Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].F[C:16]1[C:17](C)=[C:18]([C:22]2C=CC(C(O)=O)=C[C:23]=2COC)[CH:19]=[CH:20][CH:21]=1.C(C1C=CC=CC=1B(O)O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:22]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:16][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14])[CH3:23]
Reactant: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccccc1-c1ccc(C(=O)OC)cc1COC
Temperature: 100 °C
Yield: 83 %

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1 Step 2, 12.0 g, 46.3 mmol) in toluene (150 mL) and water (35 mL) under N2, was added 2-ethylbenzene boronic acid (9.02 g, 60.1 mmol) followed by potassium carbonate (19 g, 139 mmol) and Pd(PPh3)4 (2.67 g, 2.31 mmol). The reaction mixture was degassed with N2 and heated at 100° C. for 12 hours. The reaction mixture was diluted with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (100 mL), water (2×100 mL) and brine (100 mL). It was then dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, pet ether/EtOAc) to afford the title compound as a pale yellow liquid (12.0 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 8.25 (1H, s), 8.00 (1H, d), 7.35 (2H, m), 7.25 (2H, m), 7.08 (1H, d), 4.12-4.21 (2H, m), 3.94 (3H, s), 3.29 (3H, s), 2.28-2.43 (2H, m), 1.03 (3H, t).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[OH-].[Na+].Br[CH2:19][CH2:20][Cl:21].C(OCC)(=O)C.ClCCl>CS(C)=O>[Cl:21][CH2:20][CH2:19][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[CH2:11][CH2:12]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccccc1N1CCN(CCCl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A mixture of 1-(2-methoxyphenyl)piperazine HCl (52.5 mmol) and powdered sodium hydroxide (105 mmol) in DMSO (40 mL), was stirred at ambient temperature. After 0.5 h, 1-bromo-2-chloroethane (78.8 mmol) was added to the solution and left to stir for 4 h. The reaction was monitored by TLC (ethyl acetate: dichloromethane 1:4), upon completion, the mixture was poured into 200 mL of ice water and the product was extracted with dichloromethane twice, dried with sodium sulfate, and solvent was removed under vacuum. Flash chromatography (ethyl acetate: dichloromethane, 1:5 yielded an oil of the title compound (7.30 g).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][N:11]=[CH:12][C:5]=12.C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CN(C=O)C>[I:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[N:11]=[CH:12][C:5]=12
Reactant: Ic1ccnc2[nH]ncc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ncc2c(I)ccnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of NaH (0.9 g) in anhydrous THF (25 ml) at −5° C. was added 4-iodo-1H-pyrazolo[3,4-b]pyridine (5 g) in anhydrous THF (75 ml) and DMF (25 ml). Triethylamine (3 ml) was added and the reaction was stirred for 30 min at 0° C. Benzenesulfonyl chloride (2.9 ml) in anhydrous THF (25 ml) was added dropwise over 10 min and the reaction was stirred for 1 h at 0° C. then quenched with water. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and then evaporated to yield a solid residue that was triturated with methanol to give title compound, 4.1 g.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]1[NH:6][C:7](=[O:24])[C:8]2[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:12][N:11]([CH3:23])[C:9]=2[N:10]=1)[CH2:2][CH3:3].CN(C)C=O.[H-].[Na+].[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O>[CH2:35]([N:6]1[C:7](=[O:24])[C:8]2[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:12][N:11]([CH3:23])[C:9]=2[N:10]=[C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)[nH]1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a solution of 2-(dipropylamino)-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (50 mg, 0.14 mmol) and dimethylformamide (3 ml) was added sodium hydride (60% in oil, 10 mg, 0.25 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of benzylchloride (64 mg, 0.50 mmol) and dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 1 hour, the mixture was heated at 80° C. After cooling to room temperature, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1) to give 11 mg (17%) of the title compound.
Reaction SMILES: O=C(C[N:8]1C(=O)C2C=CC=CC=2NC2N=CC=CC1=2)CC([O-])=O.O=[C:25]([CH2:31][N:32]1[C:38](=O)[C:37]2[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=2[NH:35][C:34]2[N:44]=[CH:45][CH:46]=[CH:47][C:33]1=2)[CH2:26][C:27]([O:29][CH3:30])=[O:28].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N:8]1[C:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:31][N:32]2[C:38]=1[C:37]1[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=1[NH:35][C:34]1[N:44]=[CH:45][CH:46]=[CH:47][C:33]2=1
Reactant: COC(=O)CC(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Reactant: O=C([O-])CC(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COC(=O)Cc1cn2c(n1)-c1ccccc1Nc1ncccc1-2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 3-oxo-4-(6-oxo-6,11-dihydro-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-5-yl)butanoate (crude product from step 1, 0.36 g, 1 eq.) in acetic acid (5 mL) was added ammonium acetate (0.385 g, 20 eq. based on the amount of starting material used in step 1). The reaction was stirred at 120° C. for 2 hours. The reaction was poured onto water (25 mL) and extracted with dichloromethane (2×25 mL). The combined extracts were washed with water (1×25 mL), saturated sodium bicarbonate (25 mL), brine (1×25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10% methanol in dichloromethane) gave the methyl 2-(9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetate (0.4 g). LCMS: 307 [M+H].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:6][C:7](Cl)=[O:8].[CH3:10][C:11]([C:13]1[C:14]([OH:20])=[CH:15][CH:16]=[CH:17][C:18]=1[OH:19])=[O:12].C(OCC)(=O)C>[N+](C1C=CC=CC=1)([O-])=O>[C:11]([C:13]1[C:14]2[O:20][CH2:6][C:7](=[O:8])[C:15]=2[CH:16]=[CH:17][C:18]=1[OH:19])(=[O:12])[CH3:10]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)c1c(O)cccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1c(O)ccc2c1OCC2=O
Temperature: 0 °C
Yield: 71 %

Procedure:
The synthesis was performed with reference to the known literature (Journal of the Pharmaceutical Society of Japan (Yakugaku Zasshi), Vol. 88, p. 589, 1968). A suspension of aluminum chloride (3.5 g, 26 mmol) in nitrobenzene (10 mL) was stirred at 0° C. under an argon atmosphere. This suspension was added with chloroacetyl chloride (1.1 g, 9.9 mmol), and then the mixture was added dropwise with a suspension of 2,6-dihydroxyacetophenone (1.0 g, 6.6 mmol) in nitrobenzene (6.0 mL). After completion of the addition, the reaction mixture was stirred at 50° C. for 17 hours. The reaction mixture was added with ethyl acetate and ice water, the mixture was stirred at room temperature for 1 hour, and then the organic layer was separated. The organic layer was extracted with 1 N aqueous sodium hydroxide, and the aqueous layer was made acidic with 3 N hydrochloric acid to precipitate solid. The precipitated solid was collected by filtration and dried to obtain 7-acetyl-6-hydroxybenzofuran-3(2H)-one (0.90 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(N3CCCC3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(N3CCCC3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted 1-Methyl-7-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.[CH:11]1[C:16]([O:17][C:18](Cl)=[O:19])=[CH:15][CH:14]=[C:13]([Cl:21])[CH:12]=1.O>C[Si](C)(C)N[Si](C)(C)C>[Cl:21][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18](=[O:19])[N:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]2)[CH3:1])=[CH:11][CH:12]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN[C@H]1CC[C@H](CO)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: O
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.60 g (32.14 mmol) of trans-(4-Methylamino-cyclohexyl)-methanol was suspended in 85 ml hexamethyldisilazane and refluxed for 5 h. The solution was evaporated under reduced pressure and dissolved in 50 ml THF. 6.14 g (32.14 mmol) of 4-chlorophenylchloroformate were added slowly at 0° C. and stirred for 16 h at room temperature. 30 ml H2O were added and after 1 h the solvents were evaporated. The residue was extracted with water/Et2O (3×), the organic phases were washed with 10% NaCl, dried over Na2SO4 and evaporated to yield after flash-chromatography on silica gel (hexane/EtOAc 4:1 to 1:1) 5.48 g (57%) of trans-(4-Hydroxymethyl-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 298 (MH+, 1Cl).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[ClH:24]>C(OCC)C.CCCCCC.O>[ClH:24].[F:15][C:16]1[CH:17]=[C:18]([C:19](=[NH:3])[NH2:20])[CH:21]=[CH:22][CH:23]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: N#Cc1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: N=C(N)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of hexamethyldisilazane (13.8 g, 85.6 mmol) in diethyl ether (143 ml) was added dropwise a 1.6 N solution (53.5 ml, 85.6 mmol) of n-butyllithium in hexane under ice-cooling. Thereto 3-fluorobenzonitrile (5.00 g, 41.3 mmol) was added, followed by stirring at room temperature for 2 hours. Thereto 3 N hydrochloric acid (57 ml) was added dropwiseunder ice-cooling, and the reaction mixture was stirred at room temperature for 0.5 hour. Water (200 ml) was added thereto, and the ether layer was removed. The aqueous layer was basified with an aqueous 3 N sodium hydroxide solution, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to the residue, and 4.65 g (64.5%) of the desired product as a solid was collected by filtration.
Reaction SMILES: CC12[O:10][B:9]([C@@H:11]([NH:28][C:29]([C:31]3([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:33][CH2:32]3)=[O:30])[CH2:12][C:13]3[C:14](OC)=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18]C(C)(C)C)=[O:17])[O:8]C1CC1CC2C1(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:8][B:9]1[C@@H:11]([NH:28][C:29]([C:31]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][CH2:33]2)=[O:30])[CH2:12][C:13]2[CH:25]=[CH:24][CH:23]=[C:15]([C:16]([OH:18])=[O:17])[C:14]=2[O:10]1
Reactant: COc1c(C[C@H](NC(=O)C2(c3ccccc3)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=C(O)c1cccc2c1OB(O)[C@@H](NC(=O)C1(c3ccccc3)CC1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
To a solution of tert-butyl 3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-2-(1-phenylcyclopropanecarboxamido)ethyl)-2-methoxybenzoate from step 1 (200 mg, 0.35 mmol) in anhydrous CH2Cl2 (5 mL) at −78° C. was added BCl3 (2.5 mL, 1M in DCM, 2.5 mmol), and the reaction mixture was stirred at same temperature for 1 hr, at which time the reaction mixture was warmed up to 0° C. and stirred at same temperature for additional 1 hr. The reaction was quenched by addition of water (5 mL) at 0° C. The aqueous phase was extracted by EtOAc. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude product was recrystallized in EtOAc/Hexane to afford the product (35 mg) as white solid. ESI-MS m/z 352 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:22])[F:21])[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:20]([F:21])([F:23])[F:22])[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc(CC2CCN(C)CC2)c(C(F)(F)F)c1
Solvent: CO
Product: CN1CCC(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 6), except that ethyl 4-(1-methylpiperidin-4-ylmethyl)-3-trifluoromethylbenzoate obtained in the step 1 was used, and that the crude product was mixed with methanol and stirred, insolubles were removed by filtration, the filtrate was distilled off under reduced pressure, and then the residue was crystallized by adding acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[I-:11].[Na+].C(Cl)(=O)C.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(OCC)C>[I:11][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1
Reactant: [I-]
Reactant: Clc1ccn2nccc2n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Ic1ccn2nccc2n1
Yield: 51.7 %

Procedure:
Dissolve 5-chloro-pyrazolo[1,5-a]pyrimidine (Hans Reimlinger et al., Chem. Ber. 1970, 103, 3252-3265; 1.15 g, 7.5 mmol) and sodium iodide (5.6-g, 37.4 mmol) in anhydrous acetonitrile (50 mL). Add acetyl chloride (2.7 ml, 37.9 mmol). Stir and reflux under nitrogen for 20 h. Pour the reaction mixture into a stirring mixture of 0.5M aqueous potassium carbonate (200 mL), 1.0M aqueous sodium sulfite (50 mL), and diethyl ether (350 mL). Separate the organic layer, dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Chromatograph the crude product on flash silica using neat dichloromethane to obtain 950 mg (51%) of the title compound as a yellow solid. TOF MS ES+ exact mass calculated for C6H4N310): m/z=245.9528; Found: 245.9517. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=7 Hz, 1H), 8.18 (d, J=2 Hz, 1H), 7.32 (d, J=7 Hz, 1H), 6.69 (d, J=2 Hz, 1H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:10][OH:11])=O)(C)(C)C.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26].Cl>>[NH2:8][C@@H:9]([CH2:12][S:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH2:10][O:11][C:25](=[O:26])[C:24]([CH3:29])([CH3:28])[CH3:23]
Reactant: COc1ccc(CSC[C@H](CO)NC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Product: COc1ccc(CSC[C@H](N)COC(=O)C(C)(C)C)cc1

Procedure:
(S)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propanol prepared in Step C, trimethylacetylchloride and HCl (4 N dioxane solution) were reacted according to the same procedures as Steps D and E of Preparation 31 consecutively to give the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].C(C1C=CC=CC=1N)#[N:21]>>[C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])#[N:21]
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Reactant: N#Cc1ccccc1N
Product: N#Cc1ccccc1NC(=O)C1CCCCC1
Yield: 75 %

Procedure:
This compound was prepared following the procedure described for compound 26A in example 26, except that 2-cyanoaniline was used in place of 2-trifluoromethylaniline. Yield 75%. M.p. 135-137° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[NH2:20]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26](=[O:30])[N:27]([CH3:28])[CH3:29])[NH:20][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)COc1ccc(N)cc1Cl
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC(=O)N(C)C)c(Cl)c3)ncn2)c1
Yield: 46 %

Procedure:
Using an analogous procedure to that described in Example 18, 4-chloro-6-(3'-methylanilino)pyrimidine (0.33 g) was reacted with 3-chloro-4-(N,N-dimethylcarbamoylmethoxy)aniline to give 4-[3'-chloro-4'-(N,N-dimethylcarbamoylmethoxy)anilino]6-(3'-methylanilino)pyrimidine is 46% yield, m.p. 190°-193° C.;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:18]([F:19])=[C:17]([CH3:20])[C:16]([F:21])=[C:15]([F:22])[C:10]=1[C:11](OC)=[O:12].O.Cl>[Na]>[CH3:7][O:8][C:9]1[C:18]([F:19])=[C:17]([CH3:20])[C:16]([F:21])=[C:15]([F:22])[C:10]=1[CH2:11][OH:12]
Reactant: COC(=O)c1c(F)c(F)c(C)c(F)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: COc1c(F)c(C)c(F)c(F)c1CO
Reaction time: 3 h
Yield: 91.6 %

Procedure:
Lithium aluminium hydride (0.5 g) was added to a stirred solution of methyl 2-methoxy-4-methyl-3,5,6-trifluorobenzoate (6.2 g) in sodium dried diethyl ether (50 cm3) and the mixture stirred for a further three hours. The mixture was then stood at the ambient temperature for a further 17 hours. After pouring the mixture into water and acidifying with dilute hydrochloric acid the resultant mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure yielded 2-methoxy-4-methyl-3,5,6-trifluorobenzyl alcohol (5.0 g) as a low melting white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:10](SC)[C:9]2[C:4](=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[CH:6]=[CH:7][CH:8]=2)[NH:3]1>[Ni].C(O)C>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COc1ccccc1Oc1cccc2c1NC(=O)C2SC
Agent: [Ni]
Solvent: CCO
Product: COc1ccccc1Oc1cccc2c1NC(=O)C2
Yield: 21.2 %

Procedure:
A mixture of 2-oxo-3-methylthio-7-(2-methoxyphenoxy)indoline (3.9 g) and Raney nickel (3.9 ml) in dried ethanol (70 ml) was treated in a similar manner to that of Preparation 15-(2) to give 2-oxo-7-(2-methoxyphenoxy)indoline (0.7 g), mp 145°-147° C.
Reaction SMILES: [CH2:1]([N:19]=[C:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:22]([CH2:47][CH2:48][OH:49])([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:46])([F:45])[F:44])([F:42])[F:41])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23]>>[CH2:1]([NH:19][C:20]([O:49][CH2:48][CH2:47][C:22]([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:44])([F:45])[F:46])([F:41])[F:42])([F:38])[F:39])([F:35])[F:36])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Octadecyl isocyanate (29.5 g, 0.1 moles) and C8F17CH2CH2OH (46.4 g, 0.1 moles) were mixed under nitrogen and heated with stirring to 90° C. for 8 hours. An infrared spectrum showed no -NCO absorption, indicating completion of the reaction. The product is a white wax melting at 72-75° C. NMR showed proton resonances at 4.7 ppm (1 proton NH), 4.4 ppm (2 proton CH2OCO-), 3.2 ppm (2 protons CH2CH2NH), 2.5 ppm (2 protons C8F17CH2), 1.3 ppm (32 protons CH3(CH2)16) and 0.8 ppm (3 protons CH3 (CH2)16).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C.O>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH3:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC[O-]
Reactant: Cc1cnc(Cl)c(Br)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(C)cc1Br
Temperature: 100 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
To a solution of 3-bromo-2-chloro-5-methylpyridine (4.00 g, 19.37 mmol) in ethanol (100 mL) was added sodium ethoxide (6.59 g, 96.9 mmol) in three portions. The mixture was stirred under nitrogen at 100° C. for 2 days. The reaction was cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 20%, EtOAc/hexanes) afforded the title compound (3.00 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J=0.8, 2.3 Hz, 1H), 7.89-7.82 (m, 1H), 4.31 (q, J=7.0 Hz, 2H), 2.18 (t, J=0.8 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:31][C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Br)#[N:34]>>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:31]([CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[C:33]#[N:34])[C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2[nH]c(C3CCCC(NC(=O)OCc4ccccc4)C3)nc2c2ccccc21
Reactant: N#Cc1ccccc1CBr
Product: Cn1c(=O)c2c(nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n2Cc2ccccc2C#N)c2ccccc21
Yield: 82 %

Procedure:
According to the procedure described in example 3, step E; [3-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (90 mg, 0.21 mmol) was alkylated with 2-cyanobenzyl bromide (61 mg, 0.31 mmol) to give, after work-up and chromatography, {3-[3-(2-cyano-benzyl)-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (94 mg, 82% yield). 1H-NMR (CDCl3): δ 8.38 (m, 1H), 7.74 (m, 1H), 7.25–7.57 (m, 10H), 6.82 (m, 1H), 6.21 (m, 1H), 5.97 (m, 1H), 5.08 (s, 2H), 3.78 (s, 3H), 3.67 (m, 1H), 2.87 (m, 1H), 2.08 (m, 1H), 2.0 (m, 1H), 1.87 (m, 2H), 1.72 (m, 2H), 1.61 (m, 1H), 1.49 (m, 1H), 1.32 (m, 1H). MS: calculated for C33H31N5O3+H 546.3; found: 546.2.