Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31].C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:30](=[O:31])[C:29]3[CH:28]=[C:27]([O:26][CH3:25])[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CNCCO1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCOC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
1.28 g (4.63 mmole) of 2-[2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol [prepared as described in step (d) above] were dissolved in 30 ml of methylene chloride, and 2.66 g (26.3 mmole) of triethylamine, 1.28 g (5.55 mmole) of 3,4,5-trimethoxybenzoyl chloride and 5 mg of 4-dimethylaminopyridine were added to the resulting solution. The mixture was then stirred at room temperature for 6 hours. At the end of this time, the reaction solution was poured into an aqueous solution of sodium hydrogencarbonate and extracted with methylene chloride. The extract was then washed with a saturated aqueous solution of sodium chloride. The organic extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of methylene chloride and acetone ranging from 4:1 to 7:3 by volume as the eluent, to obtain 1.72 g of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)[N:13]=1>N1C=CC=CC=1>[C:1]([O:18][C:17]1[C:12]([F:11])=[N:13][C:14]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)CCCCCCC)c(F)n2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
1.2 ml (7.1 mmol) of octanoyl chloride are added dropwise at 0° C. to 1.5 g (4.7 mmol) of 2-fluoro-3-hydroxy-6-(4-octyloxyphenyl)pyridine (prepared as described in Example 3) in 20 ml of pyridine, and the mixture is stirred at 0° C. for 3 hours. It is then poured onto ice water, filtered off and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and by recrystallization from acetonitrile, giving 1.34 g of 2-fluoro-6-(4-octyloxyphenyl)pyridine-3-yl octanoate. ##STR20##
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:7][CH:6]=1)=[O:4].[F:34][C:35]([Si](C)(C)C)([F:37])[F:36].[F-].[Cs+].Cl>COCCOC.O>[F:31][C:28]([F:30])([F:29])[CH2:27][N:14]([CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:4])([C:35]([F:37])([F:36])[F:34])[C:2]([F:32])([F:33])[F:1])=[CH:10][CH:9]=1)[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=1
Reactant: N#Cc1ccc(N(CCOc2ccc(C(=O)C(F)(F)F)cc2)CC(F)(F)F)cc1C(F)(F)F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a solution of 4-[(2-{[4-(trifluoroacetyl)phenyl]oxy}ethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.106 g, 0.22 mmol, example 37) and (trifluoromethyl)trimethylsilane (0.040 mL, 0.26 mmol) in dry DME at rt, under N2, was added anhydrous CsF (0.0020 g, 0.011 mmol). The mixture was stirred 3 h at rt and an additional portion of (trifluoromethyl)trimethylsilane (0.040 mL, 0.26 mmol) was added, and the mixture stirred another 2 h. 2N HCl (5 mL) was added, and the mixture was stirred for 60 h at rt. The mixture was diluted with water and the whole extracted with EtOAc (×2). Combined organics were washed (water, brine, dried over Na2SO4 and concentrated in vacuo, affording 0.051 g of the title compound as a pale yellow solid: MS (ESI) m/z 553 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([OH:26])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-])=O)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.O.O.[Sn](Cl)(Cl)(Cl)Cl.[C:34](=O)(O)[O-].[Na+]>CO>[NH2:20][C:11]1[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:23][C:24]([O:26][CH3:34])=[O:25])=[CH:4][C:3]=2[O:2][CH3:1])=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:19])[NH:15]2
Reactant: O=C([O-])O
Reactant: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C)cc2c1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2N)c(OC)c1
Temperature: 65 °C

Procedure:
A solution of 1.2 (1.00 g, 2.81 mmol) and tin chloride dihydrate (5.07 g, 22.5 mmol) dissolved in methanol (10 mL) was heated to 65° C. (external temperature, oil bath) overnight. The reaction solution was poured into aqueous 5% sodium bicarbonate solution and the resulting bi-phase passed through a pad of Celite, rinsing with water and ethyl acetate. The filtrate was separated and the organic layer washed with water and brine then stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a yellow-green foamy solid. The product was isolated by chromatography on silica gel, eluting with ethyl acetate/hexane gradient, to afford a yellow foamy solid. LC-MS ESI (pos.) m/z: 341.2 (M+H).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12]([C:14]#[C:15][CH3:16])[CH:11]=[C:10]2[CH:17]=[O:18])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(NC(C)C)(C)C>N1C=CC=CC=1>[C:19]([O:8][CH2:7][C@H:5]1[O:6][C@@H:1]([N:9]2[CH:13]=[C:12]([C:14]#[C:15][CH3:16])[CH:11]=[C:10]2[CH:17]=[O:18])[CH2:2][C@@H:3]1[OH:4])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC#Cc1cc(C=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)NC(C)C
Product: CC#Cc1cc(C=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c1
Temperature: 25 °C
Reaction time: 29 h
Yield: 80.4 %

Procedure:
To a solution of 1-(2-deoxy-β-D-ribofuranosyl)-4-(1-propynyl)pyrrole-2-carbaldehyde (249 mg, 1.00 mmol) (I. Hirao, et al., Nature Methods, 3: 729-735 (2006)) dissolved in anhydrous pyridine (10 ml) were added trityl chloride (1.18 g, 4.21 mmol) and N,N-diisopropylamine (1.11 ml, 6.40 mmol), and the reaction mixture was stirred at room temperature for 29 hours, and then at 50° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, and the organic layers were washed twice with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The resulting crude product was purified by column chromatography on silica gel (eluent:dichloromethane:ethyl acetate=100:0→400:3, then dichloromethane:methanol=100:2) to give the title product (395 mg, 80%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:14]=2)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: COC(=O)CCC(CCCCN)c1cccc(-c2cccnc2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(F)cc1)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.144 g (0.44 mmol) methyl 8-amino-4-[m-(3-pyridyl)-phenyl]-octanoate in 2 ml methylene chloride is added a catalytic amount (0.02 g) 4-dimethylaminopyridine followed by 0.08 ml (0.57 mmol) triethylamine and 0.098 g (0.5 mmol) p-fluorophenylsulfonyl chloride. The mixture is stirred at room temperature for 18 h, diluted with methylene chloride, washed with saturated sodium bicarbonate solution, water and brine, dried, filtered and evaporated to give a greenish oil which is purified by chromatography using 3:2 ethyl acetate/hexane as eluent to obtain methyl 8-(p-fluorophenylsulfonamido)-4-[m-(3-pyridyl)-phenyl]-octanoate as an oil; NMR (CDCl3): delta 3.63 (s,3H), 2.9 (q,2H), 8.95 (d,1H), 8.67 (dd,2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.IC.[C:23](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[C:9]([CH3:13])([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 18.43 g (0.187 mole) of 2-chloro-9-cyclopentyl-7,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-38) and 500 mL of dimethylformamide was added 26.6 g (0.187 mole) of iodomethane and 30.6 g (0.0939 mole) of cesium carbonate. The mixture was stirred overnight at ambient temperature. The mixture was then filtered and concentrated under reduced pressure. The residue was partitioned between 500 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted twice with 200 mL of ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 18.47 g of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CCN(CC)CC.[C:18]([PH2:22])([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.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>[C:18]([PH:22][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)P
Reactant: BrC1=Cc2ccccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)PC1=Cc2ccccc2C1
Temperature: 25 °C

Procedure:
To 9.61 g (0.049 mol) of 2-bromo-1H-indene and 1.13 g (0.98 mmol) of Pd(PPh3)4 in 25 ml of toluene, 7.5 ml (5.45 g, 0.054 mol) of Et3N and 4.88 g (0.054 mol) of tBuPH2 were added. This mixture was refluxed for 14 hours, cooled to room temperature, and filtered through glass frit (G3) to separate out compound 15. The filtrate was evaporated to dryness. The crude product was distilled in vacuum (108–110° C./3 mm). Yield 3.07 g (31%) of crystalline solid of 14.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1ccn2c(Br)cnc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cnc3cc(C)ccn23)c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 3-bromo-7-methylimidazo[1,2-α]pyridine (18.0 g, 86 mmol) and 3-methoxyphenylboronic acid (17.0 g, 112 mmol) in 1,2-dimethoxyethane (250 ml) and sodium carbonate (120 ml of a 2M aqueous solution) was degassed for 25 minutes. Tetrakis(triphenylphosphine)pallidum(0) (500 mg, 0.4 mmol) was then added and the mixture heated at reflux for 17 hours. After cooling to ambient temperature the reaction was poured into water (400 ml), extracted with ethyl acetate (3×400 ml) and the combined organics dried over anhydrous magnesium sulphate. Filtration and evaporation to dryness afforded 3-(3-methoxyphenyl)-7-methylimidazo[1,2-α]pyridine as a colourless oil (19 g, 93%). 1H NMR (360 MHz, CDC3) δH 2.40 (3H, s), 3.84 (3H, s), 6.63-6.65 (1H, m), 6.91-6.95 (1H, m), 7.05-7.07 (1H, m), 7.10-7.12 (1H, m), 7.30-7.38 (1H, m), 7.42 (1H, s), 7.66 (1H, s), 8.22 (1H, d, J 7); m/z (ES+) 239 (M++H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([CH3:25])[C:8]([CH3:24])=[C:9]([CH3:23])[C:10]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:5]1=O.C1(C)C=CC=CC=1.S(=O)(=O)(O)O>CO>[CH3:3][C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:17][CH:18]=1)[C:9]([CH3:23])=[C:8]([CH3:24])[C:7]=2[CH3:25]
Reactant: Cc1c(C)c2c(c(-c3ccc(C(C)(C)C)cc3)c1C)CC(C)C2=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1=Cc2c(c(C)c(C)c(C)c2-c2ccc(C(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
5 g (131 mmol) of sodium borohydride and 21 g (80 mmol) of 2,5,6,7-tetramethyl-4-(4′-tert-butylphenyl)-1-indanone (3d) together with 200 ml of toluene were placed in a reaction vessel. At 50° C., 25 ml of methanol were added slowly and the reaction mixture was stirred at 50° C. for 3 hours. After cooling to room temperature, 35 ml of 2 N sulfuric acid were added and the mixture was stirred for 30 minutes. After phase separation, the organic phase was washed twice with a total of 60 ml of 2 N sulfuric acid, most of the solvent was removed and the residue was taken up in 200 ml of toluene and admixed with 0.2 g of p-toluenesulfonic acid. Water was distilled off from this reaction mixture by refluxing for 1.5 hours on a water separator until reaction was complete. The reaction mixture was washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After removal of the solvent, the residue was dried in an oil pump vacuum. Crude product was purified by recrystallization in heptane. This gave 9.0 g of (3e).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][C:10](=O)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[C:20]([CH:21]=O)=[CH:19][CH:18]=[CH:17][N:16]=1.[OH-].[K+]>C(O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CCNC(=O)OC(C)(C)C
Reactant: Nc1ncccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1ccc2cccnc2n1

Procedure:
A solution of 10-4 (10 g, 53.4 mmol), 2-amino-3-formylpyridine 1-3 (7.2 g, 64 mmol), 20% aq. KOH (1 mL), and ethanol (200 mL) was heated at reflux for 3 h. Evaporation of the solvents and flash chromatography (silica, 70 CHCl3/28 EtOAc/2 MeOH) gave 10-5 as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][O:15][C:16]3[C:17]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:18][S:19][N:20]=3)=[CH:7][CH:8]=2)[O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:21]1([C:17]2[C:16]([O:15][CH2:14][CH2:13][O:12][C:6]3[CH:5]=[C:4]4[C:9]([CH:10]=[CH:11][C:2](=[O:1])[O:3]4)=[CH:8][CH:7]=3)=[N:20][S:19][N:18]=2)[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCOc2ccc3ccc(=O)oc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2ccc(OCCOc3nsnc3N3CCNCC3)cc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product obtained in Step 3 (176 mg) was diluted in CH2Cl2 (1.5 mL) and cooled to ˜0° C. Trifluoroacetic acid (0.5 mL) was added and the reaction mixture was stirred for 1 h at 5° C. After solvent removal in vacuo, the residue was purified by chromatography on silica gel using hexane/EtOAc (1:1) followed by CH2Cl2/MeOH/Et3N (90:5:5) as eluents This furnished 45 mg (40%) of the title product as a white solid. MS m/z 375 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([F:13])[C:3]=1[O:14]COCCOC.C([Li])CCC.[CH:26](N1CCCCC1)=[O:27]>C1COCC1.CCCCCC>[F:13][C:4]1[C:3]([OH:14])=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:26]=[O:27]
Reactant: CCCCOc1ccc(Br)c(OCOCCOC)c1F
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOc1ccc(C=O)c(O)c1F
Reaction time: 1 h
Yield: 69.9 %

Procedure:
21.0 g (59.3 mmol) of 1-bromo-4-butoxy-3-fluoro-2-(2-methoxyethoxymethoxy)benzene (9) are dissolved in 200 ml of THF and treated at −78° C. with 37 ml (60 mmol) of a 15% strength solution of n-butyllithium in hexane. After 1 h, 6.8 ml (61 mmol) of N-formylpiperidine are added dropwise in 50 mmol of THF. The mixture is subsequently stirred for 1 h, and the mixture is allowed to thaw. After hydrolysis, the solution is acidified and extracted with MTBE. The combined organic phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, the residue is taken up in 150 ml of THF, and after addition of 30 ml of conc. hydrochloric acid the mixture is stirred at room temperature overnight. The mixture is taken up in MTBE and washed with water (pH 5). The solvent is removed in vacuo and the crude product is filtered through silica gel using MTBE. 8.80 g (53%, 2 stages) of 3-fluoro-4-butoxy-2-hydroxybenzaldehyde (11) are obtained as a slightly violet solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6](=[S:8])[NH:5][N:4]=1)[CH3:2].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30]Cl)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30][S:8][C:6]3[NH:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=3)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCc1n[nH]c(=S)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nnc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)[nH]1
Reaction time: 18 h
Yield: 72.7 %

Procedure:
Dissolve 5-ethyl-1H-1,3,4-triazole-2-thione (92 mg, 0.71 mmol) in anhydrous DMF (5 mL). Add sodium hydride (40 mg, 0.925 mmol, 60% dispersion in mineral oil) at room temperature under a nitrogen atmosphere and stir for 10 min. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (210 mg, 0.65 mmol) in anhydrous DMF (5 mL) at room temperature over 3 min and stir under nitrogen for 18 h. Quench with saturated aqueous NH4Cl (ca. 1 mL) and pour into water (100 mL). Extract the aqueous phase with EtOAc (3×25 mL) and wash the combined organic extracts with brine. Dry the organic solution over Na2SO4, filter and concentrate in vacuo to obtain crude 3-tert-butoxycarbonyl-7-chloro-6-(5-ethyl-1H-1,3,4-triazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 73%) suitable for use without further purification. MS (ES+) m/z: 423 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: Oc1ncnc2ccc(-c3ccccn3)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccc(-c3ccccn3)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Preparation D12, Step 3: A suspension of 6-(pyridin-2-yl)quinazolin-4-ol (106 mg, 0.47 mmol) in phosphorous oxychloride (15 mL) was heated at reflux for 1.5 h, during which time a clear, amber solution was observed. The solution was cooled to room temperature, concentrated in-vacuo, and stripped 2× from 30 mL methylene chloride to remove any remaining phosphorous oxychloride. The residue was partitioned between EtOAc and saturated sodium bicarbonate, and the mixture was stirred for 10 min. The layers were separated, and the organic phase was washed successively with saturated sodium bicarbonate, water, and brine, dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with methylene chloride followed by 1:1 methylene chloride/EtOAc, to yield 105 mg of 4-chloro-6-(pyridin-2-yl)quinazoline as a white solid. MS (ES+)=242 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>ClCCl>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:15]2[CH:10]3[CH2:11][CH2:12][CH:13]2[CH2:14][N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:9]3)=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Clc1cccnc1N1CC2CCC(C1)N2
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)N2C3CCC2CN(c2ncccc2Cl)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(3-Chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane (129 mg, 577 μmol) in dry dichloromethane (5 mL) was treated with 1-tert-butyl-4-isocyanatobenzene (101 mg, 577 μmol) and allowed to stir overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (3:1, hexanes:ethyl acetate) to provide the title compound. MS (DCI/NH3) m/z: 399 (M+H)+; 1H NMR (CDCl3) δ 1.30 (s, 9H), 2.01 (m, 2H), 2.17 (m, 2H), 3.25 (d, 2H), 3.64 (dd, 2H), 4.38 (dd, 2H), 6.32 (s, 1H), 6.86 (dd, 1H), 7.32 (s, 4H), 7.59 (dd, 1H), 8.17 (dd, 1H).
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[CH3:37][N:38]=[C:39]=[O:40]>>[NH2:36][C:15]1[N:16]=[C:17]([N:19]2[CH:28]([CH3:29])[CH2:27][C:26]3[C:21](=[CH:22][C:23]([CH:30]4[CH2:31][CH2:32][N:33]([C:39]([NH:38][CH3:37])=[O:40])[CH2:34][CH2:35]4)=[CH:24][CH:25]=3)[CH2:20]2)[CH:18]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[N:14]=1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CN=C=O
Agent: Cl
Product: CNC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and methyl isocyanate. LCMS (M+H)+: m/z=479.2.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:18]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCON=C(C(C)=O)C(=O)OCC
Yield: 99.9 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformamide (200 ml.), potassium carbonate (52 g.) and pentyl bromide (37.9 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer, 57.5 g.), oil.