Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([NH:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:22])=[O:21])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=S>[Hg]=O.C(Cl)(Cl)Cl>[NH:4]1[C:3]2[CH:37]=[CH:38][CH:39]=[CH:40][C:2]=2[N:1]=[C:5]1[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([NH:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:22])=[O:21])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(=S)Nc3ccccc3N)c2)c1)c1ccccc1
Agent: O=[Hg]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(Nc3nc4ccccc4[nH]3)c2)c1)c1ccccc1

Procedure:
43 g (75 mmol) of Ethyl 3-{[(3′-{[(2-aminoanilino)carbothioyl]amino}[1,1′-biphenyl]-3-yl)sulfonyl]amino}-3-phenyl-propanoate 11.1.1 and 16.24 g (75 mmol) of yellow mercury oxide were mixed with 1.51 CHCl3 and refluxed for 6 h. The resulting material was purified via flash chromatography (dichloromethane/acetic acid ethyl ester 3+1). Recrystallization from acetic acid ethyl ester led to 27.8 g (68%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:18].FS(O[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[Cl:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]=1[NH:1][CH3:24]
Reactant: COS(=O)(=O)F
Reactant: Nc1c(Cl)ccc2c1C(=O)c1ccccc1C2=O
Solvent: Cc1ccccc1
Product: CNc1c(Cl)ccc2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h

Procedure:
A solution of 1-amino-2-chloroanthraquinone (2.6 grams; 0.01 mole) and methyl fluorosulfonate (1.254 grams; 0.011 mole) in toluene (50 mls) was refluxed for 22 hours and filtered while hot. The residue in the flask was combined with the filter cake and the combined solids were slurried in 5 N sodium hydroxide at 25° C. for 0.5 hour. The slurry was then filtered, and the solid was rinsed with water and dried. The yield of product obtained was 41% of theoretical.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[O:18][C:17]2=[O:24])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CCOCC.O1CCOCC1>[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[O:18][C:17]2=[O:24])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CC(C(=O)O)OC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCc1ccc(N2CC(C(=O)O)OC2=O)cc1

Procedure:
3.36 g of 3-(4-tert-butoxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinecarboxylic acid [obtainable according to Example 14; m.p. 166°] are stirred at room temperature for 1 h in a mixture of 30 ml of ether and 30 ml of dioxane, which has been saturated beforehand with HCl gas. The precipitate is then filtered off with suction and washed with ether. 3-(4-Aminomethylphenyl)-2-oxo-5-oxazolidinecarboxylic acid is obtained, m.p. 211°-212°.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:4][C:3]1=[O:19].S(Cl)([Cl:23])(=O)=O.N>C(O)(=O)C>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:23])=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:4][C:3]1=[O:19]
Reactant: Cc1csc2c1c(-c1ccccc1F)nc(=O)n2C
Reactant: O=S(=O)(Cl)Cl
Agent: N
Solvent: CC(=O)O
Product: Cc1c(Cl)sc2c1c(-c1ccccc1F)nc(=O)n2C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 500 mg of 1-methyl-4-(o-fluorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 15 ml of glacial acetic acid is added 295 mg of sulfuryl chloride in 3 ml of glacial acetic acid at 40°C. After stirring the reaction mixture for 19 hours at room temperature, the reaction mixture is neutralized with aqueous ammonia under cooling, then extracted with chloroform. The chloroform extracts are washed with water, dried, and evaporated under reduced pressure to a residue to give crystals of 1-methyl-4-(o-fluorophenyl)-5-methyl-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one, which are recrystallized from ethanol-ether to give crystals having a melting point of 175° - 176°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)#[N:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:29]3[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3ccc(C#N)cc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0.459 mmol) and 4-cyanophenol were reacted as starting materials at 150° C. for 13 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (108.0 mg, 57.5%). Melting point: 167.3-170.5° C. (ethyl acetate-hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].O.Cl>ClCCl>[N:1]1([CH2:8][C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COC(=O)CC(=O)CCl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.27 g (14.6 mmol) of morpholine are added to a solution of 1.0 g (6.64 mmol) of methyl 4-chloroacetoacetate in 10 ml of dichloromethane, and the mixture is stirred at room temperature for 4 hours. Water is then added and the mixture is neutralized with 2N hydrochloric acid. The organic phase is dried over sodium sulfate and concentrated, and the residue is chromatographed on silica gel with cyclohexane/ethyl acetate (10:1→4:1→1:1) as mobile phase.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2C#Cc2cccc(C)n2)CCN(C)C1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CCc2cccc(C)n2)CCN(C)C1

Procedure:
To a degassed stirred solution of 2,8-dimethyl-5-(6-methyl-pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.317 mmol) in MeOH (5 mL) was added Pd/C (35 mg, 35% w/w) and purged the reaction mixture with H2 gas at RT for 2 h. The progress of reaction was monitored by TLC and NMR. Reaction mass was filtered through a Celite bed washed with MeOH (3×5 mL). Filtrate was concentrated under reduced pressure and residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-[2-(6-methyl-pyridin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.2 (dd, 1H), 7.63 (d, 1H), 7.57 (d, 1H), 7.21 (d, 1H), 7.02 (d, 1H), 6.96 (d, 1H), 4.7 (d, 1H), 4.58 (t, 2H), 4.37 (d, 1H), 3.82 (m, 1H), 3.57 (m, 1H), 3.4 (t, 2H), 3.2 (m, 2H), 3.18 (s, 3H), 2.61 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18]>C(=S)=S>[C:5]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[NH:9][C:10](=[O:18])[CH2:11]2)(=[O:7])[CH3:6]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Reaction time: 0.08 h

Procedure:
To 95 ml. of carbon disulfide was added 27 g. (0.202 mole) of aluminum chloride, followed by the dropwise addition of a solution of 3 ml. (0.042 mole) of acetyl chloride in 5 ml. of carbon disulfide, with stirring. Stirring was continued for 5 minutes and then 4.4 g. (0.033 mole) of 2-oxindole was added. The resulting mixture was heated under reflux for 4 hours and cooled. The carbon disulfide was removed by decantation and the residue was triturated under water and recovered by filtration. After drying, 3.2 g. of the title compound was obtained, m.p. 225°-227° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([OH:16])=O)[CH:8]=2)=[O:4].[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([NH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:16])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(C(=O)O)cc2[nH]1
Reactant: NCCN1CCOCC1
Solvent: CO
Product: COC(=O)c1cc2ccc(C(=O)NCCN3CCOCC3)cc2[nH]1
Yield: 78 %

Procedure:
2-(Methoxycarbonyl)indole-6-carboxylic acid was coupled with 4-(2-aminoethyl)-morpholine by the method described above to give 2-(methoxycarbonyl)-N-[2-(4-morpholinyl)ethyl]indole-6-carboxamide as a white powder (78%), mp 226-227.5° C. (MeOH). 1H NMR [(CD3)2SO] δ12.24 (s, 1H, indole NH), 8.42 (t, J=5.6 Hz, 1H, amide NH), 7.97 (s, 1H, H-3 or H-7), 7.71 (d, J=8.4 Hz, 1H, H-4), 7.56 (dd, J=8.4, 1.5 Hz, 1H, H-5), 7.20 (s, 1H, H-3 or H-7), 3.90 (s, 3H, CO2Me), 3.58 (t, J=4.6 Hz, 4H, CH2O), 3.41 (q, J=6.5 Hz, 2H, CONHCH2), 2.48 (t, J=7.0 Hz, 2H, CONHCH2CH2), 2.42 (t, J=4.1 Hz, 4H, NCH2CH2O); 13C NMR δ166.6 (CONH), 161.5 (CO2Me), 136.7, 131.0, 129.1, 128.5 (C-2,6,8,9), 121.6, 118.9, 112.3, 107.5 (C-3,4,5,7), 66.2 (CH2O), 57.3, 53.2 (CH2N), 51.9 (OCH3), 36.6 (NHCH2). Anal. (C17H21N3O4) C,H,N.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13].Cl.[F:18][B-:19]([F:22])([F:21])[F:20].[Na+]>C(OCC)(=O)C.CO>[F:18][B-:19]([F:22])([F:21])[F:20].[CH2:10]([NH:14][C:15]([NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN=C=O
Reactant: CCCCCCCCN
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCNC(=O)NCCCC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A four necked flask equipped with a thermometer, stirrer and drip funnel was charged with 2.58 g of octylamine and 200 g of ethyl acetate. To this was added dropwise a solution of 1.98 g of n-butylisocyanate in 30 g of ethyl acetate with stirring over 30 minutes while maintaining the inner temperature at 10° C. and allowed to react until the absorption of isocyanato group (2240 cm-1) disappeared IR spectrometrically. After dissolving the solidified reaction product in 50 g of methanol, a mixture of 2.086 g of 35% hydrochloric acid and 50 g of methanol was added dropwise to the solution over 30 minutes and allowed to react at room temperature for 20 hours. Then a solution of 2.2 g of sodium tetrafluoroborate in 50 g of methanol was added dropwise over 30 minutes and allowed to react at room temperature for 20 hours. The reaction mixture was then filtered to remove NaCl by-product and evaporated to remove the solvent. 6.1 g of the title compound was obtained as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](N2C=CN=C2)=[O:10])=[C:4]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:9](=[O:10])[N:28]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:16]2([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[OH:24]
Reactant: NCC(F)(F)F
Reactant: O=C(c1ccc(Br)cc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(Br)cc2)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a solution of N-[4-chloro-2-(4-bromobenzoyl)phenyl]-1H-imidazole-1-carboxamide (4.0 g, 9.9 mmol) in THF (20 mL) was added 2,2,2-trifluoroethylamine (1.1 g, 10.9 mmol). The reaction was heated to 50° C. After 19 h at 50° C., the reaction was cooled to ambient temperature and concentrated in vacuo. The light yellow foam was partitioned between n-butyl chloride (15 mL) and aqueous 10% citric acid (15 mL) with vigorous stirring. The resulting precipitate was collected by vacuum filtration to give 6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H); 7.50 (br d, 2H, J=8.79 Hz); 7.34 (br d, 2H, J=8.79 Hz); 7.22 (m, 2H); 6.97 (dd, J=1.46 and 7.57 Hz, 1H); 4.35 (dq, 1H, J=8.78 and 16 Hz); 3.53 (dq, 1H, J=8.55 and 17 Hz); 3.22 (s, 1H). MS (Electrospray): m/z M+Na, Br=79, 457.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][NH:16][CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc3c(n2)CCNC3)c1=O
Reaction time: 0.33 h

Procedure:
tert-Butyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate 158c (3.2 g, 7.4 mmol) was suspended in methylene chloride (20 mL), saturated hydrogen chloride in dioxane (20 mL) was added dropwise. The reaction mixture was stirred for 20 minutes and concentrated under reduced pressure to give 205a, which was used without further purification in the next step. LC/MS: m/z 336 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:26])[N:16]2[C@H:19]2[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]2)=[C:12]([Cl:27])[N:11]=1.CO.[CH3:30]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(#N)C>[Cl:27][C:12]1[N:11]=[C:10]([N:9]2[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[N:1]=[CH:30]2)[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:26])[N:16]2[C@H:19]1[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]1
Reactant: COC(OC)OC
Reactant: Nc1ccc(F)cc1Nc1nc(Cl)c2[nH]c(=O)n([C@H]3CC[C@H](O)CC3)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: CO
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a flask containing crude 2-(2-amino-5-fluorophenylamino)-6-chloro-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (12 mg, 0.03 mmol) was added anhydrous methanol (3 mL), followed by anhydrous trimethylorthoformate (0.5 mL) and p-toluenesulfonic acid (catalytic) and the reaction mixture was stirred under Ar at room temperature for 18 h (HPLC monitoring). A solution 10% acetonitrile in water (total volume 10 mL) was added and a pale yellow solid precipitated. Filtration under vacuum provided the desired product as a pale yellow solid (10.6 mg, 88% yield). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.07 (br s, 1H), 8.30 (br d, 1H), 7.82-7.70 (m, 1H), 7.27-7.15 (m, 1H), 4.48-4.42 (m, 1H), 3.88-3.80 (m, 1H), 2.67-2.50 (m, 2H), 2.33-2.18 (m, 2H), 2.10-1.95 (m, 2H), 1.70-1.56 (m, 2H); MS (EI) m/z 403.1 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=[O:12].[BH4-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][OH:12]
Reactant: Cn1c(C=O)nc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(CO)nc2ccccc21

Procedure:
To 432 mg of 1-methyl-1H-benzoimidazole-2-carbaldehyde (2.7 mmol, 1 eq) dissolved in a mixture of THF (10 mL) and methanol (10 mL) was added 340 mg of sodium borohydride (9.0 mmol, 3.33 eq) in several portions. After 12 h the reaction mixture was quenched with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (1-methyl-1H-benzoimidazol-2-yl)-methanol in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.8 (s, 3 H) 4.7 (d, J=5.6 Hz, 2 H) 5.6 (t, J=5.7 Hz, 1 H) 7.2 (m, 1 H) 7.2 (m, 1 H) 7.5 (m, 1 H) 7.6 (m, 1 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[C:11]([C:13](=[CH2:17])[C:14]([O-:16])=[O:15])#[N:12].C1(=O)OC(=O)C=C1.C1(C=CC(O)=CC=1)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[C:11]([C:13](=[CH2:17])[C:14]([OH:16])=[O:15])#[N:12].[C:11]([C:13](=[CH2:17])[C:14]([OH:16])=[O:15])#[N:12].[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1
Reactant: C=C(C#N)C(=O)[O-]
Agent: O=C1C=CC(=O)O1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: OCc1cccc(CO)c1
Solvent: Cc1ccccc1C
Product: C=C(C#N)C(=O)O
Temperature: 25 °C

Procedure:
A mixture consisting of 30.0 g (0.0474 mole) bisanthracene adduct/1,3-bis (hydroxymethyl) benzene bits (2-cyanoacrylate), 27.8 g (0.284 mole) maleic anhydride, 0.1 g hydroquinone, and 0.5 g phosphorous pentoxide in 125 ml. dry xylene is heated at 139°-141° C for 5 hours, cooled to room temperature, and suction-filled to give 26.1 g, mp 257°-259° C, of A/MA adduct. Solvent stripping of the filtrate and crystallization of the residue from benzene gives another 3.5 g, mp 258°-260° C, of A/MA adduct. The mother liquor is solvent stripped and the excess maleic anhydride sublimed off at 60°-65° C/0.1-0.2mm. The semi-crystalline residue (11.4g) is taken-up in 50 ml. hot benzene, the solution decanted from some insolubles (3.5 g, mp>300° C) and cooled to give another 1.3 g, mp 260°-262° C, of A/MA adduct. The filtrate is concentrated in vacuo to give 6.2 g (44% theory) of crude monomer as a pale orange liquid. IR and NMR analysis indicated the presence of considerable anhydride-containing and other unknown impurities.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1.[NH:30]1[CH2:36][CH2:35][CH2:34][C@H:31]1[CH2:32][OH:33].CS(C)=O>C([O-])(O)=O.[Na+]>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:3]=[C:2]([N:30]2[CH2:36][CH2:35][CH2:34][C@H:31]2[CH2:32][OH:33])[N:7]=[CH:6][C:5]=1[N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]1[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1)([CH3:11])[CH3:12]
Reactant: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(N2CCC[C@H]2CO)cc1-c1ccccc1Cl
Temperature: 13 °C
Reaction time: 22 h
Yield: 88 %

Procedure:
To a solution of 0.15 g (0.32 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide and 0.25 g (2.47 mmol) L-prolinol in 2 ml dimethyl sulfoxide 0.2 g (1.55 mmol) Na2CO3 was added and the solution was stirred at 13° C. for 22 h. After cooling to ambient temperature, the solution was poured into 20 ml 0.5 N NaHCO3-solution and extracted three times with 30 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 1:2) to give 0.15 g (87%) of the title compound as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[C:8]3[NH:23][C:24]4[CH:25]=[CH:26][C:27](Br)=[CH:28][C:29]=4[C:7]3=[CH:6][C:5]2=1>CN(C=O)C.[Pd]>[CH:3]1[CH:2]=[CH:14][CH:13]=[C:12]2[C:4]=1[C:5]1[CH:6]=[C:7]3[C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:23][C:8]3=[C:9]([O:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[C:10]=1[NH:11]2
Reactant: CCN(CC)CCOc1c2[nH]c3ccc(Br)cc3c2cc2c1[nH]c1ccc(Br)cc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1c2[nH]c3ccccc3c2cc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of 2-(2,10-dibromo-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-diethylethanamine (133.0 mg, 0.2513 mmol) and 10% Pd/C (0.05 equivalent) in DMF (8 mL) in a hydrogenation flask was filled with H2 and then evacuated with house vacuum for three times, and then filled with H2 (30˜40 psi). The reaction was stirred at room temperature overnight. When TLC and MS showed the reaction was complete, the DMF solvent was removed under vacuum pump. The residue was dissolved in methanol and filtered through celite. The crude product was purified by flash chromatography to provide the desired product 2-(5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-diethylethanamine (59.3 mg, 64%). 1H-NMR (400 MHz, CD3OD) δ ppm 8.47 (s, 1H), 8.09 (d, J=7.6 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.33 (t, J=8.0 Hz, 2H), 7.16 (t, J=7.6 Hz, 2H), 4.57 (t, J=5.0 Hz, 2H), 3.79 (t, J=5.0 Hz, 2H), 3.49 (q, J=7.6 Hz, 4H), 1.45 (t, J=7.6 Hz, 6H); MS (ESI) m/z 370.3 (M−H)−; MS (ESI) m/z 372.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:11]>O1CCOCC1>[NH2:11][C:6]1[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: N#Cc1c(Cl)ncnc1Cl
Solvent: C1COCCO1
Product: N#Cc1c(N)ncnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
4,6-Dichloropyrimidine-5-carbonitrile (4.8 g, 27.59 mols) was suspended in 30 mL dioxane and the mixture was cooled at 0° C. in an ice bath. Ammonia solution (7N in methanol, 20 mL, 140 mmol) was added dropwise over 20 min. The mixture was stirred at 0° C. for 30 min. The solvent was evaporated and the crude was re-dissolved in tetrahydrofuran. A precipite was formed and filtered and washed with more tetrahydrofuran. The organics were evaporated under reduced pressure. The residue was purified using a SP1® Purification System (20%-80%, hexane-ethyl acetate) to give 2.38 g (56% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4[CH2:30][C:31](O)=[O:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].O>CN(C=O)C>[CH3:48][S:49]([NH:52][C:31](=[O:32])[CH2:30][N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][C@@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)(=[O:51])=[O:50]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)O)no2)cc1C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)NS(C)(=O)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To a solution of [4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetic acid (100 mg) in DMF (1 ml) was added CDI (39 mg), and after 30 min, methanesulfonamide (23 mg) and 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine (37 mg) were added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was added with water to complete the reaction. It was extracted with EtOAc, the obtained organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain N-(methylsulfonyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (56.4 mg) as a white solid.