Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34](S(C)(=O)=O)=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>Cl>[NH:50]([C:34]1[N:33]=[C:32]2[N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:22]=3)[C:28](=[O:49])[N:29]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[CH2:30][C:31]2=[CH:36][N:35]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC(C)(C)[Si](OCCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(S(C)(=O)=O)nc32)c1)(c1ccccc1)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Product: CC(C)(C)[Si](OCCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 96 %

Procedure:
A mixture of 980 mg (1.22 mmol) of 1-[3-(2-t-butyldiphenylsilyloxyethyl)phenyl]-3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 5 ml of aniline was heated at 100° C. for 30 minutes. The reaction was allowed to cool then poured into 50 ml of 2M hydrochloric acid. The product was collected by filtration, washed with water (50 ml), then hexane (50 ml) and dried to give 960 mg (96%) of 7-anilino-1-[3-(2-tert-butyldiphenylsilyloxyethyl)phenyl]-3-(2,6-dichlorophenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one as a fawn solid. [Mass spectrum (ESI) MH+ =744].
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4][C:3]1=[O:18]>CO.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH:5]2[CH2:4][C:3](=[O:18])[N:2]([CH3:1])[C:7](=[O:8])[CH2:6]2)=[CH:14][CH:13]=1
Reactant: CN1C(=O)CC(c2ccc([N+](=O)[O-])cc2)CC1=O
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)CC(c2ccc(N)cc2)CC1=O
Yield: 94.6 %

Procedure:
A suspension of 348 mg (1.40 mmol) of 1-methyl-4-(4-nitro-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in MeOH (10 mL) was hydrogenated over 10% Pd/C at 20 psi for 1 h at RT. The mixture was filtered through Celite, the filter cake was washed with MeOH, and the solvents were evaporated in vacuo to afford 289 mg (94%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C12H14N2O2, 219.1 (M+H). found 219.1.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]\[C:4](O)=[O:5].[CH2:9]([C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=1[NH2:13])[CH3:10]>C(OC(C)C)(C)C>[CH2:9]([C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=1[N:13]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:8])[CH3:10]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CCc1cccc(C)c1N
Solvent: CC(C)OC(C)C
Product: CCc1cccc(C)c1N1C(=O)C=CC1=O
Temperature: 100 °C
Yield: 88.3 %

Procedure:
196 g of maleic acid arthydride were dissolved in 2.5 l of diisopropyl ether at room temperature. A solution of 270.4 g of 2-ethyl-6-methyl-aniline in 200 ml of diisopropyl ether was added dropwise at room temperature in the course of 4 hours, the resulting suspension was cooled to 15° to 20° C. and the solid was filtered off with suction and introduced into a mixture of 670 ml of acetic arthydride and 65 g of anhydrous sodium acetate. The suspension formed was heated to 100° C., while stirring, stirred at this temperature for 30 minutes, subsequently cooled to 30° C. and introduced into 1.3 l of ice-water. The precipitate was filtered off with suction, washed with ice-water and petroleum ether and dried. 321 g of N-(2-ethyl-6-methylphenyl)-maleimide (92.9% of theory) with a content of 97.8% by weight (determined by HPLC) and a melting point of 84.5° to 85° C. were obtained.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:13])[CH2:5]1)[CH:2]=C.[O:14]=[O+][O-]>CO.ClCCl>[Cl:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH:4]([CH2:1][CH2:2][OH:14])[CH2:5]2
Reactant: C=CCC1Cc2cccc(Cl)c2C1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: OCCC1Cc2cccc(Cl)c2C1
Reaction time: 16 h

Procedure:
Amalgamated zinc (prepared from zinc powder (6 g), mercuric chloride (0.6 g)) was heated under reflux for 7 hours with 2-allyl-4-chloro-indan-1-one (3 g), toluene (20 ml), conc. hydrochloric acid (20 ml), water (8 ml) and acetic acid (2 ml). Upon cooling conventional work-up gave a crude product which was purified by chromatography (silica/hexane) to give a 2-allyl-4-chloroindane (1.8 g). 2-Allyl-4-chloroindane (0.8 g) in dry methanol (10 ml) and dry dichloromethane (2 ml) was reacted at -35° with ozone until the blue colour persisted. After purging with nitrogen the solution was stirred 16 hours with dimethyl sulphide (2.58 g). The volatiles were removed and the residue taken up in tetrahydrofuran (10 ml) and heated under reflux with 4-toluenesulphonic acid (30 mg) and water (circa 0.5 ml) for 2 hours. After conventional work up the product, 2-(4-chloro-2-indanyl) ethanol, was obtained as a yellow oil (0.8 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[CH2:7][C:8]([C:18]1([F:21])[CH2:20][CH2:19]1)([OH:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1>CN(C)C=O>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:18]2([F:21])[CH2:19][CH2:20]2)([OH:17])[CH2:7][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1)C1(F)CC1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Product: OC(Cc1ccc(Cl)cc1)(Cn1cncn1)C1(F)CC1
Temperature: 80 °C
Yield: 30.1 %

Procedure:
Under an atmosphere of nitrogen, 27.6 g (0.4 mol) of 1,2,4-triazole and 33.6 g (0.3 mol) of potassium tert.-butylate in 100 ml of absolute dimethylformamide are introduced as an initial charge and heated to 80° C. At this temperature, a solution of 26.3 g (0.1 mol) of 1-chloro-2-(1-fluoro-cyclopropyl)-3-(4-chlorophenyl)-propan-2-ol in 50 ml of absolute dimethylformamide is added dropwise thereto while stirring. The mixture is stirred for another 6 hours at 100° C. and then concentrated by stripping off the diluent under reduced pressure. The residue is taken up in ethyl acetate, the solution is washed with water, and, after drying over sodium sulphate, the solvent is evaporated under reduced pressure. The product left behind is chromatographed on a silica gel column, using chloroform as the mobile solvent. In this way, 8.9 g (35% of theory) of 1-(4-chlorophenyl)-2-(1-fluoro-cyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of a solid.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:15][CH2:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:23]([C@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:30][C:31]([O:33]CC)=[O:32])=[O:24])[N:10]2[CH2:13][CH3:14])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>C(O)C>[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH2:15][CH2:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:23]([C@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH2:30][C:31]([OH:33])=[O:32])=[O:24])[N:10]2[CH2:13][CH3:14])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(CC[C@@H]2CCCCN2C(=O)[C@H]2CCCN2CC(=O)O)cc2ccc(C(=N)N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
In a 50 ml flask; 140 mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-amidino-1-ethylindol-2-yl)ethyl]piperidyl]carbonyl]pyrrolidinyl]acetate was dissolved in 10 ml of ethanol, and 0.5 ml of 2N NaOH was added thereto. The reaction solution was stirred for 3 hours at room temperature and evaporated under reduced pressure to remove the solvent. The residue was purified with column choromatography [eluent: ethyl acetate/methanol (1:1)] on NH-DM1020 silica to obtain 60 mg of the title compound as a yellowish white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:3]1[NH2:12].[C:14]([N:16]=[CH:17]OCC)#[N:15]>C(O)C>[C:14]([N:16]=[CH:17][NH:12][CH:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:10][CH2:11][C:2]1([CH3:13])[CH3:1])#[N:15]
Reactant: CCOC=NC#N
Reactant: CC1(C)CCC2CCCCC2C1N
Solvent: CCO
Product: CC1(C)CCC2CCCCC2C1NC=NC#N
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a stirred and heated (<40° C.) solution of 96 parts of decahydro-2,2-dimethyl-1-naphthalenamine in 400 parts of ethanol were added dropwise 48 parts of ethyl N-cyanomethanimidate. Upon complete addition, stirring was continued for 2 hours. The precipitated product was filtered off (and set aside) and the filtrate was evaporated. The residue was treated with 2,2'-oxybispropane. The precipitated product was filtered off and combined with the product, which was set aside (see above). Both were crystallized from acetonitrile. The product was filtered off and dried, yielding 67 parts (54.1%) of N'-cyano-N-(decahydro-2,2-dimethyl-1-naphthalenyl)methanimidamide; mp. 227.6° C. (intermediate 7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[CH:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:25][CH:24]=2)O)=[CH:5][CH:4]=1.[ClH:39]>C(OCC)(=O)C>[ClH:39].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]=2[CH2:21][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:25][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=C(C(O)c3ccc(OCCCN4CCCCC4)cc3)c3ccc(OC)cc3CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2Cc2ccc(OCCCN3CCCCC3)cc2)cc1
Yield: 97 %

Procedure:
Reaction of the product of Example 21 (1.5 g, 2.9 mmol) with hydrochloric acid (50 mL of a saturated ethyl acetate solution) in ethyl acetate (50 mL) according to the procedure in Example 18 gave a 97% yield of the desired product: 1H-NMR (300 MHz, CDCl3) δ 7.70-7.80 (m, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.15-7.30 (m, 3H), 7.05 (m, 1H), 6.85-6.95 (m, 4H), 6.69 (d, J=8.6 Hz, 2H), 4.34 (s, 2H), 3.97-4.03 (m, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.50-3.60 (m, 2H), 3.05-3.20 (m, 2H), 2.57-2.70 (m, 2H), 2.20-2.50 (m, 4H), 1.80-2.00 (m, 4H); MS (FD) m/e 495 (M+-hydrochloric acid); Anal. Calc'd. for: C, 74.49; H, 7.20; N, 2.63. Found: C, 74.74; H, 7.36; N, 2.75.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:22])[C:8]([CH2:18][CH2:19][CH:20]=O)=[C:9]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[N:10]=1)(=[O:3])[CH3:2].[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:22])[C:8]([CH2:18][CH2:19][CH2:20][NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=2)=[C:9]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[N:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)cc1
Reaction time: 17 h
Yield: 24 %

Procedure:
A mixture of 1.25 g (4.00 mmol) of 3-[2-(acetylamino)-4-(diacetylamino)-1,6-dihydro-6-oxo-5-pyrimidinyl]propionaldehyde, 0.743 g (4.50 mmol) of ethyl p-aminobenzoate, 1.0 ml of glacial acetic acid, and 3A molecular sieves in 25 ml of methanol was stirred at room temperature for 3 hours under nitrogen before 0.28 g (4.47 mmol) of sodium cyanoborohydride was added during a 2 minute period. After stirring for 17 hours, the mixture was filtered. The filtrate was spin evaporated in vacuo to a yellow foam. The product was separated from a mixture by flash chromatography on Silica Gel 60 (100 g; 230-400 mesh, EM Reagents) with ethyl acetate. Appropriate fractions were combined on the basis of TLC correlation, and solent was removed by spin evaporation in vacuo. Recrystallization from ethyl acetate yielded 0.44 g (24% of theory) of ethyl 4-[3-[2-(acetylamino)-4-(diacetylamino)-1,6-dihydro-6-oxo-5-pyrimidinyl]propylamino]benzoate as a white solid, mp 197°-198°; TLC (ethyl acetate), Rf =0.5; NMR (DMSO-d6) δ 1.28 (t, J=7.1 Hz, 3H, CH3), 1.65 (m, 2H, CCH2C), 2.14 (s, 3H, Ac), 2.2 (m, 2H, CH2Het), 2.23 (s, 6H, 2Ac), 3.05 (m, 2H, CH2N), 4.22 (q, J=7.1 Hz, 2H, CO2CH2), 6.5 (br, 1H, AcNH obscured by Ar), 6.57 (d, 2H, ArH), 7.69 (d, 2H, ArH). Elemental analysis. Calculated for C22H27N5O6, 0.5 H2O (MW 466.49): C, 56.64; H, 6.05; N, 15.01. Found: C, 56.88; H, 6.01; N, 14.88.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH2:27])[CH:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH3:14].N1C=CC=CC=1>ClC(Cl)C>[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:12])[CH:4]=1)(=[O:10])=[O:9])[CH:18]([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:26])[F:24])[CH3:14]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(F)c1
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(NS(=O)(=O)c1ccc(Cl)c(F)c1)C(C(F)(F)F)C(F)(F)F
Reaction time: 18 h
Yield: 62.5 %

Procedure:
To a vial containing a solution of 4-chloro-3-fluorobenzenesulfonyl chloride (181 mg, 0.79 mmol) and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (200 mg, 0.79 mmol) in anhydrous dichloroethane (3 mL) was added pyridine (192 μL). The vial was capped and shaken for 18 h. The solvent was removed in vacuo and the residue transferred to a separatory funnel with EtOAc (100 mL) and washed with distilled water (100 mL×2). The organic layer was removed and the combined aqueous washings were extracted with EtOAc (100 mL×2). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4), filtered, and evaporated to give a yellow solid (220 mg). This material was adsorbed onto silica gel and purified by column chromatography, eluent: HCCl3, to afford a white solid (186 mg, 53%). Mass Spectrum (+ESI): 446 [M−H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C@@H:10]([O:21][CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(F)cc2)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 112.4 %

Procedure:
Dissolve tert-butyl-(3R,4R)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate (496 mg, 1.51 mmol) in THF (3 mL) and cool to 0° C. in an ice water bath. Add sodium hydride (84.6 mg, 2.12 mmol), stir for 30 min, and then add methyl iodide (141 uL, 2.27 mmol). Warm to ambient temperature and stir for 5 hours. Quench the reaction with water (5 mL) and separate layers. Extract aqueous layer three times with methyl tert-butyl ether (8 mL), combine organic extracts; dry over magnesium sulphate; filter; collect the filtrate; and concentrate under vacuum to give the title product as a yellow oil (525 mg, 99.9%). MS (m/z): 210 (M+1-Boc).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=2)=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(Br)cn2)cs1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47 %

Procedure:
2-[(4-{2-[(5-Bromopyridin-2-yl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (12.5 g) obtained in Example 242-1 was dissolved in tetrahydrofuran (20 mL), 1 mol/L-borane/tetrahydrofuran complex (100 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (100 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, 2-aminoethanol (40 mL) was added, and the mixture was stirred at 70° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1) to give the title compound (5.7 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: Cc1ccccc1CC(=O)O
Product: CCC(NC(=O)Cc1ccccc1C)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2ncn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 4-difluoromethyl-8-ethynyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.31) (190 mg, 0.56 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (153 mg, 0.56 mmol) according to general procedure II. Obtained as a brown solid (192 mg, 64%). MS (ISN) 527.1 [(M−H)−]; mp 149° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH:11]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:21]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:30][S:27]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9][NH:7][CH3:6])=[CH:26][CH:25]=2)[CH:21]=[CH:22]1)(=[O:29])=[O:28]
Reactant: CN(CCC(c1ccccc1)c1ccc2c(ccn2S(C)(=O)=O)c1)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCC(c1ccccc1)c1ccc2c(ccn2S(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 71 %

Procedure:
To a 0° C. solution of [3-(1-Methanesulfonyl-1H-indol-5-yl)-3-phenyl-propyl]-methyl-carbamic acid tert-butyl ester LXXVI (56 mg, 0.127 mmol) in DCM (3 ml) was added triethylsilane (300 μl) and TFA (1.5 ml). The resulting mixture was stirred at 0° C. for 5 minutes and at room temperature for 40 minutes. The mixture was concentrated, and the residue was partitioned between a saturated solution of NaHCO3 and EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) affording [3-(1-Methanesulfonyl-1H-indol-5-yl)-3-phenyl-propyl]-methyl-amine LXXVIII as a white solid (31 mg, 71% yield). The amine LXXVIII (31 mg, 71% yield) was dissolved in Et2O (3 ml) and HCl (1M in Et2O, 95 μl) was added. The precipitate was filtered, washed with Et2O and dried in vacuo to afford the hydrochloride as a white powder (33 mg, 96% yield). MS (M+H)=343
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]=[C:6]3[C:11]4[C:16]([CH2:17][C:5]3([CH3:18])[C:4]=2[CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[CH3:19][Li].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH3:19][C@@:6]12[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][C@:5]1([CH3:18])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=1[NH:7]2
Reactant: [Li]C
Reactant: Cc1ccc2c(c1)C1(C)Cc3ccccc3C1=N2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc2c(c1)[C@@]1(C)Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 9b,10-dihydro-8,9b-dimethylindeno[1,2-b]indole, (5.05 g, 0.022 mol) in dry tetrahydrofuran (100 cm3) at -78° C., under nitrogen, in a flame dried flask, was added dropwise methyllithium, (1.4M solution in diethyl ether, 23.2 cm3, 0.032 mol). The mixture was stirred at -78° C. for 2 hours and then at -15° C. for a further 1 hour. Saturated ammonium chloride solution (3 cm ) was then added and the mixture allowed to warm to room temperature. The reaction mixture was portioned between ether and saturated ammonium chloride solution and the layers separated. The aqueous phase was extracted with diethyl ether (2×25 cm3) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated to afford the title compound as an off white solid. This was purified by flash chromatography on silica gel eluting with 3-10% ethyl acetate/60°-80° petrol to yield a colourless solid. Yield: 2.73 g, 51% .M.p. 208°-212° C. 1H NMR (CDCl3) δ: 7.1-7.3 (4H, m), 6.94 (1H, m), 6.77 (1H, d, J=7.8 Hz), 6.46 (1H, d, J=7.8 Hz), 3.35 (1H, d, J=15.9 Hz), 3.06 (1H, d, J=15.9 Hz), 2.22 (3H, s), 1.46 (3H, s), 1.34 (3H, s).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:9][C:8]1([CH3:20])[CH3:19])(=[O:3])[CH3:2].[C:21]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[OH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[K+].[I-].[K+]>O.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:32]2[CH2:33][CH2:34][CH:29]([C:27]([OH:28])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][CH2:31]2)=[CH:9][C:8]1([CH3:20])[CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1C=CC(C(=O)CCCCl)=CC1(C)C
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OCCC1C=CC(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)=CC1(C)C

Procedure:
Mix 4-(4-chloro-1-oxobutyl)-2,2-dimethylphenethyl acetate (99.5 g, 0.335 mol), α,α-diphenyl-4-piperidinemethanol (101.8 g, 0.335 mol), potassium hydrogen carbonate (83.8 g, 0.838 mol), potassium iodide (1.00 g, 0.006 mol), toluene (600 mL) and water (220 mL). Stir at reflux for 72 hours, add toluene (200 mL) and deionized water (100 mL). Filter through filter aid while at 80° C. and separate the organic phase. Dry (MgSO4), filter and purify by chromatography (ethyl acetate) to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethyl acetate as an oily solid.