Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC.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>[F:14][C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:19]3[CH:20]=[N:21][CH:22]=[C:17]([CH3:16])[CH:18]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cncc(-c2nc3c(C)c(F)ccc3cc2C=O)c1
Yield: 79.8 %

Procedure:
Prepared according to the procedure described for Intermediate 41, utilising 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (5.0 g, 22.36 mmol), 5-methylpyridin-3-ylboronic acid (6.95 g, 50.75 mmol), tetrakis(triphenylphosphine)palladium(0) (258 mg, 0.22 mmol) and Na2CO3 (3.55 g, 33.54 mmol) in water (30 mL) and DME (60 mL). The crude material was triturated in diethyl ether (75 mL), and the solid was filtered off and dried under vacuum to give the title compound (5.0 g, 80%) as a brown solid. δH (DMSO-d6) 10.12 (s, 1H), 9.06 (s, 1H), 8.72 (d, J 1.9 Hz, 1H), 8.60 (d, J 1.5 Hz, 1H), 8.24 (dd, J 9.0, 6.4 Hz, 1H), 7.99 (d, J 0.6 Hz, 1H), 7.68 (t, J 9.2 Hz, 1H), 2.66 (d, J 2.4 Hz, 3H), 2.44 (s, 3H). LCMS (ES+) 281 (M+H)+, RT 1.66 minutes.
Reaction SMILES: C[O:2][C:3]1([CH3:10])O[CH:8]2[CH:5]([CH2:6][CH2:7]2)[O:4]1.C[Si](C)(C)[Br:13]>C(Cl)Cl>[Br:13][C@@H:8]1[CH2:7][CH2:6][C@H:5]1[O:4][C:3](=[O:2])[CH3:10]
Reactant: COC1(C)OC2CCC2O1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CC[C@H]1Br
Yield: 92.7 %

Procedure:
107.0 g (0.743 mol) of 3-methoxy-3-methyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 122.0 g (0.8 mol) of trimethylbromosilane are heated under reflux in 400 ml of methylene chloride for 15 hours. Concentration and distillation in vacuo give 132.9 g (93%) of trans-1-bromo-2-acetoxy-cyclobutane. Boiling point11 78°, nD20 1.4748.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:23]=[C:22]([C:24]2([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27][NH:26][CH2:25]2)[CH:21]=[C:20]([C:33]([F:36])([F:35])[F:34])[N:19]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:23]=[C:22]([C:24]2([C:29]([F:30])([F:31])[F:32])[CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([CH:13]4[CH2:15][CH2:14]4)=[O:12])[CH3:9])=[CH:4][CH:3]=3)[CH2:25]2)[CH:21]=[C:20]([C:33]([F:34])([F:35])[F:36])[N:19]=1
Reactant: FC(F)(F)c1cc(C2(C(F)(F)F)CCNC2)cc(C(F)(F)F)n1
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](NC(=O)C1CC1)c1ccc(N2CCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
To the solution of N-[(1S)-1-(4-bromophenyl)ethyl]cyclopropanecarboxamide (0.134 g) and 2,6-bis(trifluoromethyl)-4-[3-(trifluoromethyl)pyrrolidin-3-yl]pyridine (0.195 g) in toluene was added sodium tert-butoxide (0.096 g), tris(dibenzylideneacetone)dipalladium chloroform complex (0.010 g) and xantphos (0.017 g) and the vessel was applied by Ar gas. The vessel was sealed and applied to microwave reactor at 120° C. for 10 min. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield N-[(1S)-1-(4-{3-[2,6-bis(trifluoromethyl)pyridin-4-yl]-3-(trifluoromethyl)pyrrolidin-1-yl}phenyl)ethyl]cyclopropanecarboxamide (0.272 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH3:6])=[O:4].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:15]([NH:1][C@@H:2]([CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH3:6])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC1CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCCC1)NCc1ccccc1

Procedure:
1.04 g (5.22 mmol) methyl (S)-2-amino-3-cycloheptyl-propionate were stirred with 0.62 ml (5.22 mmol) benzylbromide, 1.44 g (10.4 mmol) potassium carbonate and 20 ml DMF at 100° C. for 3.5 h. Then water was added and the mixture was extracted with ethyl acetate. The organic phase was evaporated down and the residue was purified by flash chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH2:47][CH2:48][O:49]S(C)(=O)=O)[CH:44]=[CH:45][CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1.C1C[O:63]CC1>>[CH:48]([OH:49])=[O:63].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][N:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Reactant: C1CCNCC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCN5CCCCC5)c4)c4ccccc43)cn12
Product: O=CO

Procedure:
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and piperidine (30 μL, 0.30 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (26 mg, 55%). LCMS (Method 5): Rt 3.75 min, m/z 730.7 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.28 (9H, s), 1.31-1.37 (2H, m), 1.43-1.55 (6H, m), 1.62-1.71 (2H, m), 1.75-1.97 (4H, m), 2.00-2.17 (2H, m), 2.41 (4H, t, J=4.4 Hz), 2.52-2.56 (2H, m), 2.79 (2H, t, J=7.9 Hz), 2.90 (1H, ddd, J=12.1, 9.1, 4.0 Hz), 3.16 (1H, dt, J=11.8, 4.1 Hz), 3.28-3.35 (1H, m), 4.82 (1H, td, J=8.6, 5.5 Hz), 5.52 (1H, t, J=4.3 Hz), 6.32 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.9, 2.1 Hz), 7.24-7.42 (8H, m), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.69 (1H, d, J=2.1 Hz), 8.11 (1H, s), 8.19 (1.4H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH:13]=[CH:14]C.BrN1[C:21](=[O:22])CCC1=O.O>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH:13]([CH3:14])[CH:21]=[O:22]
Reactant: CC=Cc1cc(OC)c(OC)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OC)c(C(C)C=O)cc1OC
Yield: 45 %

Procedure:
A mixture of 2,4,5 trimethoxy phenyl propene (1 mmol), N-bromosuccinimide (1.5 mmol), water (12 ml), DMSO (3 ml), cetyltrimethyl ammonium bromide (0.3 mmol) was taken in a 100 ml Erlenmeyer flask fitted with loose funnel at the top. The flask was shaken well and placed inside the multimode microwave oven and irradiated (900 W) for 8 minutes in parts. After completion of reaction, the reaction mixture was worked up as in example-1 to provide the corresponding 2-(2,4,5 trimethoxy phenyl)propionaldehyde (45% yield) whose spectral data matched with that mentioned in example-1.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][CH2:12][CH2:11][CH2:10][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: Cc1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(OCCCCl)cc1
Yield: 102 %

Procedure:
A mixture of 27 g (0.25 mole) of p-cresol, 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.7 g (0.75 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and concentrated in vacuo at 90° C. to give 47.1 g of an oil residue. The oil was subjected to vacuum distillation to give 39.3 g (85%) of clear oil, bp 85°-90° C. at 0.1 mm Hg.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=[O:5].Cl[C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].CCN(CC)CC>C(Cl)Cl.O>[O:24]=[C:18]([NH:2][CH2:3][C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:10][CH:11]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCC(=O)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a solution of 2-amino-1-(4-(trifluoromethoxy)phenyl)ethanone hydrochloride (9.5 g, 37 mmol) in DCM (150 mL) at 0° C. was added dropwise ethyl 2-chloro-2-oxoacetate (5.6 g, 41 mmol), followed by Et3N (16 mL, 111 mmol). The mixture was stirred at RT for 16 h and then diluted with H2O (200 mL) and extracted with EtOAc (4×80 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1 to 1:1) to give the title compound as a yellow solid (7.8 g, 66%). MS (ES+) C13H12F3NO5 requires: 319. found: 320 [M+H]+.
Reaction SMILES: C(OC(NCCC[N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24](=[O:32])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:33]([OH:35])=[O:34])=O)C1C=CC=CC=1>CO.[Pd]>[C:33]([OH:35])(=[O:34])[CH3:16].[NH2:15][CH2:16][CH2:17][CH2:18][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([C:24](=[O:32])[NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:19]=2)[NH:15][C:16]=1[C:33]([OH:35])=[O:34]
Reactant: O=C(NCCCn1c(C(=O)O)cc2cc(C(=O)Nc3ccccc3)ccc21)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)O
Product: NCCCc1c(C(=O)O)[nH]c2ccc(C(=O)Nc3ccccc3)cc12
Reaction time: 5 h

Procedure:
A reaction flask equipped with a stir bar was charged with a solution of the above carboxylic acid (40 mg, 0.08 mmol) in methanol (10 mL). 10% Palladium on carbon (20 mg) was added. The reaction mixture was sealed with a rubber septum and the air was evacuated under house vacuum. A balloon filled with hydrogen gas was attached to the flask, and the reaction mixture was stirred for 5 h. The mixture was filtered through diatomaceous earth and the filtrate was evaporated. The residue was washed with 2 mL of ether and 2 mL of hexane. The product was dried and 5 mL of acetic acid was added. The acetic acid was evaporated under high vacuum to give the title compound as the acetate salt (25 mg, 71%).
Reaction SMILES: Br[CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[C:13]([CH3:16])=[N:14][N:15]=[C:3]12.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:26]([O-])([O-])=O.[Cs+].[Cs+]>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>[CH3:16][C:13]1[N:4]2[C:5]3[CH:12]=[CH:11][C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:9][C:6]=3[N:7]([CH3:26])[CH2:8][CH2:2][C:3]2=[N:15][N:14]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nnc2n1-c1ccccc1NCC2Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1N(C)CC2
Yield: 40.5 %

Procedure:
A solution of bromo-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (50 mg, 0.17 mmol), phenylboronic acid (42 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (10 mg) and Cs2CO3 (110 mg, 0.34 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=10:1) to afford 1,6-dimethyl-8-phenyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (20 mg, yield 41%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH2:13]([NH2:19])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1.COC(OC)OC.[BH4-].[Na+]>CO.CC(O)=O>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:19][CH2:13][C:14]2[O:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: NCc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CCCOc1ccc(CNCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
4-Propoxy benzaldehyde (5 g, 31 mmol) and furfuryl amine (3.9 g, 40 mmol) in a mixture of methanol (50 mL), trimethylorthoformate (10 mL) and AcOH (˜1 mL) were stirred at room temperature, under an atmosphere of nitrogen for 16 hours. Sodium borohydride (1.4 g, 35 mmol) was added in 4 portions, over a period of 30 minutes (exothermic reaction). The reaction was stirred for an additional 2 hours at room temperature. The solvent was removed on the rotovap and the residue taken up in ethyl acetate (150 mL). The organic phase was washed with H2O (200 mL) and aqueous phase was back extracted with ethyl acetate (2×, 100 mL). The combined organic layers were concentrated and the residue was purified on silica gel (70% ethyl acetate in hexanes with ˜2% triethylamine) to afford N-(4-propoxybenzyl)-1-(furan-2-yl)methanamine (5.3 g, 75%) as a yellow oil. NMR (CDCl3, 400 MHz): δ 1.03 (t, J=7.2 Hz, 3H), 1.79 (m, J=6.4 Hz, 2H), 3.71 (s, 2H), 3.76 (s, 2H), 3.90 (t, J=6.8 Hz, 2H), 6.17 (d, J=3.2 Hz, 1H), 6.32 (m, 1H), 6.85 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.37 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CC(C)=O>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])=[CH:13][CH:14]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(OCCCCCCBr)cc1
Yield: 86.2 %

Procedure:
A solution of 6.56 g (29.4 mmol) of (4-Hydroxy-phenyl)-methyl-carbamic acid tert-butyl ester dissolved in 250 ml of acetone was treated with 12.2 g (88.1 mmol) of K2CO3 and 13.4 ml (88.1 mmol) of 1,6-dibromohexane. The suspension was heated under reflux overnight, cooled, filtered and concentrated. Purification by flash chromatography on silica gel with toluene/EtOAc (95:5) as eluent yielded 9.79 g (86%) of [4-(6-Bromo-hexyloxy)-phenyl]-methyl-carbamic acid tert-butyl ester, MS: 386 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=3[CH3:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.CO>[C:39]1([S:45]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([C:13]4[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=4[CH3:18])[S:11][CH:12]=3)=[CH:4][CH:3]=2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=S)c1cc(-c2nc(-c3ccc(N)cc3)cs2)c(C)s1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=S)c1cc(-c2nc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cs2)c(C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.3 %

Procedure:
Methyl 4-(4-(4-[(phenysulfonyl)amino]phenyl(1,3-thiazol-2-yl))-5-methiothiothiophene-2-carboxylate: Methyl 4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (100 mg, 0.28 inmol) was dissolved in dry dichloromethane (10 mL). To this, N-methyl morpholine (46 μL, 0.42 mmol) and dimethylaminopyridine (3.4 mg, 0.028 mmol) were added, the mixture was cooled on an ice bath, and benzenesulfonyl chloride 35 μL, 0.28 mmol) was added dropwise. The mixture was then stirred for 24 h at room temperature. Workup was carried out as in Example 134, step (c). Trituration with dichloromethane and methanol gave methyl 4-(4-{4-[(phenylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (44 mg, 31%) as a crystalline solid. 1H-NMR (DMSO-d6; 300 MHz) δ 10.46 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.91 and 7.19 (AB quartet, 2H, J=8.7 Hz), 7.81 (m, 2H), 7.64-7.54 (m, 3H) 3.85 (s, 3H), 2.74 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C22H18N2O4S4 504.2 (M+H), found 504.1
Reaction SMILES: [CH:1]1([C:4]2([F:25])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:14]([CH3:17])(=O)=O)[N:11]=[C:10]([NH:18][C:19]4[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=4)[CH:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.[F:26][C:27]([F:40])([F:39])[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36]C(S)=[CH:34][CH:33]=1)=[O:30]>CC#N>[CH3:24][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[CH:9]=[C:8]([N:6]3[CH2:7][C:4]([CH:1]4[CH2:3][CH2:2]4)([F:25])[CH2:5]3)[N:13]=[C:12]([S:14][C:17]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:27]([F:40])([F:26])[F:39])=[CH:37][CH:36]=3)[N:11]=2)[NH:23][N:22]=1
Reactant: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(S(C)(=O)=O)n2)[nH]n1
Reactant: O=C(CC(F)(F)F)Nc1ccc(S)cc1
Solvent: CC#N
Product: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(Sc3ccc(NC(=O)CC(F)(F)F)cc3)n2)[nH]n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
A slurry of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (61 g, 170 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (41 g, 175 mmol) in CH3CN (1300 mL) was heated to reflux for 1.5 hours. During this time, the slurry transformed from thin and yellowish to thick and brilliant white. The mixture was then cooled to 0° C. and stirred at this temperature for 15 min. The mixture was then filtered and washed with cold CH3CN (650 mL). The resulting solid was dried for 20 hours at 38° C. under house vacuum. The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3(sat) (1300 mL). The mixture was stirred until no more solid remained. Then, the aqueous and organic layers were separated and the aqueous layer was washed with EtOAc (390 mL). The combined organic layers were dried over MgSO4, filtered, washed with EtOAc (130 mL) and concentrated to a minimal volume on rotavap. The resulting mixture was re-crystallized out of EtOAc and hexane to give the desired product as a white solid (56.2 g, 72%) 1H NMR (MeOD, 400 MHz): 0.40-0.45 (2H, m), 0.60-0.65 (2H, m), 1.3-1.4 (1H, m), 2.05 (2H, s), 3.25-3.40 (2H, m), 3.85-3.40 (4H, m), 5.40-5.50 (2H, m), 7.50-7.55 (2H, d), 7.65-7.70 (2H, d). ES+ 522.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl:39][CH2:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43].N1C=CC=CC=1>ClCCCl>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH2:40][Cl:39])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)CCl)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Yield: 82.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), chloropivaloyl chloride (166 mg) and pyridine (86 μl) were added, and the mixture was refluxed for 2 hours 30 minutes. The reaction mixture was successively washed with water,1N hydrochloric acid, and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 509 mg of the titled compound (Yield: 81%).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@@H:13]([OH:25])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>CN(C=O)C>[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:14][C@@H:13]([O:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2ncn3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In DMF (4 mL, 0.05 mol) was suspended sodium hydride (47 mg, 0.0012 mol) at 0° C., to which was added a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (0.200 g, 0.000554 mol) in 2.5 mL DMF. The mixture was stirred at 0° C. for 10 minutes and was added a solution of 6-Chloro-9-(tetrahydropyranyl)purine (0.265 g, 0.00111 mol) (Example 33, step b) in 4 mL DMF. The reaction was stirred at 0° C. for 1 h and warmed to 23° C. overnight. The reaction was quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate, washed with brine, dried (NaSO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 5% acetone/toluene) to obtain 271 mg (86.8%).