Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[CH:12]=[C:13]([C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[C:21]([CH:20]=[C:19]([C:13]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([NH:10][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH:12]=1)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)#[N:22]
Reactant: CCOc1cc(C(=CC#N)c2ccc(OC)c(N)c2)ccc1OC
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=CC#N)c2ccc(OC)c(NC(=O)N(C)C)c2)ccc1OC
Temperature: 85 °C
Yield: 67.8 %

Procedure:
N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was added to a mixture of (E/Z) 3-(3-amino-4-methoxy-phenyl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile (0.70 g, 2.2 mmol) and dimethylcarbamyl chloride (1.6 mL, 17.3 mmol). The reaction mixture was heated at 85° C. for 3 h. CH2Cl2 (100 ml) was added and the mixture was extracted with water (2×50 mL), 4 N HCl (2×50 mL), water (2×50 mL), saturated NaHCO3 (2×50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-{5-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-vinyl]-2-methoxy-phenyl}-1,1-dimethyl-urea as a solid (0.59 g, 69% yield): mp, 143-145° C.; 1H NMR (CDCl3) δ 1.40-1.47 (m, 6H, 2CH3), 3.02-3.05 (2s, 12H, 4CH3), 3.88-3.94 (3s, 12H, 4OCH3), 3.99-4.12 (m, 4H, 2CH2), 5.55-5.61 (2s, 2H, 2CH), 6.79-7.18 (m, 12H, Ar), 8.18-8.36 (m, 2H, 2NH); 13C NMR (CDCl3) δ 14.71, 36.33, 55.93, 56.00, 64.46, 92.06, 92.33, 109.21, 109.30, 110.93, 110.99, 112.74, 114.22, 118.56, 118.69, 118.79, 120.27, 122.25, 123.06, 123.41, 123.74, 128.97, 129.24, 129.73, 130.11, 131.68, 132.25, 147.83, 148.14, 148.81, 149.27, 150.68, 151.37, 155.22, 155.31, 162.66, 163.11; Anal. Calcd for C22H25N3O4: C, 66.82; H, 6.37; N, 10.63. Found: C, 66.84; H, 6.48; N, 10.43.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C1(C)C=CC(S(N[CH2:20][CH2:21][O:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])(=O)=O)=CC=1>>[C:29]1([CH3:32])[CH:30]=[CH:31][C:26]([S:23]([O:22][CH2:21][CH2:20][N:1]2[CH2:9][CH2:8][N:7]([CH2:20][CH2:21][O:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:6][CH2:5][N:4]([CH2:20][CH2:21][O:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: C1CNCCNCCN1
Reactant: Cc1ccc(S(=O)(=O)NCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: Cc1ccc(S(=O)(=O)OCCN2CCN(CCOS(=O)(=O)c3ccc(C)cc3)CCN(CCOS(=O)(=O)c3ccc(C)cc3)CC2)cc1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), 2-(p-toluenesulfonylamino)-1-(p-toluenesulfonyloxy)ethane (1.1.16) and base.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C([Li])CCC.[CH2:24]([O:31][C@@H:32]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][C:33]1=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:24]([O:31][C@@H:32]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[O:35][C:33]1([C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)[OH:34])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Brc1ccc2scc(CCc3ccccc3)c2c1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc3scc(CCc4ccccc4)c3c2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
To a solution of 5-bromo-3-(2-phenylethyl)benzo[b]-thiophene (0.94 g) in tetrahydrofuran (25 mL) was added n-butyllithium (2.44 mol/L n-hexane solution, 1.24 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (0.80 g) in tetrahydrofuran (4 mL), and the mixture was warmed to 0° C. and stirred for 30 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1) to give the title compound (1.1 g).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:37]([NH2:43])[C:38]1[O:42][CH:41]=[CH:40][CH:39]=1>>[O:42]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:37][NH:43][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: NCc1ccco1
Product: O=C(NCc1ccco1)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 96.9 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 56 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 578 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[F:37])#[N:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:33]2[CH:34]=[CH:35][C:36]([F:37])=[C:31]([C:29]#[N:30])[CH:32]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CC(c1ccc(-c2ccc(F)c(C#N)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-cyano-4-fluorophenylboronic acid to give the title compound as a colorless solid. MS (m/e)=519.2 [M+H+].
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:29]O>C(OCC)(=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([O:24][CH3:29])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: -2.5 °C

Procedure:
A suspension of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid (23.5 g, 0.0636 mol) in methanol (235 ml, 10 vol) was stirred and cooled to 0 to −5° C. under nitrogen. Thionyl chloride (9.3 ml, 0.1272 mol, 0.40 vol) was charged dropwise over 20 minutes, maintaining the temperature −5 to +5° C. The resulting slurry was then heated and stirred at reflux under nitrogen for 16 h after which time LC analysis showed 1.4% by area of acid remaining. The solution was evaporated to dryness in vacuo at 40° C. to give a brown sludge. The sludge was dissolved in ethyl acetate (118 ml, 5 vol) and water (235 ml, 10 vol) and the layers separated. The aqueous layer was washed with ethyl acetate (118 ml, 5 vol) and basified to pH 11 with saturated aqueous potassium carbonate (118 ml, 5 vol). The product was extracted into dichloromethane (3×118 ml, 3×5 vol) and the combined extracts dried over magnesium sulfate (23 g, 1 wt) and concentrated in vacuo at 40° C. to yield title compound (21.7 g, 98% from the nitrile) as a cream solid.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[Na+].[I-].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][C:22]=1[F:29]>C(#N)C>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:8]2[CH:7]=[C:6]([C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:5]=[CH:4][C:3]2=[O:2])=[CH:23][C:22]=1[F:29]
Reactant: Fc1cc(CBr)ccc1Cl
Reactant: COc1ccc(-c2nc3ccccc3s2)cn1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1ccc(-c2nc3ccccc3s2)cn1Cc1ccc(Cl)c(F)c1
Temperature: 90 °C
Reaction time: 14 h
Yield: 56 %

Procedure:
According to Scheme 4, Step 1: A mixture of 2-(6-methoxypyridin-3-yl)benzo[d]thiazole (1 eq, 0.25 mmol, 60 mg), NaI (5 eq, 1.20 mmol, 0.19 g) and 4-chloro-3-fluorobenzylbromide (5 eq, 1.20 mmol, 0.28 g) in acetonitrile (10 mL) was stirred for 14 hours at 90° C. The crude residue was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 95/5 as eluent to afford 1-(4-chloro-3-fluorobenzyl)-5-(benzo[d]thiazol-2-yl)pyridin-2(1H)-one (0.14 mmol, 0.05 g, 58%) as a beige solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:12])[N:10]=[CH:11][C:6]2=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:4]=1.CCN(CC)CC.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C>[CH3:12][N:9]1[C:7]2=[N:8][C:3]([CH2:2][N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[CH:4][C:5]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[C:6]2[CH:11]=[N:10]1
Reactant: CN1CCNCC1
Reactant: Cn1ncc2c(-c3ccc([N+](=O)[O-])cc3)cc(CBr)nc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2cc(-c3ccc([N+](=O)[O-])cc3)c3cnn(C)c3n2)CC1
Temperature: 90 °C

Procedure:
900 mg of 6-bromomethyl-1-methyl-4-(4-nitro-phenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate 17.7; 2.59 mmol, 1 eq.) were dissolved in 13.5 mL DMF and treated sequentially with 0.54 mL Et3N (3.9 mmol, 1.5 eq.) and 0.35 mL methyl piperazine (3.11 mmol, 1.2 eq.). The reaction mixture was heated to 90° C. for 45 min, partitioned between CH2Cl2 and water, the aqueous layer was re-extracted and the combined organic layers were dried and concentrated in vacuo to yield the crude piperazine product, which was used without further purification.
Reaction SMILES: [CH:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[C:8]([O:10][C:11]([CH3:21])([CH3:20])[C:12]#[C:13][CH2:14]N(CC)CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N#C[Br:31].O.Cl>C(OCC)C>[CH:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[C:8]([O:10][C:11]([CH3:21])([CH3:20])[C:12]#[C:13][CH2:14][Br:31])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC#CC(C)(C)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: N#CBr
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(C#CCBr)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 9.5 g 4-diethylamino-1,1-dimethyl-2-butynyl α-cyclohexyl-α-phenylglycolate in diethyl ether, was added dropwise an etheral solution of 3.2 g cyanogen bromide, and the mixture was stirred for one hour under ice cooling and then for 18 hours under cooling with water. 2N-HCl (14 ml) was added to the reaction mixture under ice cooling, and the separated etheral layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue left was purified by silica gel column chromatography (Wako Gel C-200; 1:15 mixture of ethyl acetate and n-hexane), giving 6.0 g of the objective compound as colorless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:27]=[CH:26][C:12]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)=[O:7])(O)=[O:2].P(C#N)(OCC)(OCC)=O.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CN(C)C=O.C(N(CC)CC)C>[CH2:38]([N:40]([CH2:41][CH3:42])[C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:26][CH:27]=1)=[O:7])=[O:2])[CH3:39]
Reactant: O=C(O)CCC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: CCNCC
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)CCC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
1-[4-(3-Carboxypropionylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) is dissolved in dimethylformamide (1 ml) and thereto is added dropwise diethyl cyanophosphate (0.25 g) under ice-cooling. The mixture is stirred at room temperature for 30 minutes and then cooled again with ice. Thereto are added dropwise a solution of diethylamine (0.11 g) in dimethylformamide (1 ml) and triethylamine (0.34 g). The mixture is stirred at room temperature for 16 hours. The solvent is distilled off under reduced pressure and water is added to the resulting residue. The mixture is extracted with dichloromethane. The organic layer is washed successively with diluted hydrochloric acid, water, saturated sodium hydrogen carbonate solution, water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate), and recrystallized from n-hexane/ethyl acetate to give 1-[4-(3-diethylaminocarbonylpropionylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.42 g) as colorless scales, m.p. 165°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1.Cl[CH2:32][C:33]1[N:34]=[C:35]([CH3:38])[S:36][CH:37]=1>C(O)C.O.O.C(O)C>[CH3:38][C:35]1[S:36][CH:37]=[C:33]([CH2:32][N:10]([CH2:11][C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:9][CH2:8][N:7]([CH2:32][C:33]2[N:34]=[C:35]([CH3:38])[S:36][CH:37]=2)[CH2:6][C:5]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:34]=1
Reactant: COc1cc(CNCCNCc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Reactant: Cc1nc(CCl)cs1
Solvent: CCO
Solvent: O
Product: COc1cc(CN(CCN(Cc2cc(OC)c(OC)c(OC)c2)Cc2csc(C)n2)Cc2csc(C)n2)cc(OC)c1OC
Temperature: 45 °C

Procedure:
1.5 g N,N'-bis-(3,4,5-trimethoxybenzyl) ethylenediamine dichlorhydrate were solubilized in 30 ml of a 1:1 ethanol/water mixture. The pH of the solution was brought to 11 using a soda solution. A solution of 1.25 g 4-chloromethyl-2-methylthiazole in solution in 10 ml water were added all at once. The mixture was heated for 5 hours at 45° C., while maintaining the pH at between 10 and 11 by adding a soda solution. After cooling, the ethanol was evaporated under a vacuum and the mixture was acidified to a pH of 1 using concentrated HCl. Extraction was carried out using 3×25 ml dichloromethane, then the organic phase was dried and dry-evaporation effected. The oil obtained was taken up in 10 ml ethanol +0.5 ml concentrated HCl. The resultant precipitate was filtered and washed in ethylic ether. The solid was then recrystallized in 20 ml isopropanol containing 1% water. In this way, 600 mg of a white powder having a melting point of 190° C. was obtained, whose proton NMR spectrum (400 MHZ) and ultimate analysis matched the expected structure (existing as a dichlorhydrate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH3:39]>>[CH2:38]([N:40]1[CH2:45][CH2:44][N:43]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42][CH2:41]1)[CH3:39]
Reactant: CCN1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CCN1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-ethylpiperazine according to conditions described in general procedure C. Mp: 185-186° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.98 (t, J=6.9 Hz, 3 H), 2.31 (bs, 6 H), 3.27 (t, J=4.0 Hz, 6 H), 3.50 (bs, 2 H), 3.77 (t, J=4.4 Hz, 4 H), 6.22-6.24 (m, 1 H), 7.04 (d, J=12.0 Hz, 1 H), 7.27 (d, J=8.0 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1 H), 7.50 (s, 1 H), 7.56-7.63 (m, 3 H), 7.84-7.86 (m, 1 H), 8.00 (d, J=8.0 Hz, 1 H), 8.27-8.29 (m, 1 H), 10.48 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[C:6]([F:19])[CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([F:19])[CH:5]=1
Reactant: COC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC(=O)O)c(F)c1
Yield: 99 %

Procedure:
A solution of 4-tert-butoxycarbonylmethoxy-3-fluoro-benzoic acid methyl ester in CH2Cl2 was treated with trifluoroacetic acid (14.9 ml, 130 mmol, 10.6 eq.) (20 ml) for 3.5 hrs. at r.t. Following evaporation to dryness, the title compound (2.77 g, 99% yield) was obtained as an off-white solid. MS: m/e=228 (M+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=[O:9]>O.[OH-].[Na+]>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
To 4-chloro-2-fluoroaniline (2.7 g, 19.0 mmol) in H2O (12 mL), cooled to 0° C., conc. HCl (4.5 mL) was added and stirred for 10 min. NaNO2 (1.3 g, 18.8 mmol), dissolved in water (13 mL), was added slowly to the reaction mixture and stirred at 0° C. for an additional 30 min., the solids were filtered to give the diazonium salt. In another set up, to ethyl 2-oxocyclohexanecarboxylate (3 g, 19.3 mmol) in H2O (10 mL), 5N NaOH (5 mL) was added. The reaction mixture was stirred at room temperature for 24 h and washed with EtOAc (15 mL). The aqueous layer was separated, cooled to 0° C. and conc. HCl (5 mL) was added dropwise to obtain 2-oxocyclohexanecarboxylic acid (2.7 g, crude). 2-oxocyclohexanecarboxylic acid (2.7 g, 19.0 mmol) and diazonium salt (prepared above) were mixed together at 0° C. and the reaction mixture was slowly warmed to room temperature and stirred for 1 h during which time a solid precipitated out which was filtered, washed with hexane (20 mL) and air dried to give the title compound as a yellow solid (2.2 g, 45%). 1H NMR (200 MHz, CDCl3, δ in ppm) 13.64 (bs, 1H), 7.684 (t, J=8.8 Hz, 1H), 7.10 (t, J=10.0 Hz, 2H), 2.74-2.67 (m, 2H), 2.56-2.50 (m, 2H), 1.90-1.83 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(Br)c(C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(C)c(C(=O)O)c1Br
Temperature: 20 °C
Reaction time: 18 h
Yield: 14.1 %

Procedure:
To a solution of ethyl 4-bromo-1,3-dimethyl-1H-pyrazole-5-carboxylate (200 mg) (for example, available from Sinova) in methanol (10 ml) was added 2M sodium hydroxide (5 ml) and the mixture stirred at 20° C. for 18 h. The mixture was concentrated in vacuo and the residue taken up in water (10 ml) and acidified to pH=5 using 2M hydrochloric acid. The mixture was extracted with ethyl acetate (20 ml) dried over sodium sulphate and evaporated to give the title compound (25 mg) as a white solid.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:30])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:18]([CH:20]=[CH2:21])[CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.ClCCl>[CH2:3]([O:5][C:6](=[O:30])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:18]([CH:20]=[CH2:21])[CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: C=Cc1cc(CC(C(=O)OCC)C(=O)OCC)cnc1NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: C=Cc1cc(CC(C(=O)O)C(=O)OCC)cnc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.1 %

Procedure:
A solution of KOH (0.71 g, 12.6 mmol, 85%) in ethanol (10 ml) was added to a solution of 2-(6-tert-butoxycarbonylamino-5-vinyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (4.30 g, 11.0 mmol) in ethanol (25 ml) and dichloromethane (10 ml) at 0° C. The mixture was stirred for 6 h at room temperature. The solvent was evaporated in vacuo and the residue dissolved in water. The aqueous layer was washed with ether, acidified to pH 4 by 1 M HCl and extracted with dichloromethane. The organic layer was washed with water and brine and dried. Filtration and concentration under reduced pressure followed by flash chromatography (10% MeOH in CH2Cl2) gave 2-(6tert-butoxycarbonylamino5-vinyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (3.05 g, 76%).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N2CCCC(C)C2)ncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 99 mg of 3-methylpiperidine was added therein, and the mixture was stirred for 4 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 181 mg of 4-(2-butynyloxy)-6-(3-methylpiperidino) pyrimidine (hereinafter, referred to as Compound (19)).