Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7][C:6]1=[O:16].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]([CH3:15])=[CH:7][C:6]3=[O:16])[CH2:18][CH2:19]2)=[CH:24]1
Reactant: Cc1cc(=O)n(CCCCl)c2ccccc12
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(CCCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc12
Temperature: 0 °C
Yield: 64.4 %

Procedure:
A suspension of 1-(3-chloropropyl)-4-methyl-2(1H)-quinolinone (VI-4) (455 mg, 1.93 mmol), 3-(4-piperidinyl)-1H-indole (350 mg, 1.75 mmol) and sodium hydrogencarbonate (220 mg, 2.63 mmol) in dry dimethylformamide 6 ml was allowed to react at 90 ° C. for 15 hours. Ice-water was poured into the reaction mixture and then the separated solid was filtered off by aspiration. The solid was dissolved in chloroform, then dried and the solvent was distilled off under the reduced pressure. The residue was dissolved in developing solvent (chloroform: methanol=9:1) and purified by silica gel column chromatography. After removing the first eluted impurity, a colorless solution was collected and the solvent was distilled off to give the desired product (VII-4) (450 mg) as a pale yellow solid (yield 64.4%, mp 74°-77 ° C.).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12](O)=[O:13])=[CH:8][CH:7]=1>ClCCl>[Cl:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([Cl:3])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccc(Cl)cc1
Temperature: 43 °C
Reaction time: 3 h

Procedure:
7 ml of thionyl chloride are added dropwise to a suspension of 1.75 g of 4-chlorocinnamic acid in 40 ml of anhydrous dichloromethane, with stirring at 43° C. After reacting for 3 hours, the excess acid that has not reacted remains undissolved and is removed by decanting. The filtrate is evaporated to dryness, yielding 4-chlorocinnamic acid chloride.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH:19]([C:20]([O:22][CH3:23])=[O:21])[C:18](=[O:24])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+].O>O1CCCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH:18]([OH:24])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)C1C(=O)c2ccccc2OC1c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1C(O)c2ccccc2OC1c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of methyl 2-(benzo[d][1,3]dioxol-5-yl)-4-oxochroman-3-carboxylate (58 mg, 178 μmol) in tetrahydrofuran (1.0 mL) was diluted with methanol (2.0 mL) and stirred on an ice/acetone bath. Sodium borohydride (7 mg, 178 μmol) was added and the resulting mixture was stirred for 40 min. After this time, water (about 10 mL) was added and the mixture was stirred while warming to rt. The resulting white solid was collected by filtration, washed with water and dried under vacuum to provide racemic methyl 2-(benzo[d][1,3]dioxol-5-yl)-4-hydroxychroman-3-carboxylate (51 mg, 87%). 1H NMR (400 MHz, CDCl3) δ ppm 2.69 (s, 1 H) 3.47 (dd, J=6.6, 2.5 Hz, 1 H) 3.51 (s, 3 H) 5.25 (d, J=5.6 Hz, 1 H) 5.31 (d, J=2.5 Hz, 1 H) 5.99 (s, 2 H) 6.82 (d, J=8.1 Hz, 1 H) 6.89 (d, J=8.1 Hz, 1 H) 6.92 (m, 2 H) 7.03 (t, J=7.4 Hz, 1 H) 7.23 (td, J=7.1, 1.0 Hz, 1 H) 7.57 (d, J=7.6 Hz, 1 H). Mass spectrum m/z 351.20 (M+Na)+.
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([Cl:13])(Cl)=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:10]([Cl:13])=[O:11])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: O=C(Cl)Nc1cccc(Cl)c1

Procedure:
Other of the ureas and thioureas of this invention are prepared by reacting arylamines with activated derivatives of carbonic acid such as phosgene or thiophosgene to yield an intermediate, for instance, an arylcarbamyl chloride. This intermediate is then reacted with a secondary amine to yield the urea or thiourea. The preparation of this intermediate is conducted in an aprotic solvent such as toluene or xylene at temperatures from about room temperature up to the boiling point of the solvent in the presence of a base, for example, N,N-dimethylaniline. The intermediate is then reacted with a secondary amine in an aprotic solvent such as toluene at temperatures from room temperature or below up to the boiling point of the solvent. An example of this process is the reaction of phosgene with 3-chloroaniline to yield the intermediate N-(3-chlorophenyl)carbamyl chloride which is then reacted with di-(n-butyl)amine to yield 1,1-di-(n-butyl)-3-(3-chlorophenyl)urea.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:22]([OH:24])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]([F:44])([F:43])[C:27]([NH:29][C@H:30]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:31]O)=[O:28].N[C@H](C([O-])=O)CO>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:22]([O:24][CH2:31][C@@H:30]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[NH:29][C:27](=[O:28])[C:26]([F:25])([F:43])[F:44])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@H](CO)NC(=O)C(F)(F)F
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: N[C@@H](CO)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@@H](COCc1ccccc1)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of O-benzyl-N-benzyloxycarbonyl-L-serine (1 g) and benzyl N-trifluoroacetyl-L-serinate (873 mg) in methylene chloride (20 ml) was added N,N-diethylaminopropyl-N'-ethylcarbodiimide hydrochloride (573 mg) and -N,N-dimethylaminopyridine (37 mg) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for an hour at room temperature. The reaction mixture was diluted with ethyl acetate (200 ml) and washed successively with 0.2N hydrochloric acid, water, 10% aqueous sodium hydrogen carbonate, water and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was chromatographed on silica gel eluting successively with a 1:1 mixture of methylene chloride and hexane, methylene chloride, a 50:1 mixture of methylene chloride and acetone to give benzyl O-(O-benzyl-N-benzyloxycarbonyl-L-serinyl)-N-trifluoroacetyl-I,-serinate (1.5 g).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[O:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH:13]=[C:14](Cl)C=O)([O-:5])=[O:4].S(=O)(=O)(O)O>O1CCOCC1>[C:13]([C:12]1[CH:11]=[C:10]([CH:20]=[CH:19][CH:18]=1)[O:9][C:8]1[CH:21]=[CH:22][C:23]([N+:24]([O-:26])=[O:25])=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)#[CH:14]
Reactant: O=CC(Cl)=Cc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C#Cc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1

Procedure:
To 50 ml of refluxing 1N sodium hydroxide solution, under a nitrogen atmosphere, was added a solution containing 10 g (0.028 mole) of m-(3,4-dinitrophenoxy)-α-chlorocinnamaldehyde dissolved in 50 ml of 1,4-dioxane. The dark mixture was refluxed for 1/2 hour at which time the solution was cooled and acidified with 10% sulfuric acid. The reaction mixture was extracted with several 50 ml portions of ether, and the combined extracts evaporated to dryness. The residue was chromatographed on a 1" × 12" dry column of silica gel. Elution of the column using 3/1 hexane/methylene chloride produced a first band of side-product. Further elution using 1/1 hexane/methylene chloride yielded a second band which contained the desired product. Evaporation of the eluate to dryness in vacuo afforded 2 g (25%) of 4-(3-ethynylphenoxy)-o-dinitrobenzene as light yellow crystals, m.p. 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=S(=O)(Nc1ccccc1O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A flask with a stirrer was charged with 10.9 g of 2-aminophenol, 10.1 g of triethylamine and 100 ml of acetone, and a solution of 22.7 g of 2-naphthalenesulfonyl chloride in 50 ml of acetone was dropwise added with cooling with ice over 30 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethyl acetate/n-hexane mixed solvents, to give 15.0 g of an end product. Melting point 136.0° C.
Reaction SMILES: [NH:1]([CH2:3][C:4](O)=O)[CH3:2].[OH-:7].[Na+].Cl[NH:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:3]([NH:1][C:2]([NH:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:7])[CH2:4][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCC(=O)NCl
Reactant: CNCC(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCNC(=O)NC(=O)CCCCCCCCCCC
Temperature: 50 °C
Yield: 85.7 %

Procedure:
A solution of 8.9 g (0.1 mol) of sarcosine and 8 g (0.2 mol) of sodium hydroxide in 40 ml of water was added to a suspension of 23.35 g (0.1 mol) of lauric N-chloramide in 200 ml of water. While the reaction mixture was heated to 50° C., acyl urea separates from the suspension in the form of flocks and was isolated by filtration to yield 17 g (86% yield) of N-n-undecyl-N'-lauroyl urea of the formula ##STR19## having a melting point of 104°-106° C. 105° C.; 108° C.; (literature: Jefreys, Am. 22, 33; Ehestaedt, thesis (Freiburg i.B., 1886) p. 15).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][C:3]1=[O:12].[N:13]([O-:15])=[O:14].[Na+]>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([CH3:11])=[CH:10][C:5]=2[O:4][C:3]1=[O:12]
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)oc(=O)n2C
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2oc(=O)n(C)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 64.8 %

Procedure:
The compound (3.33 g, 20.4 mmol) obtained in step A was dissolved in trifluoroacetic acid (60 ml), sodium nitrite (1.41 g, 20.4 mmol) was gradually added under ice-cooling with stirring, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into ice water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (2.75 g, yield 65%) as a pale-bistered solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:14]([NH2:15])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: [H][H]
Reactant: COc1cc(OCCN(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCN(C)C)ccc1N
Yield: 90.6 %

Procedure:
A mixture of [2-(3-Methoxy-4-nitrophenoxy)ethyl]dimethylamine (1.0 g, 4.2 mmol) and 5% Pd—C (0.2 g) in ethyl acetate (75 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 0.80 g of the product as a light gold oil, in 91% yield: 1H NMR (CDCl3) δ 2.33 (s, 6H), 2.69 (t, J=5.8 Hz, 2H), 3.82 (s, 3H), 4.00 (t, J=5.8 Hz, 2H), 6.35 (dd, J=8.3 Hz, J=2.6 Hz, 1H), 6.50 (d, J=2.6 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH:5](C1C=C(Br)C=CC=1OCC1C=CC=CC=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C>[C:6]1([CH2:5][CH2:4][C:3]([OH:27])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccccc1

Procedure:
A solution of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid methyl ester (0.391 g, 0.92 mmol) in ethanol (5 ml) was treated at 50° C. with excess aqueous sodium hydroxide solution until the milky emulsion became clear. The reaction mixture was then acidified (pH 3), evaporated and extracted with dichloromethane. The organic extract was evaporated and the remaining oil was redissolved in a minimum of boiling ethanol. The precipitation formed after 18 hrs at 4° C. was filtered off and dried in vacuo to yield 0.27 g (71.4%) of (±)-3-(2-Benzyloxy)-5-bromophenyl)-3-phenylpropionic acid, colourless crystals, m.p. 124.9° C.; tlc: (1) 0.15 (starting material methyl ester 0.75); NMR (CDCl3): 39.15, 40.26, 70.25, 113.21, 113.90, 126.62, 127.27, 127.98, 128.17, 128.47, 128.54, 130.46, 130.68, 134.34, 136.45, 142.16, 154.95, 177.65. LC-MS: 412/410 (14/11%, M+.), 394/392 (15/13%), 321/319 (17/22%), 304/302 (17/21%), 259 (24%), 194 (22%), 178 (21%), 167 (65%), 152 (49%), 92 (100%). IR (KBr): 3434, 3030, 1708, 1485, 1452, 1403, 1289, 1243, 1126, 1018, 804, 735, 698, 649. Calculated for C22H19BrO3 (mol-wgt. 411.30): C, 64.25%, H, 4.66%, Br, 19.43%, O, 11.67%; found: C, 63.72%, H, 4.70%, Br, 19.75%, O, 11.80%.
Reaction SMILES: C[I:2].[ClH:3].[N:4]1([CH2:9][CH:10]([N:12]2[C:25]3[CH:24]=[C:23]([C:26]([NH2:28])=[NH:27])[CH:22]=[CH:21][C:20]=3[S:19][C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH:29](OC(C)C)(C)C>CN(C)C=O>[ClH:3].[I-:2].[CH3:29][N+:4]1([CH2:9][CH:10]([N:12]2[C:25]3[CH:24]=[C:23]([C:26]([NH2:28])=[NH:27])[CH:22]=[CH:21][C:20]=3[S:19][C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)cc21
Reactant: CI
Reactant: CC(C)OC(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C[N+]1(C)CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)cc21
Product: [I-]
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Methyl iodide (0.036 g) is added to a solution of 10-[1-(1-pyrrolidinyl) (2RS)-2-propyl]-2-phenothiazinecarboxamidine hydrochloride (0.1 g) in dimethylformamide (1 cc) and the mixture is stirred for 16 hours at a temperature of about 20° C. The reaction solution obtained is poured into isopropyl ether (15 cc) and the oil formed is decanted, washed with isopropyl ether (15 cc) and again dissolved in a mixture of acetone and methanol (85-15 by volume) (12 cc). The preceding solution is poured dropwise, with stirring, into isopropyl ether (50 cc), and the yellow solid formed is filtered off and dried under reduced pressure (5 mm Hg; 0.67 kPa) at 50° C. 10-[1-(1-methyl-1-pyrrolidinio) (2RS)-2-propyl]-2-phenothiazinecarboxamidine iodide hydrochloride (0.11 g) is obtained in the form of a yellow powder which melts above 250° C.,
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1F)([O-:3])=[O:2].[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([Cl:22])[CH:21]=1)[NH:18][C:17]([CH3:23])=[C:16]2[CH3:24].C([OH:27])C>>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH+:12]([O-:27])[C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([Cl:22])[CH:21]=1)[NH:18][C:17]([CH3:23])=[C:16]2[CH3:24])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: CCO
Reactant: Cc1[nH]c2c(Cl)cc(N)cc2c1C
Product: Cc1[nH]c2c(Cl)cc([NH+]([O-])c3cnccc3[N+](=O)[O-])cc2c1C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-nitro-3-fluoropyridine N-oxide (1.2 g) and 5-amino-7-chloro-2,3-dimethylindole (1.4 g) in thoroughly degassed absolute ethanol was stirred at 50° C. for 30 minutes and thereafter cooled slowly to 0° C. The precipitate was collected and air-dried to give 2.37 g of N-(4-nitro-3-pyridinyl)-7-chloro-2,3-dimethyl-1H-indol-5-amine N5 -oxide as a powder.
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[I:18][CH3:19]>C(#N)C>[I-:18].[N:8]1([C:6]([N:1]2[CH:5]=[CH:4][N+:3]([CH3:19])=[CH:2]2)=[O:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(N1CCCc2ccccc21)n1ccnc1
Reactant: CI
Solvent: CC#N
Product: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Product: [I-]
Reaction time: 20 h

Procedure:
13.3 g of 1-(1H-imidazol-1-ylcarbonyl)-1,2,3,4-tetrahydroquinoline, 133 ml of acetonitrile and 14.6 ml of iodomethane are introduced into a 500 ml round-bottomed flask. The reaction mixture is stirred for 20 h and then the solvent is evaporated under reduced pressure to result in 23 g of 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-3-methyl-1H-imidazol-3-ium iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:43]([N:46]=[C:47]=[O:48])([CH3:45])[CH3:44]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][C:47](=[O:48])[NH:46][CH:43]([CH3:45])[CH3:44])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:33])[CH3:34])=[CH:4][CH:3]=1
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 50 °C

Procedure:
5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.27 mmol, 1.0 equiv) was dissolved in tetrahydrofuran and treated with triethylamine (1.50 equiv) and isopropyl isocyanate (0.4 mmol, 1.50 equiv). The resulting mixture was heated to 50° C. for 18 h. The reaction mixture was concentrated and crude product was purified on silica using gradient elution from ethyl acetate (100%) and ethyl acetate/methanol (5%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42](O)=[O:43])[CH:38]=[CH:39][CH:40]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:42](=[O:43])[CH2:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cccc(F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-fluorophenylacetic acid (0.37 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was then washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 40% EtOAc in CH2Cl2 for 5 min then increase to 80% EtOAc in CH2Cl2 over 20 min.) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-fluoro-phenyl)-acetamide as a white solid (0.63 g, 69%): mp, 192-194° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.0 min (98%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.57 (s, 2H), 4.73 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.03-7.14 (m, 3H), 7.31-7.39 (m, 1H), 7.63-7.67 (m, 1H), 7.78-7.81 (m, 2H), 8.69 (t, J=6.0 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.94, 30.90, 37.86, 41.67, 48.82, 113.08, 113.35, 115.69, 115.98, 121.91, 125.19, 125.22, 127.13, 129.98, 130.09, 131.51, 133.22, 134.67, 138.77, 138.87, 139.03, 160.38, 163.60, 166.88, 167.41, 169.78, 170.06, 172.73. Anal Calcd for C22H18FN3O5: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.55; H, 4.04; N, 9.80; F, 4.36.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CCN(S(C)(=O)=O)CC3)=[CH:8][C:6]=2[N:7]=1.ClC1N=C(N2CC[O:41]CC2)C2SC=CC=2N=1.[Li]CCCC>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH:11]=[O:41])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
Scheme 4 shows the synthesis of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine 9 starting with formylation at the 7-position of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 4 (1.0 equiv.) in THF with n-BuLi in hexanes to give 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 5 after acidification. Reductive amination of aldehyde 5 was accomplished with 4-(methylsulfonyl)piperazin-1-ium chloride 8 and sodium acetate (anhydrous powder) in 1,2-dichloroethane. Trimethyl orthoformate was added and stirred for 6 hours, followed by the addition of sodium triacetoxyborohydride to give 9.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[NH4+].[Cl-]>CCOCC.C1COCC1>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[B:18]([OH:23])[OH:19]
Reactant: COc1cc(I)c(I)cc1OC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(I)c(B(O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 1,2-diiodo-4,5-dimethoxybenzene (Example 6(b), 2.0 g, 5.13 mmol) in 120 mL of a mixture of THF and Et2O (1:1) was added dropwise at −78° C. isopropylmagnesium chloride (2 M in THF, 2.67 mL, 5.39 mmol). After the mixture was stirred for 2 h at that temperature, B(OiPr)3 (10.89 ml, 15.39 mmol) was added. The solution was warmed to room temperature overnight; then a saturated solution of NH4Cl was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times), dried over Na2SO4 and concentrated. To the concentrated sample, hexane was added and the resulting precipitate was isolated to give 1.05 g of the pure product (67%).