Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:19]=O)=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]=2[C:7]1=[O:21])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]2[C:34]3[CH2:41][C:40](=[O:42])[NH:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH:28]=[CH:29][C:30]=1[F:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]2[C:34]3[C:41](=[CH:19][C:13]4[NH:12][C:9]5[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:22][CH3:23])[CH2:1][CH3:2])[C:7](=[O:21])[C:8]=5[C:14]=4[C:15]([F:17])([F:18])[F:16])[C:40](=[O:42])[NH:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C(F)(F)F)c2C1=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ncnc(Nc5ccc(F)c(Cl)c5)c43)c(C(F)(F)F)c2C1=O
Yield: 48.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 123 with 5-(2-diethylamino-ethyl)-3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]-pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[5-(2-diethylamino-ethyl)-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (43 mg, 48.5%) as a yellow solid.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25]([NH2:34])[C:24]=2[N:23]=[C:22]1[CH2:35][CH2:36][CH2:37][CH3:38]>ClCCl>[NH2:34][C:25]1[C:24]2[N:23]=[C:22]([CH2:35][CH2:36][CH2:37][CH3:38])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][S:12]([C:7]3[C:6]4[CH:5]=[CH:4][N:3]=[CH:2][C:11]=4[CH:10]=[CH:9][CH:8]=3)(=[O:14])=[O:13])[C:33]=2[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A suspension of isoquinoline-5-sulfonyl chloride hydrochloride (0.83 g in 50 ml of pyridine, 3.1 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2 mmol) and dichloromethane (175 ml). The solution turned a bright yellow color and was maintained at room temperature for 4 hours. An additional 0.18 g of isoquinoline-5-sulfonyl chloride hydrochloride was added and the reaction was maintained an additional 60 hours. The yellow solution was concentrated in vacuo, dissolved in dichloromethane, and washed sequentially with saturated aqueous sodium bicarbonate and water. The organic fraction was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol) to provide 0.7 g of N5-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-isoquinolinesulfonamide as a white crystalline solid, m.p. 96.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 9.44 (d, J=0.7 Hz, 1H), 8.64(d, J=6.1 Hz, 1H), 8.41-8.35 (m, 2H), 8.30 (dd, J=7.4, 1.2 Hz, 1H), 8.11 (t, J=5.6 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 7.61 (dd, J=8.3, 1.2 Hz, 1H), 7.41 (dt, J=7.7, 1.2 Hz, 1H), 7.22 (dt, J=7.6, 1.2 Hz, 1H), 6.47 (broad s, 2H), 4.38 (t, J=7.5 Hz, 2H), 2.86-2.74 (m, 4H), 1.78-1.63 (m, 4H), 1.50-1.34 (m, 4H), 0.94 (t, J=7.4 Hz, 3H); MS (EI) m/e 502.2151 (502.2151 calcd for C27H30N6O2S). Anal calcd for C27H30N6O2S: C, 64.52; H, 6.02; N, 16.72. Found C, 64.03; H, 6.03; N, 16.55.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[S:15])[C:10]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:9]=2[O:8]1>>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[S:15])[C:10]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:9]=2[O:8]1
Reactant: CNC
Reactant: CN1CC(CCCl)Oc2ccc([N+](=O)[O-])cc2C1=S
Product: CN(C)CCC1CN(C)C(=S)c2cc([N+](=O)[O-])ccc2O1
Reaction time: 144 h

Procedure:
To 50 ml of freshly collected dimethylamine was added 4.25 g (0.014 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepine-5(4H)-thione. The reaction flask was sealed tightly and allowed to stand at room temperature for 6 days. The dimethylamine was evaporated at room temperature. The solid residue was taken up in methylene chloride, washed twice with 1N hydroxide and once with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Approximately 0.8 g of the crude solid residue was triturated with isopropyl/ether to give the crystalline free base, m.p. 104°-109° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[Br:22][CH2:23][C:24]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[C:11]([F:12])([F:13])[F:14])=[O:25]
Reactant: CC(C)c1ccc(N)c(C(F)(F)F)c1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)CBr)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
50 g (246.06 mmol) of 4-isopropyl-2-(trifluoromethyl)aniline and 27.39 g (270.66 mmol) of triethylamine are initially charged in 1000 ml of dichloromethane. At 0°-5° C., 54.63 g (270.66 mmol) of bromoacetyl bromide, dissolved in 200 ml of dichloromethane, are added dropwise. The mixture is stirred at room temperature for 20 hours. The reaction mixture is then extracted successively with water, 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and water. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified chromatographically. The product is recrystallized from cyclohexane/n-pentane, filtered off with suction and dried under reduced pressure at 40° C. for 20 hours. This gives 32.45 g (41% of theory) of the title compound.
Reaction SMILES: [ClH:1].C([N:9]1[C:13]2([CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14]2)[CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1>[Pd].CO>[ClH:1].[ClH:1].[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:15]2[CH2:16][CH2:17][C:13]3([NH:9][CH2:10][CH2:11][CH2:12]3)[CH2:14]2)[CH:19]=1
Reactant: c1ccc(CN2CCCC23CCN(c2cccnc2)C3)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1cncc(N2CCC3(CCCN3)C2)c1
Reaction time: 24 h
Yield: 88.2 %

Procedure:
Aqueous hydrochloric acid (0.5 mL of 12 M) and 10% palladium on carbon (0.100 g) were added to a solution of 1-benzyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane (1.0 g, 3.41 mmol) in methanol (30 mL). The mixture was shaken under a hydrogen atmosphere (50 psi) in a Parr hydrogenation apparatus for 24 h and filtered through Celite. The filtrate was concentrated by rotary evaporation and column chromatographed on Merck silica gel 60 (70-230 mesh). Elution with 0.01:1:9 (v/v) aqueous ammonia/methanol/chloroform, and concentration of selected fractions, gave 0.650 g (93.8%) of viscous, brown oil. A portion (300 mg, 1.48 mmol) of this material was treated with aqueous hydrochloric acid (2 mL). The water was azeotropically removed by repeated treatment with small volumes of ethanol (˜5 mL) and rotary evaporation. The resulting solid was recrystallized from hot isopropanol to give 360 mg (88.2%) of fine tan crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]=[CH:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:20][S:21]([NH2:24])(=[O:23])=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]=[CH:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(OCC2CC=CCC2)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CC=CCC2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-4-(cyclohex-3-en-1-ylmethoxy)-2-fluorobenzoic acid (53 mg), methanesulfonamide (35 mg), HBTU (95 mg), and DIPEA (0.13 mL) in dichloromethane (0.83 mL) was stirred at rt for 4 hr. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (2×) and brine, and dried (Na2SO4). The crude was purified with HPLC. LCMS (Method D): RT=5.62 min, m/z: 362.1 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.4 Hz, 1H), 5.69 (d, J=2.1 Hz, 2H), 4.06 (dd, J=6.5, 1.3 Hz, 2H), 2.28-1.97 (m, 4H), 1.98-1.76 (m, 2H), 1.50-1.29 (m, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O.C(OC(C)C)(=O)C.O.[Cu]>[F:16][C:10]([F:17])([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)C
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(C)cc1
Temperature: 55 °C
Yield: 69.8 %

Procedure:
The compound was prepared by modification to the procedure of Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A. Chemical & Pharmaceutical Bulletin 47(7), 1013-1016 (1999). To a solution of 1-iodo-4-methylbenzene (25.1 g, 115 mmol) in DMSO (125 mL) was added ethyl bromo(difluoro)acetate (24.7 g, 122 mmol) and copper (16.8 g, 264 mmol), and the resulting solution was heated to 55° C. After 14 h the reaction was cooled to room temperature and diluted with isopropyl acetate, then cooled to 0° C. and treated with a solution of potassium hydrogen phosphate (23.3 g) in water (250 mL). The mixture was filtered through a pad of Celite, rinsing with isopropyl acetate. The phases were separated and the aqueous layer was washed with isopropyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography (5% methylene chloride, 1-8% ethyl acetate/hexanes gradient) gave the title compound (17.2 g) as an oil.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C([Li])CCC.[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:17]=1C(Cl)=O>O1CCCC1>[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:17]=1[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Temperature: -36 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere a 50 gallon kettle was charged with 50.9 kg of tetrahydrofuran, 5.2 kg of monoethyl malonate and about 5 g of 2,2'-dipyridyl. After cooling the mixture to -36° C., 41.6 kg of n-butyllithium (15% in hexane) was added over 3 hours maintaining the temperature at -25° to -35° C. The resultant slurry was cooled further to -60° C. and then treated over about 50 minutes with the acid chloride of part (a) at -62° to -54° C. The green/yellow mixture was stirred for 2 hours at ambient temperature and allowed to warm further overnight. The mixture (-24° C.) was quenched (vacuum) into ambient dilute hydrochloric acid (15 L of muriatic acid and 61 L of deionized water). The quench mixture was separated and the organic phase was washed with 2×40 L of deionized water. The combined aqueous phases were back extracted with 40 L of hexane-ether (1:1). All organic layers were combined and washed with 100 L of saturated sodium bicarbonate solution; again back extracting the aqueous phase with 40 L of hexane-ether (1:1). The combined organic layers were concentrated to an oil in vacuo followed by dissolution in 20 L of hexane and repeated concentration to dryness. The hot oil was finally dissolved in 19 L of hexane. The solution was cooled to -5° C. and the crystallized solids were filtered using 4.8 L of cold (-6° C.) hexane as wash. The material was dried in vacuo at room temperature affording 4234 g of product suitable for use in the next step. A second crop was obtained by concentrating the combined filtrate and wash and cooling to low temperature. The combined yield for the first and second crops was 4841 g (74.9%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][N:6]1[C:10]([I:11])=[C:9]([I:12])[C:8]([I:13])=[C:7]1[I:14])C.O.[OH-].[Na+]>O1CCOCC1>[I:14][C:7]1[N:6]([CH2:5][C:4]([OH:15])=[O:3])[C:10]([I:11])=[C:9]([I:12])[C:8]=1[I:13]
Reactant: CCOC(=O)Cn1c(I)c(I)c(I)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cn1c(I)c(I)c(I)c1I
Yield: 96.8 %

Procedure:
TO a solution of 23.2 g of compound B), 2,3,4,5-tetraiodopyrrol-1-acetic acid ethyl ester (35.32 mmol) , in 840 mL of a dioxane (750 mL) / H2O (90 mL) mixture, 36 mL of 1M NaOH (36 mmol) are quickly added (10 min) and the final solution is kept at room temperature for 4 h. The reaction mixture is treated with carbon Carbopuron 4N, filtered, then acidified with 37% HC1 (w/w) and diluted in 500 1 of H2O, to give a solid which is filtered and purified by chromatography (silica gel (product E. Merck item 9385): eluent: CHCl3 : MeOH : 25% NH4OH (w/w) =7.5:2:0.3 (v/v/v)). Fractions with similar purity are collected, evaporated and diluted with 200 mL of H2O. By acidifying the aqueous phase with 40 mL of 1M HCl , a solid precipitates, which is filtered, washed with H2O and dried under reduced pressure. 21.5 g of 2,3,4,5-tetraiodopyrrol-1-acetic acid(34.20 mmol) are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:29]2[CH2:28][CH:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:31][CH2:30]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a dried flask, (1 S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropyl-cyclopentanecarboxylic acid (200 mg, 0.7 mmol) and 4-phenyl-1,2,3,6-tetrahydropyridine (160 mg, 0.81 mmol) were suspended in methylene chloride (4 mL) under N2. Triethylamine (0.22 g, 2.2 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.36 g, 0.81 mmol). The reaction was stirred overnight at room temperature and quenched by addition of saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (gradient: 0-45% B over 15 min. Bottle A=hexanes, bottle B =EtOAc) to give 234 mg (80%) of desired product. MS calculated for C25H36N2O3: (M+H) 413; found 413.2.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:14][Si:2]([CH3:13])([CH3:1])[C:3]#[C:4][CH:5]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:7][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)C#CCOC1CCCCO1
Reactant: c1ccccc1
Product: C[Si](C)(C)C#CC(C/C=C\CCc1ccccc1)OC1CCCCO1

Procedure:
Reaction of trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)silane (4.6 g, 21.6 mmol 4.6 g, 21.6 mmol) and (z)-5-bromo-pent-3-enyl)-benzene, (4.1 g, 18 mmol)) according to General Procedure 11.A provided the title compound. The material was used in the next step without purification.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[O:15][CH3:16])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[CH3:16][O:15][C:7]1[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:6]=1[O:5][Si:4]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:1]([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Yield: 77.6 %

Procedure:
Dissolve triisopropyl-(2-methoxy-4-nitro-phenoxy)-silane (95.7 g, 294.0 mmol) in EtOH (1800 mL) and add 5% Pd/C (10.0 g). Hydrogenate the slurry at RT under 50 psi hydrogen for 8 h. Filter the slurry through a pad of Celite® and rinse with EtOH. Concentrate the filtrate in vacuo to give a brown oil. Purify the oil by flash chromatography, using a gradient from 100% hexanes to 20% EtOAc/hexanes, to provide 67.4 g (77.6%) of the title compound as a brown solid. MS/ES m/z 296.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:12](Cl)=[N:11][C:10]2[N:9]([CH2:14][CH3:15])[C:8]3[N:16]=[CH:17][C:18]([CH:20]=[CH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:7]=3[C:6](=[O:28])[NH:5][C:4]=2[C:3]=1[CH3:29].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:14]([N:9]1[C:8]2[N:16]=[CH:17][C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][C:7]=2[C:6](=[O:28])[NH:5][C:4]2[C:3]([CH3:29])=[CH:2][CH:12]=[N:11][C:10]1=2)[CH3:15]
Reactant: CCN1c2ncc(C=Cc3ccccc3)cc2C(=O)Nc2c1nc(Cl)c(Br)c2C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCN1c2ncc(CCc3ccccc3)cc2C(=O)Nc2c(C)ccnc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 58.4 %

Procedure:
3-Bromo-2-chloro-5,11-dihydro-11-ethyl-4-methyl-8-(2-phenylethen-1-yl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.22 g) was dissolved in 20 mL of methanol, and ammonium formate (2.0 g) and 10% palladium on carbon (0.13 g) were added. The reaction mixture was stirred at room temperature under argon for 6 d. Additional ammonium formate (1.5 g) was added, and the reaction mixture was stirred for an additional 2 d. The reaction mixture was filtered and diluted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated to give 98 mg of the title compound, which was recrystallized from ethyl acetate/isopropyl ether, to give 51 mg, m.p. 174°-175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[F:28][C:29]([F:42])([F:41])[C:30]1[CH:31]=[C:32]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[NH2:33]>CCCCCCC.C(OCC)(=O)C>[F:28][C:29]([F:41])([F:42])[C:30]1[CH:31]=[C:32]([NH:33][C:11](=[O:12])[C:6]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[CH:10][CH:9]=[N:8][CH:7]=2)[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 3,5-bis(trifluoromethyl)aniline (commercially available; CAS RN 328-74-5) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow foam (44%). MS (ESI): m/z=495.010 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[Cl:10].[CH3:11][N:12]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N>[Cl:10][C:3]1[C:4]([CH3:9])=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: CN1CCCC1=O
Reactant: Cc1c(O)ccc(Br)c1Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1c(O)ccc(C#N)c1Cl
Yield: 54 %

Procedure:
A stirred solution of 4-bromo-3-chloro-2-methylphenol (0.427 g), zinc cyanide (0.271 g), and tetrakis[triphenylphosphine]palladium (0.056 g) in N-methyl-2-pyrrolidinone (5 mL) was heated under microwave irradiation (150 W) at 130° C. for 35 min. The reaction mixture was filtered through anhydrous magnesium sulfate, partitioned between 1:2 ethyl acetate/diethyl ether (15 mL) and water (15 mL). The aqueous phase was re-extracted with 1:2 ethyl acetate/diethyl ether (2×15 mL). The organics were combined, washed with water (2×20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The compound was purified by column chromatography using 1:9 ethyl acetate/iso-hexane as eluent, to give the desired product as a peach coloured solid (174 mg, 54%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([OH:33])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Oc1cncc(Br)c1
Product: Oc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-3-pyridinol (156 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (280 mg, 62%). MS (ISP) 449.2 [(M+H)+]; mp 258-260° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].CO[C:17]([C:19]1([OH:28])[CH2:24][CH2:23][N:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1)=[O:18].CC(C)([O-])C.[K+]>O1CCCC1>[CH3:27][N:25]([CH3:26])[N:22]1[CH2:21][CH2:20][C:19]2([O:28][C:3](=[O:2])[CH:4]([C:5]3[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[CH3:13])[C:17]2=[O:18])[CH2:24][CH2:23]1
Reactant: COC(=O)Cc1c(C)cc(C)cc1C
Reactant: COC(=O)C1(O)CCN(N(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C2C(=O)OC3(CCN(N(C)C)CC3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a degassed solution of 0.5 g (2,4,6-trimethyl-phenyl)-acetic acid methyl ester and 0.63 g 1-dimethylamino-4-hydroxy-piperidine-4-carboxylic acid methyl ester in 20 ml tetrahydrofuran is added under argon at room temperature 5.72 ml of a 1M potassium tert-butoxide solution in tetrahydrofuran dropwise. The reaction mixture is stirred at room temperature for one hour, and at reflux overnight. The solvent is evaporated, the residue poured into ice/water and the pH adjusted to 5-6 by addition of aqueous 2N hydrochloric acid. The water phase is extracted with diethyl ether, the combined organic layer dried over sodium sulfate, and the solvent evaporated. The crude residue (910 mg) is purified several times by chromatography (normal and reversed phase systems) to yield pure 8-Dimethylamino-3-(2,4,6-trimethyl-phenyl)-1-oxa-8-aza-spiro[4.5]decane-2,4-dione (80 mg) as a solid with mp>200° C. 1H-NMR (DMSO-d6): 6.86 ppm (s, 2H), 2.93 ppm (m, 2H), 2.63 ppm (m, 2H), 2.38 ppm (s, 6H), 2.23 ppm (s, 3H), 2.12 ppm (m, 2H), 2.03 ppm (s, 6H), 1.60 ppm (m, 2H).