Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N1CCC(C2C=CC=CC=2)(C#N)CC1)C1C=CC=CC=1.CCOC([C:28]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)CCNCC1)=O.C(Cl)C1C=CC=CC=1.[OH:48][CH2:49][CH2:50][NH:51][CH2:52][CH2:53][OH:54]>>[OH:48][CH2:49][CH2:50][N:51]([CH2:28][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:52][CH2:53][OH:54]
Reactant: OCCNCCO
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Solvent: ClCc1ccccc1
Product: OCCN(CCO)Cc1ccccc1

Procedure:
Eisleb in Example 2 of U.S. Patent 2,167,351, issued July 25, 1939, shows the preparation of 1-benzyl-4-phenylpiperidine-4-carbonitrile hydrochloride, m.p. 259°-260° C., as an intermediate for normeperidine, namely, ethyl 4-phenylpiperidine-4-carboxylate, by first reacting benzyl chloride with N,N-bis(2-hydroxyethyl)amine to produce N,N-bis(2-hydroxyethyl)benzylamine, next reacting the latter compound with thionyl chloride to produce N,N-bis(2-chloroethyl)benzylamine and isolating it in free base form as "an oil of feebly brownish color"; and then heating N,N-bis(2-chloroethyl)benzylamine with benzyl cyanide (same as phenylacetonitrile) in toluene in the presence of sodium amide (same as sodamide).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][C:14]2[C:15]([O:17][C:18](=O)C=2C(C)C)=[O:16])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](C=[N+]=[N-])(C)C.[CH3:33][CH2:34][CH2:35]CCC.CCCCCC.[C:45]([O:48][CH2:49]C)(=[O:47])[CH3:46]>CO>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13]/[C:14](=[C:46](\[CH:34]([CH3:35])[CH3:33])/[C:45]([O:48][CH3:49])=[O:47])/[C:15]([O:17][CH3:18])=[O:16])=[CH:24][CH:25]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCCCC
Reactant: CC(C)C1=C(Cc2ccc(O[Si](C)(C)C(C)(C)C)cc2)C(=O)OC1=O
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)/C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)=C(\C(=O)OC)C(C)C
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 2-[4-(t-butyldimethylsilyloxy)benzyl]-3-isopropylmaleic anhydride (823 mg, 2.28 mmol) in methanol (15 mL) was added a 2.0 M trimethylsilyl diazomethane-hexane solution (8.5 mL, 17 mmol) with stirring at room temperature. After stirring at room temperature for 30 min, the reaction mixture was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 10:1→8:1) to give 913 mg of dimethyl 2-[4-(t-butyldimethylsilyloxy)benzyl]-3-isopropylmaleate as oil (yield: 98%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:18][C@@H:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH2:17][C:11]1[N:10]=[C:9]([NH:18][C@@H:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCC[C@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: C1CCNCC1
Product: CCC[C@H](C)Nc1nc(N)c2[nH]c(=O)n(CCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-N2-[(1S)-1-methylbutyl]-8-(methyloxy)-9H-purine-2,6-diamine and piperidine.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH3:30])=[O:28])[CH3:26])=[O:23])[CH2:20][OH:21])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:16]([NH:18][C@H:19]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH3:30])=[O:28])[CH3:26])=[O:23])[CH2:20][OH:21])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCC(N)=O

Procedure:
10.3 g (18.8 mM) of Boc-Gln-Leu-Ser-Ala-OCH3 are stirred for 35 mins. in 100 ml of dichloromethane containing 100 ml of TFA. The reaction medium is concentrated in vacuo to about 50 ml and poured over 300 ml of ether. The precipitate is drained, washed with ether and dried in vacuo.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:6]=1[NH2:7].[CH3:19]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:15]([C:3]1[C:2]([CH3:19])=[C:6]([NH2:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:4]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)c(Br)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-n1nc(C(C)(C)C)c(C)c1N
Temperature: 155 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
To a solution of 4-bromo-3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate J, 800 mg, 2.60 mmol) in DMF (5 mL) was added trimethylboroxine (0.73 mL, 5.19 mmol), [1,1′-bis(diphenylphosphino)-butane]palladium (II) dichloride (157 mg, 0.26 mmol), and potassium carbonate (1.08 g, 7.79 mmol). The reaction mixture was stirred for 18 h at 155° C. After cooling, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using hexane/EtOAc (1:9, v/v) to afford the product (243 mg, 38%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 1.24 (s, 9H), 1.97 (s, 3H), 2.03 (s, 3H), 4.48 (s, 2H) 7.14-7.32 (m, 4H). ES-MS m/z 244.2 (MH+); HPLC RT (min) 1.17.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[CH:2].C([Li])CCC.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1.[Cl-].[NH4+]>[CH2:19]([O:18][C:16](=[O:17])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:20]
Reactant: C#Cc1cccc(C)n1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1cccc(C)n1
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of 2-Ethynyl-6-methyl-pyridine (0.5 g, 4.3 mmol) in THF (20 mL) is cooled to −78° C. and treated with 1.6 M n-butyllithium in hexanes (2.9 mL, 4.7 mmol) and stirred for 0.5 hours. This solution is then treated with ethyl chloroformate (2.85 mL, 30 mmol) and stirred for 3 hours while the solution warms to room temperature The reaction is diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The solvent is concentrated to afford 0.67 g (83%) of desired product as a light yellow oil. UV (95% EtOH) λmax 286 nm (ε 10977), 238 nm (ε 9757). TOF MS ES+ exact mass calculated for C11H11NO2 (p+1): M/z=190.0868. Found: 190.0864.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]1[CH2:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:12][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[O:15]
Reactant: COC(=O)C1CCCCN1
Reactant: O=C(CCCl)c1ccc(F)cc1
Product: COC(=O)C1CCCCN1CCC(=O)c1ccc(F)cc1
Yield: 92 %

Procedure:
N-[3-(4-Fluorophenyl)-3-oxopropyl]pipecolic acid methyl ester was prepared in 92% yield by alkylation of methyl pipecolinate with 3-chloro-4′-fluoropropiophenone (Aldrich) as described in Example 20A (Step 1).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH:16]([CH3:18])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:21][CH2:22][O:23][CH3:24])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Li+].[CH3:26][CH:27]([N-]C(C)C)C.I[CH2:34]CC>C1COCC1>[CH2:1]([C:5]12[CH2:17][C:16]([CH3:34])([CH2:18][CH2:26][CH3:27])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:21][CH2:22][O:23][CH3:24])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)C2
Reactant: CCCI
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)(CCC)C2
Temperature: -78 °C

Procedure:
A solution of (2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (110 mg, 0.34 mmol) in anhydrous THF (1.5 mL) was cooled in an ice bath, stirred under a nitrogen atmosphere, and treated with 0.4M LDA in THF (1 mL, 0.4 mmol). After stirring at 0° C. for 30 minutes, the solution was cooled to −78° C. and treated with iodopropane (0.170 mL, 1.7 mmol). The resulting mixture was allowed to gradually warm to room temperature, then stirred at room temperature overnight. Workup as described in step 2 afforded a crude product (112 mg) which was purified by PLC on a 0.1×20×20 cm silica gel GF plate, using 10:1 hexanes-EtOAc as developing solvent. The band at Rf 0.20-0.27 gave recovered starting material (39 mg) and the band at Rf 0.31-0.38 afforded the product (2SR,9aRS)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (41 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH:8]=[CH:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC(CC=CC(=O)CCc1ccc2c(n1)NCCC2)c1cnc(C)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CCCC(=O)CCc1ccc2c(n1)NCCC2)c1cnc(C)nc1

Procedure:
A mixture of 4-11 (95 mg, 0.22 mmol) and 10% Pd/carbon (50 mg) in EtOH (3 mL) was stirred under a balloon of hydrogen for 2 h. Following filtration, evaporative removal of the solvent gave 4-12 as a clear oil.
Reaction SMILES: [C:1]([O:11]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:13][O:14][CH:15]([O:20][CH3:21])[CH2:16][CH2:17][CH2:18][NH2:19]>C[O-].C[O-].C([Sn+2]CCCC)CCC>[CH3:13][O:14][CH:15]([O:20][CH3:21])[CH2:16][CH2:17][CH2:18][NH:19][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:19][CH2:18][CH2:17][CH2:16][CH:15]([O:20][CH3:21])[O:14][CH3:13])=[O:11]
Reactant: COC(=O)CCCCC(=O)OC
Reactant: COC(CCCN)OC
Agent: CCCC[Sn+2]CCCC
Agent: C[O-]
Product: COC(CCCNC(=O)CCCCC(=O)NCCCC(OC)OC)OC
Yield: 67.5 %

Procedure:
Dimethyl adipate (25.00 g, 0.1435 mol) was aminated with 38.63 g (0.290 mol) of 4,4-dimethoxybutylamine and 2.50 g (0.00847 mol) of dibutyl tin dimethoxide in 200 g of mixed xylenes according to the procedure used in Example 1. This procedure afforded 36.47 g (0.0969 mol, 67.5% isolated yield) of the desired N,N'-bis(4,4-dimethoxybutyl)adipamide after recrystallization from mixed xylenes, mp 73°-75° C.; IR (KBr) 1640 (C=O), 1540, 1415, 1195, 1135, 1040 cm-1 ; 1H NMR (CDCl3 ; 300 MHz) δ8 1.42-1.63 (m, 12H, --CH2 --), 2.06-2.18 (m, 4H, CO--CH2 --), 3.13-3.20 (m, 4H, --NH2CH2 --), 3.23 (s 12H, --OCH3), 4.27 (t, 2H, J=5.2 Hz, CH2CH--), 6.38 (t, 2H, J=5.5 Hz, --NH--CH2 --); 13C NMR (CDCl3 ; 75.5 MHz) δ24.4, 25.0, 29.8, 36.0, 39.0, 52.8, 104.2, 172.7; MS (70 eV) m/z (rel. intensity) 286 (2.96), 244 (10.19), 228 (14.05), 212 (29.35), 85 (28.09), 84 (38.06), 75 (89.07), 70 (100.00); HRMS (FAB) 377.2652 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:16])=[CH:8][C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:30])[C:19]1[S:20][C:21]([CH:28]=O)=[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=12.N1CCCCC1>C(O)C>[C:1]([C:5]1[O:6][C:7]([CH:16]=[CH:28][C:21]2[S:20][C:19]([N:18]([CH3:17])[CH3:30])=[C:23]3[C:22]=2[O:27][CH2:26][CH2:25][O:24]3)=[CH:8][C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=CC(=C(C#N)C#N)C=C(C(C)(C)C)O1
Reactant: CN(C)c1sc(C=O)c2c1OCCO2
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1sc(C=CC2=CC(=C(C#N)C#N)C=C(C(C)(C)C)O2)c2c1OCCO2
Temperature: 75 °C
Yield: 48.8 %

Procedure:
As shown in the following reaction 1, 2.14 g (10 mmol) of 2-(2-tert-butyl-6-methyl-pyran-4-ylidene)-malononitrile and 2.13 g (10 mmol) of 7-dimethylamino-2,3-dihydro-thieno[3,4-b][1,4]dioxine-5-carbaldehyde were added into 100 ml of ethanol, and 0.93 g (11 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours. After cooling the reaction solution, the precipitated red solid was filtered, and recrystallized with ethanol to obtain 2 g of the target compound (Yield 48%).
Reaction SMILES: [OH:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][C:5]1[C:6]([O:16][C@@H:17]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])=[N:7][N:8]([CH2:13][CH2:14][OH:15])[C:9]=1[CH:10]([CH3:12])[CH3:11].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:44]([O:1][C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][C:5]1[C:6]([O:16][C@@H:17]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])=[N:7][N:8]([CH2:13][CH2:14][OH:15])[C:9]=1[CH:10]([CH3:12])[CH3:11])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2nn(CCO)c(C(C)C)c2Cc2ccccc2O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2nn(CCO)c(C(C)C)c2Cc2ccccc2OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.1 %

Procedure:
To a solution of 4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (35 mg) in N,N-dimethylformamide (3 mL) were added benzyl bromide (20 mg) and potassium carbonate (18 mg), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3—ethyl acetate) to give 4-(2-benzyloxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (33 mg). To a solution of 4-(2-benzyloxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (33 mg) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 9 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (20 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([O:26]C)=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCCP(=O)=O.[F:38][C:39]([F:43])([F:42])[CH2:40][NH2:41]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:28]([F:30])([F:31])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:41][CH2:40][C:39]([F:43])([F:42])[F:38])=[O:26])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(bifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxylic acid (i.e. the product from Step C) (190 mg, 0.42 mmol), 4-(dimethylamino)pyridine (77 mg, 0.63 mmol), propylphosphonic anhydride (0.38 mL, 0.63 mmol, 50% in ethyl acetate) and 2,2,2-trifluoroethylamine (0.033 mL, 0.42 mL) in dichloromethane (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to give the title product, a compound of the present invention, as a white solid (71 mg).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][C@@H:10]2[O:19][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[O:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](#[N:23])[CH:21]=[CH2:22]>C(O)C>[O:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[O:19][C@@H:10]([CH2:9][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][CH2:21][C:20]#[N:23])[CH2:11]1
Reactant: c1ccc(CNC[C@H]2COc3cccnc3O2)cc1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCN(Cc1ccccc1)C[C@H]1COc2cccnc2O1
Yield: 99.5 %

Procedure:
Intermediate (55) (0.0195 mol) was dissolved in ethanol (50 ml). 2-Propenenitrile (0.02 mol) was added and the reaction mixture was stirred and refluxed overnight. Additional 2-propenenitrile (0.02 mol) was added and the reaction mixture was stirred and refluxed for 2 hours. Additional 2-propenenitrile (0.02 mol) was added and the reaction mixture was stirred and refluxed for 6 hours. Additional 2-propenenitrile (0.02 mol) was added and the reaction mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The product fractions were collected and the solvent was evaporated, yielding 6.0 g of (S)-3-[[(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)methyl](phenylmethyl)amino]-propanenitrile (intermediate 56).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](CNC2C=CC=CC=2C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21]([NH2:23])[CH3:22]>C(O)C>[CH2:21]([NH:23][C:2]1[N:11]=[C:10]([NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:22]
Reactant: Cc1ccccc1NCc1nc(Cl)nc2ccccc12
Reactant: CCN
Solvent: CCO
Product: CCNc1nc(Nc2ccccc2C)c2ccccc2n1
Yield: 33 %

Procedure:
2-Chloro-4-(2-methylphenylaminomethyl)quinazoline (5.00 g, 0.0185 mol) and ethylamine in ethanol (33%, 30 ml) were dissolved in ethanol (35 ml) placed in a sealed vessel and heated for 5 hours at 130°. After cooling and removal of excess solvent in vacuo the residue afforded crystals of 2-ethylamino-4-(2-methylphenylamino)quinazoline (1.7 g, 33%) from ethanol/water, m.p. 127°-129°.
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:27])(C1C=CC(C)=CC=1)(=O)=O.[I-:28].[Na+]>CC(C)=O>[I:28][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:27]
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CI)O2)c(=O)[nH]c1=O
Yield: 90 %

Procedure:
To a stirred solution of the thymidine tosylate (10.65 g, 26.9 mmol) prepared according to the method of Example 23 in dry acetone (75 ml) was added sodium iodide (10 g, 66.7 mmol) and the mixture refluxed for 16 hours. The solvent was evaporated and diluted with ethyl acetate. The organic phase was washed with water (2×20 ml) and brine (10 ml) and dried with sodium sulfate. The title compound was crystallized from methanol as a white crystalline solid in 90-95% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[O:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([O:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:5])[CH3:6])[CH3:2]
Reactant: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OCCOC)c(OC)cc34)c2)n(-c2ccccc2)n1
Yield: 57 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 168B (0.115 g, 0.33 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.112 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 5 hours, to afford 1-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as solid (0.116 g, 57%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (br, 1H), 8.55 (s, 2H), 7.56 (m, 6H), 7.41 (m, 3H), 7.18 (d, 1H), 6.94 (d, 1H), 6.41 (s, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.35 (s, 3H), 3.24 (q, 2H), 1.46 (s, 6H), 1.03 (t, 3H); LC-MS (ESI) m/z 567 (M−OEt)+.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].CO.[C:17](C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:12]([O:13][CH3:17])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3]
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Reactant: C=CCc1c(O)cc(C)c2[nH]ccc12
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCc1c(OC)cc(C)c2[nH]ccc12
Temperature: 110 °C

Procedure:
4-Allyl-7-methyl-1H-indol-5-ol (Example 1-C) (2.77 g, 14.79 mmol) was dissolved in toluene (74.0 mL) and methanol (0.599 mL, 14.79 mmol) was added followed by cyanomethylenetributylphosphorane (8.93 g, 37.0 mmol). The reaction was heated at 110° C. for 1 hour. The reaction was cooled to room temperature and then concentrated. The residue was then absorbed onto silica and purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 202.17 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][NH2:15].[NH:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][NH:20][CH2:19][CH2:18]1>>[NH:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][N:20]([C:2]2[N:3]=[C:4]([NH:15][CH2:14][CH2:13][CH2:12][NH2:16])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:19][CH2:18]1
Reactant: c1ccc2c(c1)CNCCN2
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: NCCCN
Product: NCCCNc1nc(N2CCNc3ccccc3C2)nc2ccsc12

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichlorothieno[3,2-d]pyrimidine and propane-1,3-diamine, followed by reaction with 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine. MS obsd. (ESI+) [(M+H)+] 355, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.71 (d, J=5.6 Hz, 1H), 7.37 (d, J=7.1 Hz, 1H), 7.08 (d, J=5.3 Hz, 1H), 7.02-7.07 (m, 1H), 6.79-6.86 (m, 2H), 4.85 (s, 2H), 4.04-4.09 (m, 2H), 3.73 (t, J=6.6 Hz, 2H), 3.20-3.24 (m, 2H), 2.86-2.92 (m, 2H), 1.93-2.03 (m, 2H).