Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][CH:23]=1)=O.C([BH3-])#N.O1CCCC1>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:14][CH2:15][C@@H:16]([NH:19][CH2:20][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[CH:27][NH:28]5)=[CH:24][CH:23]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Clc1ccc2c(N[C@H]3CC[C@@H](NCc4ccc5cc[nH]c5c4)CC3)ccnc2c1

Procedure:
A mixture of example 23A (30 mg, 0.11 mmol), 6-formylindole (19.2 mg, 0.132 mmol) and solid supported cyanoborohydride (0.22 mmol) was shaken in 1:1 mixture tetrahydrofuran and acetic acid for 15 hours, filtered and concentrated. The residue was purified with a high throughput HPLC system to provide the desired compound as its bis TRIFLUOROACETIC ACID salt. MS (ESI(+)Q1MS m/z 405 (M+H)+); 1H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1 H), 8.74 (d, 1 H), 8.49-8.79 (m, 2 H), 7.96 (d, 1 H), 7.85 (dd, 1 H), 7.62 (d, 1 H), 7.56 (s, 1 H), 7.45 (t, 1 H), 7.13 (d, 1 H), 6.94 (d, 1 H), 6.47 (t, 1 H), 4.28 (br.s, 1 H), 4.08 (br.s, 1 H), 2.27 (s, 2 H), 1.73-2.13 (m, 9 H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][N:13]([CH3:24])[C:14](/[CH:16]=[C:17]1\[CH2:18][NH:19][CH2:20][CH2:21][CH:22]\1[OH:23])=[O:15].[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH:28](Br)[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:25][C:26]1[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=1[CH:28]([N:19]1[CH2:20][CH2:21][CH:22]([OH:23])/[C:17](=[CH:16]/[C:14](=[O:15])[N:13]([CH3:12])[CH3:24])/[CH2:18]1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)C(Br)c1ccccc1Cl
Reactant: CN(C)C(=O)/C=C1\CNCCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1Cl)N1CCC(O)/C(=C/C(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
7.95 g (23.3 mmol) of the (E)-3-(N,N-dimethylcarbamoyl)methylidene-4-hydroxypiperidine p-toluenesulfonate were dissolved in 50 ml of N,N-dimethylformamide (DMF), followed by the addition of 7.35 g (purity: 80.0%, 22.3 mmol) of 2-chloro-α-methoxycarbonylbenzyl bromide and 7.40 g (53.5 mmol) of potassium carbonate. The resulting mixture was stirred at room temperature for 15 hours. After completion of the reaction, 150 ml water were added. The resulting mixture was extracted with toluene and ethyl acetate. The extract was distilled under reduced pressure. The residue was then purified by chromatography on a silica gel column (eluting solvent: chloroform/methanol=9/1 to 4/1), whereby 6.38 g (77.9%) of the title compound were obtained as a yellowish brown oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[I:27][C:24]1[CH:25]=[CH:26][C:21]([N:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]2=3)=[CH:22][CH:23]=1
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Reactant: Brc1ccc(I)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCC2CCCCC2C1
Product: Ic1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: 200 °C
Yield: 52.1 %

Procedure:
Eighteen point two (18.2) grams (75 mmol) of 9H-tribenz[b,d,f]azepin, 63.7 g (225 mmol) of 1-bromo-4-iodo-benzene, 5.0 g (90 mmol) of potassium hydroxide, and 2.0 g (31 mmol) of a copper powder were mixed with 50 ml of decalin and stirred by heating under a nitrogen gas current for about one week at outer temperature of 200° C. After the temperature of the reaction solution was lowered to near room temperature, chloroform was added thereto, and the solution was filtered through Celite to remove insoluble matters. Water was added to the filtrate, and the solution was subjected to extraction. The obtained concentrated reaction product was purified by silica gel column chromatography to obtain 17.4 g of 9-(4-iodophenyl)-tribenz[b,d,f]azepin (yield: 52%, a small amount of 4-bromophenyl compound was contained).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:11]([NH:12][C:25](=[O:26])[CH2:24][O:23][CH3:22])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cccc(C(=O)OC)c1N

Procedure:
To a solution of methyl 2,3-diaminobenzoate (3.0 g) in THF (50 mL) was added N,N-diisopropylethylamine (4.0 mL). The solution was stirred under ice-cooling, methoxyacetyl chloride (1.81 mL) in THF (10 mL) was added dropwise slowly, and it was stirred for 3 hours at the same temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate, and THF was removed under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate, and it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain the titled compound (3.60 g) as pale yellow powder.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]#[C:36][CH3:37])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCN)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 0.300 g (0.564 mmol) of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate (from Example 199) in 1.5 mL of dichloromethane was added 1.5 mL of trifluoroacetic acid and the resulting mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate and the organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to provide 0.244 g of methyl(2R)-[4-(2-aminoethoxy)phenyl]({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate pure enough for use in the next step. Electrospray Mass Spec 433.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:25])[CH:3]=1.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)C>O1CCCC1.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1N=CN=C(NC(N2CCCC2)=O)C=1>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:37])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 4-methylpiperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (80 mg) in tetrahydrofuran (2.3 ml) was added a solution of phenylacetyl isocyanate in hexane (1.4 ml, Production Example 1), followed by stirring under a nitrogen atmosphere at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (FUJI Silysia NH, eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated to give a crude product, to which diethyl ether was then added to precipitate a solid. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (55.2 mg, 47%) as colorless powder.
Reaction SMILES: [C:1]1([S:7]([N:10]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[C:21]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)S(C2C=CC=CC=2)(=O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[OH-].[Na+]>CO>[CH3:25][C:22]1[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:20]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[O:24][N:23]=1
Reactant: Cc1noc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1-c1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccccc2)c1-c1ccccc1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 101.2 %

Procedure:
N-Benzenesulfonyl-N-(3-methyl-4-phenyl-5-isoxazolyl)benzenesulfonamide (300 mg, 0.66 mmol) was dissolved in methanol. Potassium hydroxide (300 mg, 5.5 mmol) was added and the solution was warmed to 45° C. to dissolve the sodium hydroxide. Stirring was continued for 20 min. Methanol was removed under reduced pressure. The residue was dissolved in water, cooled to 0° C. and acidified to pH 3-4 with concentrated HCl. The solid precipitate was extracted with ethyl acetate, dried and evaporated in vacuo to give 210 mg (100% yield) of N-(3-methyl-4-phenyl-5-isoxazolyl)benzenesulfonamide, which was further purified by recrystallization from ethyl acetate/hexanes, m.p. 124-126° C.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[CH2:15]1[O:25][C:24]2[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][C:17]=2[O:16]1>C(O)C>[CH2:15]1[O:25][C:24]2[CH:23]=[CH:22][C:19]([CH2:20][O:2][C:3]3[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=3)=[CH:18][C:17]=2[O:16]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OCc2ccc3c(c2)OCO3)cc1
Yield: 56.5 %

Procedure:
To a sodium alcoholate solution of 2.16 gm (94 mmol) of sodium in 100 ml ethanol were added 16.9 gm (94 mmol) of ethyl 4-hydroxyphenylacetate with agitation. Then, 16.0 gm (94 mmol) of 3,4-methylenedioxybenzyl chloride were added dropwise, and the mixture was maintained at the boiling temperature for eight hours. After evaporation, taking up of the residue in ether, washing with Na2CO3 solution and water, treating of the ether solution with activated charcoal, and evaporation, the residue was distilled at 0.13 mbar. The volatile material that was removed by distillation until a pot temperature of 240° C. was reached, amounted to 5.9 grams. The residue of 21 gm was chromatographed in a column of silica gel (granule size 0.063 to 0.200 mm, available from Merck & Co.), with methylene chloride as solvent. An amount of 16.7 gm of ethyl 4-(3,4-methylenedioxybenzyloxy)-phenylacetate (57% of theory), with a melting point of 49° to 52° C. and refractive index nD20 =1.5643, was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[N+:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41])([O-:33])=[O:32]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N+:31]([O-:33])=[O:32])(=[O:41])=[O:42])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4[N+](=O)[O-])ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 26.1 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 2-nitrobenzenesulfonyl chloride (44 mg, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was concentrated under reduced pressure. The residue was triturated with water (1 ml), filtered, and washed with of hexane:ethyl acetate (1:1). The crude product was chromatographed on silica gel, eluting with dichloromethane:methanol (399:1) to give the title compound (8 mg, 26%).
Reaction SMILES: [C-:1]#[N:2].[Na+].C(O)C.Cl[CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17]>O>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=1[CH2:8][C:1]#[N:2]
Reactant: [C-]#N
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(CC#N)c(C)c1

Procedure:
66 g of sodium cyanide is refluxed in 100 mL water and 140 mL of ethanol with stirring, until a clear solution is formed. 136 g of 2-chloromethyl-1,3,5-trimethylbenzene is slowly added dropwise to this solution and the mixture is refluxed for 3 hours with stirring. It is diluted with 1 L of water and extracted three times with 200 mL of benzene. The combined organic phases are washed with water and the solvent is distilled off under reduced pressure. The residue is fractionally distilled. Yield: 92 g (72%); bp15: 145° C.-153° C.
Reaction SMILES: [Br:1]C1C=C2C(=CC=1)NN=C2.ClC1C=C2C(=NC=1)NC=C2.FC1C=C2C(=NC=1)NC=C2.N1C2C(=CC=CN=2)C=C1.[F:40][C:41]1[C:46]([C:47]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[C:55](F)[CH:56]=3)[NH:51][CH:50]=2)=[O:48])=[CH:45][CH:44]=[CH:43][C:42]=1[NH:59][S:60]([CH2:63][CH2:64][CH3:65])(=[O:62])=[O:61]>>[Br:1][C:55]1[CH:56]=[C:57]2[C:49]([C:47]([C:46]3[C:41]([F:40])=[C:42]([NH:59][S:60]([CH2:63][CH2:64][CH3:65])(=[O:62])=[O:61])[CH:43]=[CH:44][CH:45]=3)=[O:48])=[CH:50][NH:51][C:52]2=[N:53][CH:54]=1
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(F)cc23)c1F
Reactant: Brc1ccc2[nH]ncc2c1
Agent: Clc1cnc2[nH]ccc2c1
Agent: Fc1cnc2[nH]ccc2c1
Agent: c1cnc2[nH]ccc2c1
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F

Procedure:
Using the protocol of Scheme 14, substituting 5-bromo-azaindole with either 5-chloro-7-azaindole (80, prepared as described in Example 9), 5-fluoro-7-azaindole (81, prepared as described in Example 9) or 7-azaindole in Step 6, propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide P-1013 (MS(ESI) [M−H+]−=394.1), propane-1-sulfonic acid [2-fluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-1028 (MS(ESI) [M−H+]−=378.1), and propane-1-sulfonic acid [2-fluoro-3-(1H-1-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-1056 (MS(ESI) [M+H+]+=362.2) were prepared, respectively:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH2:31][CH:32]1[CH2:34][C:33]1([F:36])[F:35].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH:32]4[CH2:34][C:33]4([F:36])[F:35])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: FC1(F)CC1CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC5CC5(F)F)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 150 °C

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (40 mg, 0.096 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (32.8 mg, 0.19 mmol) and triethylamine (20.2 μL, 0.14 mmol) in 1 mL of DMF was heated at 150° C. in a microwave reactor for 30 min. The crude product was purified by RP-HPLC to afford 5-chloro-N2-(4-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; ESMS m/z 506.2 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:27]=[CH:26][C:20]2[CH:21]=[C:22]([CH:24]=O)[O:23][C:19]=2[CH:18]=1.[C:28]([CH2:30]P(=O)(OCC)OCC)#[N:29].Cl>CN(C)C=O>[C:28]([CH2:30][CH2:24][C:22]1[O:23][C:19]2[CH:18]=[C:17]([O:16][CH2:15][C:5]3[N:6]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[O:8][C:4]=3[CH3:3])[CH:27]=[CH:26][C:20]=2[CH:21]=1)#[N:29]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(C=O)oc2c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCC#N)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Sodium hydride (60%, oily, 0.20 g) was gradually added to a solution of 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran-2-carbaldehyde (1.50 g) and diethyl cyanomethylphosphonate (0.88 g) in N,N-dimethylformamide (30 ml) at 0° C., followed by stirring at room temperature for 1 hour. The reaction mixture was poured over ice water and neutralized with 2N hydrochloric acid, followed by extraction with ethyl acetate (200 ml). After the ethyl acetate layer was washed with water and dried (MgSO4), palladium-carbon (5%, 0.70 g) was added, followed by catalytic reduction at room temperature under an atmospheric pressure of 1 atm. After the catalyst was filtered off, the filtrate was concentrated; the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform (2:98, v/v), crystals of 2-(2-cyanoethyl)-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran (1.34 g, 83%) were obtained, which was then recrystallized from dichloromethane-hexane to yield colorless prisms having a melting point of 92° to 93° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH2:26][OH:27])[O:24][CH:25]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:27][CH2:26][C:23]1[O:24][CH:25]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:21](=[O:28])[CH:22]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cc(CO)occ1OCCCCCOc1ccnc2ccc(C(F)(F)F)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3ccc(C(F)(F)F)cc23)co1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
To a solution of 5-(5-(6-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 11 (93 mg, 0.22 mmol) in CH2Cl2 (5 mL) was added at 0° C. triethylamine (37 μL, 0.26 mmol), methanesulfonyl chloride (20.5 μL, 0.26 mmol). The solution was stirred at RT for 1.5 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. (5-(5-(6-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 16 was obtained (100 mg, 90.5% yield) as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:23])=[C:7]([CH:22]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)#[N:2].[Br:24]N1C(=O)CCC1=O.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:23][Br:24])=[C:7]([CH:22]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=1)#[N:2]
Reactant: Cc1ccc(C#N)cc1OCCNC(=O)c1ccc(C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(C(=O)NCCOc2cc(C#N)ccc2CBr)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
12.0 g (39.3 mmol) of N-[2-(5-cyano-2-methylphenoxy)ethyl]-4-cyanobenzamide was dissolved in 200 ml of carbon tetrachloride. 7.00 g (39.3 mmol) of N-bromosuccinimide and 700 mg (4.26 mmol) of azoisobutyronitrile were added to the solution. After stirring at 100° C. for 3 days, 16.8 g (94.4 mmol) of N-bromosuccinimide and 2.1 g (12.8 mmol) of azoisobutyronitrile were added to the resultant mixture, and they were stirred for additional 2 days. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)=[C:2]=[S:3].Cl.[CH3:13][C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:11][O:10][C:7]1[N:8]=[CH:9][C:4]([NH:1][C:2]([N:20]2[CH2:21][CH2:22][CH:17]([O:16][C:15]3[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=3[CH3:13])[CH2:18][CH2:19]2)=[S:3])=[CH:5][CH:6]=1
Reactant: COc1ccc(N=C=S)cn1
Reactant: Cc1ccccc1OC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=S)N2CCC(Oc3ccccc3C)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
5-Isothiocyanato-2-methoxypyridine [(829 mg, 4.99 mmol), J. Org. Chem. (1980), 45, 4219] was added to a solution of 4-(2-methylphenoxy)-piperidine hydrochloride [(990 mg, 4.3 mmol), J. Med. Chem. (1978), 21, 309] and N,N-diisopropylethylamine (0.79 mL, 4.7 mmol) in dichloromethane (10 mL) and the mixture was stirred for 3 hours at room temperature. The organic solution was then diluted with dichloromethane and washed with sodium hydrogen carbonate solution and brine. The organic solution was dried over magnesium sulfate and concentrated in vacuo. Trituration of the residue with diethyl ether afforded the title compound as a solid in 85% yield, 1.3 g. LRMS APCI m/z 358 [M+H]+
Reaction SMILES: [CH2:1]([O:6]N=O)[CH2:2]C(C)C.N[C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.O.C(=O)(O)[O-].[Na+]>C(O)C.S(=O)(=O)(O)O>[CH2:1]([O:6][C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:2]
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Reactant: CC(C)CCON=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C

Procedure:
1 ml of isoamylnitrite is added to a suspension of 1 g of 3-amino-β-carboline in 100 ml of ethanol and 2 ml of concentrated sulfuric acid. The mixture is stirred at room temperature for an hour and then refluxed for an hour. As a result, a clear solution is obtained. After cooling, it is poured into a mixture of 100 ml of water and 100 ml of saturated sodium bicarbonate solution. It is extracted three times with 100 ml of ether each time and the evaporation residue of the combined ether extracts is chromatographed (silica gel, methanol/chloroform=95:5) and recrystallized from hexane. Yield: 0.3 g of 3-ethoxy-β-carboline with a melting point of 130°-133° C.