Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[C:30]1[S:31][C:32]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:33]=2[N:34]=1)[NH2:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5]([NH:26][C:25]1[CH:27]=[CH:28][C:29]([C:30]2[S:31][C:32]3[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:33]=3[N:34]=2)=[C:23]([O:22][CH3:21])[CH:24]=1)=[O:7]
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)O
Reactant: COc1ccc2nc(-c3ccc(N)cc3OC)sc2c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4cc(OC(F)(F)F)ccc4OC)cc3OC)sc2c1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
A stirred mixture of 2-methoxy-5-trifluoromethoxybenzoic acid (0.248 g, 1.05 mmol) and thionyl chloride (4 ml) was heated under reflux for 4 h. After cooling to room temperature, the excess reagent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride and 3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)aniline (0.30 g, 1.05 mmol) in dry pyridine (8 ml) to give the title compound (0.389 g, 73%) as an almost colourless solid after work-up and recrystallisation from acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[C:26]([O:31][CH2:32][CH:33]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]2)=[N:27][CH:28]=[CH:29][CH:30]=1>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([O:31][CH2:32][CH:33]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]4)=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ncccc2Br)C1
Product: CC(C)(C)OC(=O)N1CCC(COc2ncccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1
Yield: 54 %

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and tert-butyl 3-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate yielding the title compound (47 mg, 54%). MS (ESI): mass calcd. for C25H28FN5O3, 465.22; m/z found, 466.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.58 (m, 1H), 8.18-8.09 (m, 2H), 8.03-7.94 (m, 1H), 7.73-7.64 (m, 1H), 7.48-7.36 (m, 2H), 7.05-6.96 (m, 1H), 4.70 (s, 2H), 4.47-4.22 (m, 2H), 3.68-3.26 (m, 3H), 3.25-3.09 (m, 1H), 2.77-2.60 (m, 1H), 2.14-1.98 (m, 1H), 1.84-1.68 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C[CH:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37]C=CC=1.OP(O)(O)=O.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47](B(O)O)[CH:46]=1>O1CCOCC1.O>[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:12]2[N:11]=[CH:10][C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:38]2[CH:37]=[N:39][CH:31]=[CH:32][CH:33]=2)=[CH:7][CH:6]=4)[CH:46]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(N)Cc1ccccc1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1cnc(-c3cccnc3)cc12
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with (S)-7-bromo-3-chloro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (32 mg, 0.087 mmol), potassium phosphate (55.6 mg, 0.262 mmol), Amphos (1.525 mg, 2.153 μmol) and 3-pyridylboronic acid (32.2 mg, 0.262 mmol) in dioxane (0.6 mL) and water (0.200 mL). The reaction mixture was stirred and heated in a microwave at 100° C. for 30 min. The reaction mixture was diluted with water (mL) and extracted with EtOAc (2×5 mL). The organic extract was washed with saturated NH4Cl (2×5 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-10% MeOH in DCM) to provide (S)-3,7-di(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10](C3C=CN=C(SC)N=3)[C:5]2=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc3nc(Cl)ccc3[nH]2)cc1
Yield: 161.5 %

Procedure:
5-Chloro-2-(4-fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)imidazo[4,5-b]pyridine (372 mg 1 mmol) is dissolved in CH2Cl2/HOAc (7 ml 5/2) and treated with mCPBA (270 mg 70% 1.1 mmol) at 0° C. for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (ethyl acetate) to yield the title compound (400 mg 100%) as yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1I)[CH3:2].C([Sn](CC[CH2:43][CH3:44])(CCCC)/C=C/[Sn](CCCC)(CCCC)CCCC)CCC.[I:45]I>C1(C)C=CC=CC=1.C(OCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:44]=[CH:43]/[I:45])[CH3:2]
Reactant: II
Reactant: CCOC(=O)CCCOc1ccccc1I
Reactant: CCCC[Sn](/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CCCOc1ccccc1/C=C/I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.34 g of (4-(2-iodophenoxy)-butyric acid ethyl ester and 6.4 g of (E)-1,2-bis-(tri-n-butylstannyl)-ethylene (50%) are dissolved in 12 ml of toluene, mixed with 94 mg of tetrakis-(triphenylphosphine)-palladium and heated with stirring and argon atmosphere for 2 hours to 70°-80° C. (bath temperature). After cooling to room temperature, the reaction mixture is diluted with 12 ml of diethyl ether and treated with a solution of 2.04 g of iodine in 10 ml of diethyl ether, worked up and chromatographed on silica gel with n-hexane/ethyl acetate=95/5 under the conditions of example 2C. 900 mg of 4-[-[(E)-2-iodovinyl]-phenoxy]-butyric acid ethyl ester is obtained as a yellow oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]([CH3:29])[CH:24]([CH3:28])[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[Br:30][C:31]1[CH:36]=[C:35]([NH2:37])[N:34]=[C:33]([NH2:38])[CH:32]=1.CN1C(=O)CCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[N:23]([CH:24]([C:25](=[O:27])[NH:38][C:33]1[CH:32]=[C:31]([Br:30])[CH:36]=[C:35]([NH2:37])[N:34]=1)[CH3:28])[CH3:29])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Nc1cc(Br)cc(N)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C(=O)Nc1cc(Br)cc(N)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N,N′-dicyclohexylcarbodiimide (24.7 g, 120 mmol) is added slowly to a mixture of 2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid (39 g, 192 mmol) in DCM (60 ml) with ice bath cooling. Stirring is continued and the mixture warmed to RT. The mixture is stirred at RT for 30 minutes before 4-bromopyridine-2,6-diamine A (15 g, 80 mmol) in 60 ml DCM and 10 ml NMP is added dropwise. After stirring for 3 days at RT the reaction mixture is diluted with DCM, filtered and extracted with a saturated aqueous sodium hydrogencarbonate solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 19.8 g (67%). HPLC-MS: M+H=373/375; tR=0.93 min (Method—2).
Reaction SMILES: C(OCC)(=O)C.C(OC(=O)[NH:16][C@H:17]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32]CC3C=CC=CC=3)=[CH:28][C:27]=2[O:40]CC2C=CC=CC=2)[CH2:22][CH2:21]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[NH2:16][C@H:17]([CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=2[OH:40])[CH2:22][CH2:21]1)=[O:19]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H](Cc1ccccc1)C(=O)N1CCC(c2ccc(O)cc2O)CC1
Reaction time: 18 h
Yield: 97.7 %

Procedure:
In a 25 ml round-bottomed flask, 1.23 g of {(R)-1-benzyl-2-[4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]-2-oxoethyl}carbamic acid benzyl ester are dissolved in 15 ml of methanol and also 15 ml of ethyl acetate in the presence of 0.25 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered. The residue is chromatographed on silica gel (95/5 dichloromethane/methanol). 0.625 g of (R)-2-amino-1-[4-(2,4-dihydroxyphenyl)piperidin-1-yl]-3-phenylpropan-1-one is obtained. Yield=64%.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])#[CH:9].[CH2:14]([C:16]([C:27]1[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[C:29]([CH3:41])[CH:28]=1)([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)[CH2:17][CH3:18])[CH3:15]>C(#N)C.[Cu]I.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>[CH2:14]([C:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:9]#[C:8][Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:29]([CH3:41])[CH:28]=1)[CH2:17][CH3:18])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#C[Si](C)(C)C)c(C)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
Triethylamine (25.1 mL, 180.09 mmol), ethynyltrimethylsilane (25.5 mL, 180.09 mmol), CuI (1.143 g, 6.00 mmol) and tetrakis(triphenylphosphine)palladium (0) (6.93 g, 6.00 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 25 g, 60.03 mmol) in acetonitrile (300 mL) at room temperature, and the mixture was stirred at 110° C. for 18 hours and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and a 1 N hydrochloric acid aqueous solution was added to adjust the pH to about 7. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=15/1) to give the title compound (16 g, 74%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:15].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]([C:16]2[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: COc1cc(OC)cc(C(C)=O)c1
Reactant: CCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (0.5 g, 3.1 mmol) and 3,5-dimethoxyacetophenone (0.55 g, 3.1 mmol) in methanol (10 ml) was added 50% w/v of aqueous sodium hydroxide (2.4 ml, 0.031 mol). The reaction mixture was stirred for 2 h at room temperature and then extracted with ethyl acetate (3×20 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. The product was recrystallised from ethanol to give 0.978 g (93%) of off-white crystals. 1H-NMR (CDC3) δ 7.8 (d, 1H), 7.6(d, 2H), 7.3 (d, 1H), 7.15 (d, 2H), 6.9 (d, 2H), 6.65 (t, 1H), 4.0 (t, 2H), 3.9 (s, 6H), 1.85 (m, 2H), 1.05 (t, 3H). 13C-NMR (CDCl3) δ 190.2, 161.3, 160.8, 144.9, 140.6, 130.2, 127.4, 119.6, 114.9, 106.3, 104.8, 69.7, 55.6, 22.5, 10.4. Mass Spectrum m/e (M+1)327.
Reaction SMILES: ClCCl.C(OC([N:11]([CH2:40][C:41]1[CH:50]=[CH:49][C:44]2[O:45][CH2:46][CH2:47][O:48][C:43]=2[CH:42]=1)[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:39])[CH2:14][CH2:13]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CCCCCC>[O:45]1[C:44]2[CH:49]=[CH:50][C:41]([CH2:40][NH:11][CH:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][N:20]4[C:29]5[C:24](=[C:25](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=5)[CH:23]=[CH:22][C:21]4=[O:39])[CH2:16][CH2:17]3)=[CH:42][C:43]=2[O:48][CH2:47][CH2:46]1
Reactant: CCOC(=O)/C=C/c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To 3 mL of a dichloromethane solution containing 0.15 g of ethyl (2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-5-yl)acrylate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 10 with 20% aqueous sodium hydroxide solution, under ice-cooling. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue thus obtained, hexane was added and the resulting solid was filtered to give 0.12 g of ethyl (2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-5-yl)acrylate as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>CC(C)=O>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:13])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 29.2 %

Procedure:
7-methoxyquinoxalin-2(1H)-one (Intermediate 148, 300 mg, 1.70 mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.56 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.4 mmol) as described for Intermediate 2. Chromatography on silica gel with 25% acetone in hexanes gave 200 mg (29%) of the product as a colorless solid.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:22][O:23]C(Cl)Cl.Cl>ClCCl>[CH2:6]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]=1[CH:22]=[O:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Reactant: COC(Cl)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1c(Cc2ccccc2)sc2ccccc12
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Tin chloride (14.0 mL, 119.6 mmol) was added dropwise into a cold (-20° C.) solution of 2-benzyl-benzo[b]thiophene (13.4 g, 59.8 mmol) in dichloromethane (150.0 mL). After 1 h, to the reaction was added dropwise dichioromethyl methyl ether (119.6 mmol). The mixture was allowed to gradually come to 0° C., and then stirred for 20 hours. The mixture was carefully poured into HCl (2N) and ice, and extracted with ethyl ether. The ethereal extracts were dried (MgSO4) and concentrated to give 12.9 g (85%) of the title compound after crystallization from ethyl ether/hexanes, yellow solid mp 86-88 ° C.; mass spectrum m/z 252 (M+). Anal. Calcd. for C16H12Os : C 76.16; H, 4.79. Found: C, 75.77; H, 4.85
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CC(O)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:9]1[CH2:10][CH2:11][S:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1ccc(C2CNCCS2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(N3CCSC(c4ccccc4)C3)c2cc1OC
Temperature: 180 °C

Procedure:
2-Phenyl-thiomorpholine (1 mole equivalent), 4-Chloro-6,7-dimethoxy-quinazoline (1 mole equivalent) and potassium carbonate (1 mole equivalent) were added to a 1:1 mixture of toluene and 2-propanol, corresponding to a final concentration of about 0.5 molar. The reaction mixture was heated in a microwave oven at 180° C. for 15 minutes, and filtrated. The solvent was removed under vacuum and the resultant solid was subjected to preparative LC-MS-purification. Fractions containing the product were collected, pooled and evaporated in vacuo to give the product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(CNC(=O)C3CC3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10 mL), was added cyclopropanecarbonyl chloride (0.21 mL, 2.3 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temperature for one hour. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give cyclopropanecarboxylic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-amide as an off-white solid (233 mg, 42% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.01 min (98.4%); mp, 281-283° C.; 1HNMR (DMSO-d6) δ 0.64-0.74 (m, 4H, CH2CH2 of cyclopropane ring), 1.57-1.66 (m, 1H, CH of cyclopropane ring), 2.15-2.21 (m, 1H, CH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.39 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.57-7.89 (m, 3H, Ar), 8.68 (t, J=6 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 6.31, 13.55, 20.93, 23.40, 30.61, 41.77, 56.53, 120.01, 123.78, 126.58, 134.02, 138.34, 145.78, 154.55, 160.44, 169.47, 172.62, 172.70. LCMS MH=413; Anal Calcd For C19H20N4O4: C, 61.95; H, 5.47; N, 15.21. Found: C, 61.86; H, 5.49; N, 15.04.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]1[CH:7]=[C:8]([CH:12]2[C:16]([OH:17])=[C:15]([C:18]([CH3:20])=[O:19])[CH2:14][S:13]2)[CH:9]=[CH:10][CH:11]=1.S(Cl)(Cl)(=O)=O>O>[F:5][C:6]1[CH:7]=[C:8]([C:12]2[S:13][CH:14]=[C:15]([C:18]([CH3:20])=[O:19])[C:16]=2[OH:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(c2cccc(F)c2)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1csc(-c2cccc(F)c2)c1O
Temperature: 0 °C
Yield: 44.3 %

Procedure:
A chloroform (6.2 mL) solution of 2-(3-fluorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (0.61 g, 2.58 mmol, purity: 78%) was cooled to −40° C., and to this solution, a chloroform (1.2 mL) solution of sulfuryl chloride (0.21 mL, 1.0 equivalent amount) was dropwise added over a period of 3 minutes. The temperature of the solution was raised to 0° C., and water (1.2 mL) was dropwise added over a period of 1 minute, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was isolated and purified by column chromatography (eluent: hexane/ethyl acetate=5/1 (v/v)) to give the desired product as a green solid (0.27 g, yield: 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:36][CH2:35]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=S)Nc3cc4ccccc4nc3OC)CC2)c1
Yield: 81 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound.