at this temperature. After completion of addition, the reaction mixture turned brown. After 30 min, Oxetan-3-one (491 mg, 6.82 mmol) was added dropwise and the resulting mixture was stirred for 30 min at this temperature. The reaction was quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate, and the combined extracts were washed with saturated NaHCO3 solution, dried over Na2SO4 and filtered. After concentration, 3-(3-Bromo-5-fluoro-pyridin-4-yl)-oxetan-3-ol (1190 mg, 84%) was obtained as a dark red solid; ESI-MS m/z: 249 [M+1]+, Retention time 0.83 min; 1H-NMR (MeOD, 400 MHz) δ 4.77 (d, J=8.8 Hz, 2H), 5.25 (d, J=8.8 Hz, 1H), 5.26 (d, J=8.8 Hz, 1H), 8.45 (d, J=1.6 Hz, 1H), 8.56 (s, 1H).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([C@H:29]([OH:31])C)[C:25]([O:27][CH3:28])=[O:26])=[O:22])=[O:15])=[O:8])(=O)C.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:35][C:33]([NH:32][C@@H:6]([CH2:5][OH:4])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][C@@H:24]([CH2:29][OH:31])[C:25]([O:27][CH3:28])=[O:26])=[O:22])=[O:15])=[O:8])=[O:34])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](COC(C)=O)NC(=O)OCc1ccccc1)[C@@H](C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
(S)-1-((S)-3-Acetoxy-2-(benzyloxycarbonylamino)-propanoyl)-pyrrolidine-2-carboxylic acid (5) (400 mg, 1.05 mmol) was dissolved in CH2Cl2 (2 mL), NMM (0.13 mL) and IBCF (0.14 mL) were added at −15° C. and stirred for 30 minutes under inert atmosphere. A mixture of(S)-methyl-3-hydroxy-2-((S)-pyrrolidine-2-carboxamido)-propanoate hydrochloride (4) (293 mg, 1.16 mmol) and NMM (0.13 mL) in DMF (2 mL) were added drop wise to the reaction mixture and stirring was continued for another 3 h at RT. The reaction mixture was diluted with DCM (200 mL), washed with water (20 mL) and brine (10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography eluting with 5% CH3OH/CH2Cl2 to afford compound 6 (80 mg, 13%).