Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:1][C:2]2[CH:18]=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
2-{7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-N,N-dimethyl-acetamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 308c. Product isolated as a yellow foam (103 mg, 45%). LCMS (m/e) 566 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.25 (d, 1H, J=9.2 Hz), 8.02 (s, 1H), 7.59 (s, 1H), 7.39 (s, 1H), 7.26-7.19 (m, 1H), 7.03 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 6.56 (s, 1H), 6.51 (d, 1H, J=9.0 Hz), 3.93 (s, 3H), 3.95-3.88 (m, 4H), 3.30 (s, 2H), 3.19-3.13 (m, 4H), 3.16 (s, 3H), 2.99 (s, 3H), 2.95-2.89 (m, 4H), 2.76-2.68 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=O)[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[N:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:45][CH2:46][CH:47]([OH:59])[CH2:48][N:49]1[CH2:58][CH2:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50]1>C(Cl)Cl.O>[CH2:50]1[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:57][CH2:58][N:49]1[CH2:48][CH:47]([OH:59])[CH2:46][NH:45][C:14](=[O:16])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Cn1nccc1-c1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1nccc1-c1cccc(CC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
To a solution of 2-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetic acid (150 mg, 0.69 mmol) in DCM (6 mL) was added EDCI (265 mg, 1.38 mmol), HOBt (186 mg, 1.38 mmol), Et3N (209 mg, 2.07 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (142 mg, 0.69 mmol). The mixture was stirred at room temperature for 16 h then diluted with water (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were concentrated. The residue was purified by prep-HPLC to give the product as a colorless oil (60 mg, Yield 21%). 1H NMR (400 MHz, MeOD): 7.47 (s, 1H), 7.43-7.33 (m, 4H), 7.08-7.04 (m, 3H), 6.96-6.94 (m, 1H), 6.35 (s, 1H), 3.96-3.91 (m, 1H), 3.83 (s, 3H), 3.60-3.59 (m, 4H), 3.38-3.20 (m, 2H), 2.84 (t, J=6.0 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H), 2.49 (d, J=6.4 Hz, 2H). LCMS (m/z): 405.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2C#C[Si](C)(C)C)[N:4]2[CH:19]=[N:20][C:21]([C:22]3[N:26]=[C:25]([CH3:27])[O:24][N:23]=3)=[C:3]12.C(C1C=CC=C2C=1C(=O)N(C)C1N2C=NC=1C1N=C(C)ON=1)#C.CC1ON=C(C[N+]#[C-])N=1.CN1C(=O)C2C(=CC=CC=2C#C[Si](C)(C)C)NC1=O>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH:19]=[N:20][C:21]([C:22]3[N:26]=[C:25]([CH3:27])[O:24][N:23]=3)=[C:3]12
Reactant: Cc1nc(-c2ncn3c4cccc(C#C[Si](C)(C)C)c4c(=O)n(C)c23)no1
Agent: C#Cc1cccc2c1c(=O)n(C)c1c(-c3noc(C)n3)ncn21
Agent: Cn1c(=O)[nH]c2cccc(C#C[Si](C)(C)C)c2c1=O
Agent: [C-]#[N+]Cc1noc(C)n1
Product: Cc1nc(-c2ncn3c4ccccc4c(=O)n(C)c23)no1
Yield: 12 %

Procedure:
A mixture of 4,5-Dihydro-4-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-oxo-6-trimethylsilylethynyl-imidazo(1,5-a)quinazoline, M.p. 214°-217° C., and 6-ethynyl-4,5-dihydro-4-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-oxo-imidazo(1,5-a)quinazoline, M.p. 202°-206° C., by reaction between 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-trimethylsilylethynyl-quinazoline. Column chromatography(silica gel)/ethyl(acetate) of the crude product yielded 0.08 g (12%) of 4,5-dihydro-4-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-oxo-imidazo(1,5-a)quinazoline and 0.01 g (1.9%) of 6-ethylnyl-4,5-dihydro-4-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-oxo-imidazo(1,5-a)quinazoline.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:27][C:26]5[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=5)[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)c1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[2-[[3-(trifluoromethyl)phenyl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:22])[NH:41][CH2:40][CH2:39][N:38]([CH3:42])[CH3:37])[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4]
Reactant: CN(C)CCN
Reactant: COC(=O)c1c(-c2cccc(C(=O)O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(-c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2 ml) of 4-(3-carboxyphenyl)-6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and N,N-dimethylethylenediamine (23 μl) in acetonitrile were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg) and 4-hydroxybenzotriazole monohydrate (38 mg) at room temperature with stirring, and the mixture was stirred at room temperature for 12 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried and concentrated to dryness. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give the title compound (56 mg) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18](O)=[O:19])=[CH:12]2>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:18]([C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=2)=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Glycine methyl ester hydrochloride (50 mmol) and 5-chloro-1H-indole-2-carboxylic acid (50 mmol) were coupled according to procedure A, substituting the following workup: the reaction mixture was stirred in ethyl acetate (250 mL), hexanes (50 mL) and 1N NaOH (50 mL) and the suspension was filtered. The solid was washed with 1N NaOH, 1N HCl, with water, ethyl acetate, and dried: Yield 11.5 g, 86%; mp 252-254° C. with decomposition;
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[CH3:15][Si:16]([CH3:42])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.CCOCC>[CH3:42][Si:16]([CH3:15])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])=[CH:39][CH:40]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: C1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperdine, 2.5 ml. of triethylamine and 0.6 g of 4-(dimethylamino)pyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.1 g. of 4-[14-(trimethylsilyl)tetradecylamino)-benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized to yield the product as a white solid.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=O.C(N(CC)CC)C.[CH3:23][NH:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)(Cl)Cl.O.O1CCCC1>[Cl:5][C:6]1[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([N:24]([CH3:23])[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:13]
Reactant: CNCCN1CCCC1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(CCN1CCCC1)C(=O)c1cnc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
Thionyl chloride (6 ml) was added to 5,6-dichloronicotinic acid (600 mg, 3.13 mmol), and stirred under a nitrogen atmosphere at 90° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and with cooling with ice, triethylamine (1.31 ml, 9.38 mmol) and N-methyl-2-pyrrolidin-1-ylethanamine (481 mg, 3.75 mmol) were added to a tetrahydrofuran solution (4 ml) of the obtained residue, and stirred at room temperature for 3 minutes. Saturated saline water and chloroform were added to the reaction solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=4:1 to 1:1) to obtain 5,6-dichloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)nicotinamide 967 mg) as an orange oil.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:15])=[O:14])=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:2]2[N:9]3[C:5]([S:6][C:7]([C:10]4[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=4)[C:13]([NH2:15])=[O:14])=[N:8]3)=[N:4][CH:3]=2)=[CH:28][C:29]=1[C:34]([F:37])([F:35])[F:36]
Reactant: NC(=O)c1cccc(-c2nn3c(I)cnc3s2)c1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 100 °C
Yield: 2.7 %

Procedure:
A mixture of 3-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-benzamide (70 mg, 0.18 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (75 mg, 0.24 mmol), PdCl2(PPh3)2 (20 mg) and Na2CO3 (60 mg, 0.567 mmol) in dioxane (2 mL) and water (0.5 mL) was heated at 100° C. in a sealed tube for 2 h. The mixture was diluted with DCM (20 mL), washed with sat aq NaHCO3 (2×20 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography and by HPLC to give the desired product (2 mg, 3%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.26 min, [M+H]+ m/z 405.2; 1H NMR (300 MHz, DMSO) δ 8.84 (s, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 8.06 (t, J=8.6 Hz, 2H), 7.75 (s, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.55 (s, 1H), 6.67 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:17]1([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCOCC4)cc3)cc2)cc1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 302 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-morpholinylbenzoate. [M+H]+ calcd for C35H35N4O5: 591.26; found: 591.20.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Reactant: NCc1ccccc1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(NCc3ccccc3)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile and benzylamine in DME. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2].Cl[CH2:19][C:20]([CH3:22])=[CH2:21].C(O)(=O)C>ClCCl.[Cl-].[Zn+2].[Cl-]>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]2[O:14][C:20]([CH3:22])([CH3:21])[CH2:19][C:7]=2[C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: C=C(C)CCl
Reactant: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Oc1c(C(C)C)cc2c(c1C(C)C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.5 %

Procedure:
Under argon atmosphere, 294 mg of 4-acetoxy-3,5-diisopropylphenol was dissolved in 10 ml of anhydrous dichloromethane, 2.25 g of 3-chloro-2-methyl-1-propene, 202 mg of anhydrous zinc chloride and 0.5 ml of acetic acid were added, and the mixture was stirred at room temperature for 3 days. After the reaction was quenched with water, the reaction solution was extracted with hexane. The organic layers were washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 316 mg of 5-acetoxy-2,2-dimethyl-4,6-diisopropyl-2,3-dihydrobenzofuran as a yellow oil (yield 88%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1.CCOC(C)=O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH2:19][CH2:20][S:21]([N:2]([CH3:3])[CH3:1])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)CCc1cc(Cl)ccc1Br
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)CCc1cc(Cl)ccc1Br
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
To a solution of dimethylamine (1.91 mL of 2 M, 3.82 mmol) and triethylamine (386.7 mg, 532.6 μL, 3.82 mmol) in THF (8.1 mL) at room temperature was added 2-(2-bromo-5-chloro-phenyl)ethanesulfonyl chloride (405.0 mg, 1.27 mmol) and the mixture stirred for 10 min. The mixture was diluted with EtOAc and washed subsequently with water and brine, the organic layer dried (MgSO4) and concentrated to afford 2-(2-bromo-5-chlorophenyl)-N,N-dimethylethanesulfonamide as a white solid (413 mg, 99%). 1H NMR (500 MHz, d6-DMSO) δ 7.66 (1H, d), 7.60 (1H, s), 7.30 (1H, d), 3.31-3.34 (2H, m), 3.08-3.12 (2H, m).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10]C(C)C(Br)=O>CCOCC>[BrH:10].[CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Br)C(=O)Br
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3,4-dichlorobenzylchloride (49.2 g, 0.254 mole) in dry ether (125 ml) was added dropwise during one hour to magnesium (6.08 g, 0.250 mole) in a three-necked flask equipped with stirrer and reflux condenser. Refluxing was continued until all the magnesium was dissolved and the solution was then cooled. Acetone (15.0 g, 0.258 mole) was added dropwise and the solution heated to reflux for three hours. After cooling the reaction mixture was poured out on ice (125 ml) and a concentrated hydrochloric acid (23 ml). The phases were separated and the organic layer was washed with water, dried (Na2SO4) and evaporated in vacuum. The residual oil was distilled affording 1-(3,4-dichlorophenyl)-2-methyl-2-propanol (bp. 81°-83° C./0.2 mm Hg; 31.3 g, 57% yield). After several recrystallizations from petroleum ether the compound melted at 40°-41° C. The substituted propanol above (21.9 g, 0.100 mole) was mixed with dimethylaniline (12.4 g, 0.102 mole) and ether (50 ml). The solution was cooled and α-bromopropionyl bromide (21.4 g, 0.099 mole) was added dropwise during 40 minutes. Stirring at room temperature for 48 hours gave a crystalline precipitate of dimethylaniline hydrobromide, which was filtered off and washed with ether. The etheral solutions were combined and evaporated in vacuo. The residual oil was distilled affording 2-bromopropanoic acid 1-(3,4-dichlorophenyl)-2-methyl-2-propolyester (bp. 135°-143° C./0.2 mm Hg; 19.2 g, 55% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]=[CH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:14]>C(O)C.[Pt]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)=[O:14]
Reactant: COc1ccc(C=CC(=O)c2ccc(O)cc2)c(OC)c1
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(CCC(=O)c2ccc(O)cc2)c(OC)c1
Reaction time: 18 h
Yield: 25.1 %

Procedure:
A solution of 568 mg (2 mmol) of 2,4-dimethoxy-4′-hydroxychalcone in ethanol (20 ml) was added 50 mg of platinum on charcoal (10%) and hydrogenated at 20 atm for 18 h. The colourless solution was filtered and concentrated in vacuo to give 606 mg, from which 143.7 mg (24%) of 3-(2,4-dimethoxyphenyl)-1-(4-hydroxyphenyl)propan-1-on was isolated by column chromatography over silica gel 60 (Merck 0.063-0.200 mm, 60 g) using petroleum ether-ethyl acetate (4:1, 500 ml, 3:1, 500 ml) as eluents, m.p. 126.4-127.4° C.
Reaction SMILES: [S:1](=[O:13])(=[O:12])([O:3][C:4]1[CH:9]=[CH:8][C:7](C=O)=[CH:6][CH:5]=1)[NH2:2].NC1C=CC=CC=1.C([O-])(=O)C.[Na+].[BH4-].[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C(O)C>[S:1](=[O:12])(=[O:13])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:2]
Reactant: NS(=O)(=O)Oc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
32 mg of 4-formylphenyl sulfamate was added to a mixture composed of 11.5 μl of aniline, 0.2 ml of ethanol, 27 mg of sodium acetate, 84 μl of acetic acid, and 0.25 ml of water, and dissolved therein by heating. The resulting mixture was cooled with ice, and 20 mg of sodium borohydride was slowly added thereto. After the reaction mixture was stirred at room temperature for 10 minutes, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and the product was extracted with ethyl acetate. After the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 9:1 mixture of chloroform and methanol as the developing solvent) to obtain 27 mg of 4-N-phenylaminomethyl)phenyl sulfamate.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.Cl>C1COCC1>[Br:9][C:10]1[S:11][C:12]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:13][CH:14]=1
Reactant: Brc1cccs1
Reactant: Fc1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2ccc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
To a -78° C. solution of LDA (19.3 mmol) in THF was added 2-bromothiophene (3.00 g, 18.4 mmol) and the reaction mixture was stirred for 15 min. A solution of 4-fluorobenzyl bromide (3.65 g, 19.3 mmol) in THF (1 mL) was added dropwise and the reaction mixture was warmed slowly to ambient temperature and stirred for 70 hours. The reaction mixture was poured into 0.5N aqueous HCl and extracted twice with ether. The combined organic layers were washed with saturated aqueous NaHCO3 (2×) and brine, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (hexanes, then 3% ether/hexanes) gave 2-bromo-5-(4-fluorophenylmethyl)thiophene (2.25 g, 45%).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH2:15]C)[O:11][C:10](=O)[C:9]([N+]([O-])=O)=[C:8]2[OH:21])C>O>[CH3:15][C:14]1[C:5]([CH3:3])=[C:6]2[C:7]([C:8]([OH:21])=[CH:9][C:10](=[O:11])[O:1]2)=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: CCc1cc2oc(=O)c([N+](=O)[O-])c(O)c2cc1CC
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(O)cc(=O)oc2c1C

Procedure:
Dilute sodium hydroxide solution was added to a suspension of 6,7-diethyl-4-hydroxy-3-nitrocoumarin (2.90g) in water (20 ml) till the pH of the solution reached 14. Filtration gave the product as a monohydrate, m.p. 249°-251°(d), (C13H12NO5Na.H2O requires C, 51.49; H, 4.65; N, 4.62; Na, 7.58. Found: C, 52.08; H, 4.65; N, 4.83; Na, 7.81) after washing with water and drying under vacuum.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:12][NH:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of 295 (200 mg, 0.696 mol), DCM (1 mL) and TFA (1 mL) was stirred for 1 h at room temperature, concentrated under reduced pressure; NaOH (1M, 15 mL) was added to the residue and the suspension was extracted with DCM, the extract was dried (anhydrous Na2SO4) and concentrated, to afford title compound 296 (90.4 mg, 69% yield) as a syrup. MS (m/z): 188.1 (M+1).