Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32][CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:47])(=[O:46])[N:19]=1>Cl.O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:47])(=[O:46])[N:19]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)ccc3N2)c(O)c2cccnc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC4CCNCC4)ccc3N2)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 446A (0.012 g, 0.017 mmol) was dissolved in the solution of hydrogen chloride in 1,4-dioxane (4 N, 3 mL). The mixture was stirred at 25° C. for 18 hours. The solvent was removed under reduced pressure to give the title compound as its hydrochloride salt (10 mg, 92%). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.70 (m, 7 H) 2.95 (m, 2 H) 3.16 (m, 3 H) 4.49 (m, 2 H) 7.50 (m, 2 H) 7.63 (d, J=2.21 Hz, 1 H) 7.73 (d, J=9.19 Hz, 1 H) 8.17 (d, J=7.35 Hz, 1 H) 8.52 (m, 1 H) 8.56 (dd, J=7.91, 1.65 Hz, 1 H) 8.75 (m, 1 H) 8.90 (dd, J=4.60, 1.65 Hz, 1 H) 10.34 (s, 1 H) 14.08 (s, 1 H). MS (ESI−) m/z 588 (M−H)−.
Reaction SMILES: Cl.[Cl:2][C:3]1(C(OC)=O)[CH:8](O)[NH:7][C:6](=[O:10])[NH:5][C:4]1=[O:11]>>[Cl:2][C:3]1[C:4](=[O:11])[NH:5][C:6](=[O:10])[NH:7][CH:8]=1
Reactant: COC(=O)C1(Cl)C(=O)NC(=O)NC1O
Agent: Cl
Product: O=c1[nH]cc(Cl)c(=O)[nH]1

Procedure:
In 15 ml. of concentrated hydrochloric acid, 345 mg. of methyl 5-chloro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate is heated under reflux for 15 hours. The reaction mixture is cooled with ice, whereupon 92 mg. of 5-chlorouracil is obtained as colorless prisms.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][OH:16].[OH-].[Na+]>CS(C)=O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.[Cl-].[Na+].O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:16][CH2:15][C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OCc1cccs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(COCc2cccs2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86 %

Procedure:
To a solution in DMSO (30 mL) of 4-fluorobenzyl bromide (3.27 mL, 26.3 mmol), 2-thiophenemethanol (3.00 mL, 31.7 mmol), and benzyltrimethylammonium chloride (244 mg, 1.31 mmol) was added NaOH (6.31 g, 159 mmol) and the reaction mixture was stirred for 17 hours at ambient temperature. The reaction mixture was poured into brine and extracted with ether. The organic phase was washed with 1N aqueous H3PO4 (3×), H2O (3×), saturated aqueous NaHCO3 (2×), and brine, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (20% ethyl acetate/hexane) gave 2-(4-fluorophenylmethoxymethyl)thiophene (5.03 g, 86% ).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:49])OC2C=CC=CC=2)=[CH:36][CH:35]=1)(=[O:33])[NH2:32]>CN(C=O)C>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:37]4[CH:36]=[CH:35][C:34]([C:31]([NH2:32])=[O:33])=[CH:39][CH:38]=4)=[O:49])=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3CCOCC3)n2)cc1
Temperature: 90 °C
Yield: 5.3 %

Procedure:
To a solution of 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (0.6 g, 1.5 mmol) and triethylamine(4-5 mL) in dry DMF (10 mL), phenyl 4-carbamoylphenylcarbamate (1.15 g, 4.5 mmol).) was added at room temperature and mixture was heated to 90° C. for 10 hours under nitrogen atmosphere. After cooling to room temperature reaction mixture was quenched with ice water and resulting solid was filtered to get crude product. Crude product was purified by Preparative HPLC to give 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide (45 mg, 5.3% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[O:11]=[C:12]1[N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C@H:28]([CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([OH:51])=[C:46]([CH3:52])[CH:45]=3)[C:29]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:33][CH2:32]3)=[O:30])=[O:26])[CH2:21][CH2:20]2)[CH2:17][CH2:16][C:15]2[CH:53]=[CH:54][CH:55]=[CH:56][C:14]=2[NH:13]1>C(Cl)Cl>[O:11]=[C:12]1[N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C@H:28]([CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([O:51][CH:1]=[O:3])=[C:46]([CH3:52])[CH:45]=3)[C:29]([N:31]3[CH2:32][CH2:33][CH:34]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)[CH2:35][CH2:36]3)=[O:30])=[O:26])[CH2:21][CH2:20]2)[CH2:17][CH2:16][C:15]2[CH:53]=[CH:54][CH:55]=[CH:56][C:14]=2[NH:13]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCOCC3)CC2)cc(C)c1O
Solvent: O=CO
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCOCC3)CC2)cc(C)c1OC=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 100 μL acetic anhydride and 1 mL formic acid in 3 mL DCM was stirred for 2 h at RT (formation of the mixed anhydride). Then 100 mg (0.16 mmol) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1.20a) were added and the reaction mixture was stirred for 2 h at RT. The reaction solution was evaporated down and the residue was again added to a solution of the mixed anhydride and stirred overnight at RT. The mixture was evaporated down i.vac. and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [ClH:1].[CH2:2]([O:4]CC)[CH3:3].[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:8]>C(O)C>[ClH:1].[CH2:12]([O:11][C:9]([C:7](=[NH:8])[O:4][CH2:2][CH3:3])=[O:10])[CH3:13]
Reactant: CCOCC
Reactant: CCOC(=O)C#N
Agent: Cl
Solvent: CCO
Product: CCOC(=N)C(=O)OCC

Procedure:
A hydrogen chloride gas was introduced into a diethyl ether solution of an equimolar mixture of ethyl cyanoformate and ethanol at 0° C. or lower, and a precipitated crystal was filtered out and washed with diethyl ether to obtain ethyl ethoxycarbonylformimidate hydrochloride [H5C2O2CC(OC2H5)=NH.HCl]. 5.4 g of this hydrochloride, 40 ml of acetic acid, 5.0 g of phenacylamine hydrochloride (the same as used in Synthesis Example 2) and 4.85 g of anhydrous sodium acetate were mixed and reacted with stirring at 90° to 100° C. for 4 hours.
Reaction SMILES: S([N:11]1[C:23]2[CH:22]=[CH:21][C:20]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]4[CH:33]=[CH:34][CH:35]=[N:36][C:25]3=4)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C1COCC1.C(O)C.O>[CH:22]1[C:23]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[C:20]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]3[CH:33]=[CH:34][CH:35]=[N:36][C:25]2=3)[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3ccccc3c3cc(-n4c5ccccc5c5cccnc54)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: c1ccc2c(c1)[nH]c1ccc(-n3c4ccccc4c4cccnc43)cc12
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A mixture solution of 9-(9-tosyl-carbazol-3-yl)-pyrido[2,3-b]indole (9.9 g, 20.30 mmol) and NaOH (8.12 g, 203 mmol) in THF (100 mL), ethanol (50 mL) and water (50 mL) was refluxed over weekend. After cooling to room temperature, the white solid was obtained by filtration, and washed successively with water, ethanol, DCM and ethanol to yield the 9-(9H-carbazol-3-yl)-9H-pyrido[2,3-b]indole (4.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15][O:16]C3CCCCO3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1cc2c(COC3CCCCO3)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc2c(CO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 89.9 %

Procedure:
Ethyl N-(3,4-dichlorobenzyl)-4-(2-tetrahydropyranyloxy)methylindole-2-carboxylate (4.38 g) and p-toluenesulphonic acid (100 mg) in ethanol (100 ml) was stirred at ambient temperature for 3 hours, then concentrated in vacuo and the residue dissolved in ethyl acetate (100 ml), washed with water (100 ml), dried (MgSO4) and concentrated to give the product as an off-white solid (3.22 g, 90%); NMR δ(CD3SOCD3) 1.25 (t, 3H), 4.25 (q, 2H). 4.80 (d, 2H), 5.20 (m, 1H), 5.80 (s, 2H), 6.85 (m, 1H) 7.10 (d, 1H), 7.30 (m, 2H), 7.50 (m, 3H, M/z (+) 378.3 (MH+).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=1>C(Cl)Cl>[F:12][C:13]([F:24])([F:25])[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH:22]=[O:23])=[CH:18][CH:19]=1
Reactant: OCCCc1ccc(C(F)(F)F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled orange suspension of pyridinium chlorochromate (3.659 g; 16.896 mmol) in anhydrous DCM (20 ml) was added dropwise a solution of 3-(4-trifluoromethyl-phenyl)-propan-1-ol (2.300 g; 11.264 mmol) in anhydrous DCM (35 ml). The resulting black suspension was allowed to warm-up to rt and was stirred under nitrogen for 3 h. The reaction mixture was directly filtered over silicagel using DCM. After concentration to dryness under reduced pressure, the product 3-(4-trifluoromethyl-phenyl)-propionaldehyde was isolated as a pale yellow oil (1.970 g; 86.5%). LC-MS: tR=0.95 min.; [M+H]+: no ionisation.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1.O=[C:25]([CH3:39])[CH2:26][CH2:27][N:28]1C(=O)C2C(=CC=CC=2)C1=O>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:18]3[CH2:23][CH2:22][N:21]([CH:25]([CH3:39])[CH2:26][CH2:27][NH2:28])[CH2:20][CH2:19]3)[O:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CSc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Product: CSc1ccc(C2(C3CCN(C(C)CCN)CC3)Oc3ccccc3O2)cc1

Procedure:
Using general procedure B with the above amine (65 mg, 0.20 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (86 mg, 0.40 mmol) and then using general procedure D afforded 3-{4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (42 mg, 53% over 2 steps).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11]
Reactant: CCOC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)CN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(tert-butoxycarbonyl)glycyl-3-(2-methoxy-4-pyridinyl)alaninate (2.3 g, 6.03 mmol) and trifluoroacetic acid (8 mL, 108 mmol) in DCM (8 mL). The reaction mixture was stirred at 0° C. for 2 h. The solvent was removed in vacuo to give crude ethyl glycyl-3-(2-methoxy-4-pyridinyl)alaninate as a colorless tar, which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(C)C.[OH-].[K+]>C(O)C>[CH2:15]([S:22][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1c(Cl)ccc2ccncc12
Reactant: SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: O=[N+]([O-])c1c(SCc2ccccc2)ccc2ccncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.52 g. (2.5 mmole) of 7-chloro-8-nitroisoquinoline and 0.317 g. (2.56 mmole) of benzyl mercaptan in 5 ml. of degassed isopropanol under argon at 0° C. was treated with 0.16 g. (2.5 mmole) of 86% KOH in 2 ml. of ethanol dropwise over fifteen minutes. The mixture was stirred for one hour at 25° C. and filtered. The collected product was washed with water and ethanol and then dried to yield 7-benzylthio-8-nitroisoquinoline having a melting point of 151°-153° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[CH:11][NH:10][C:4]=2[N:5]=[C:6]([O:8][CH3:9])[N:7]=1>CO.[Pd]>[CH3:9][O:8][C:6]1[N:7]=[CH:2][C:3]2[CH2:12][CH2:11][NH:10][C:4]=2[N:5]=1
Reactant: COc1nc(Cl)c2cc[nH]c2n1
Agent: [Pd]
Solvent: CO
Product: COc1ncc2c(n1)NCC2
Reaction time: 8 h

Procedure:
10% Pd/C (1.000 g, 11.6 mmol) was added to a solution of 4-chloro-2-methoxy-7H-pyrrolo[2,3-d]pyrimidine (0.200 g, 1.09 mmol) in 20 mL anhydrous MeOH under H2 at room temperature. The mixture was stirred for 8 h and then filtered through a pad of Celite. The filtrate was concentrated in vacuo to give 2-methoxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine as a major product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:19]([F:22])=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:16]([O:17][CH3:18])=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:6].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:23][C:3]1[C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[CH:21][CH:20]=[C:19]([F:22])[C:4]=1[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:16]([O:17][CH3:18])=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:6]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc(N)c3F)cc12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)c4ccccc4)c3F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
3-Amino-2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.005 g, 0.0157 mmol) was taken up as a slurry in CHCl3 (1.0 mL). Three drops of pyridine were added, followed by the addition of benzenesulfonyl chloride (0.00600 mL, 0.0470 mmol). The slurry was stirred overnight at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography to provide 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(phenylsulfonamido)benzamide (5.7 mg, 79%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.59 (s, 1H), 11.01 (s, 1H), 10.39 (br s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.76-7.78 (m, 2H), 7.64-7.68 (m, 1H), 7.57-7.61 (m, 1H), 7.31-7.37 (m, 1H), 7.17-7.21 (m, 1H), 4.01 (s, 3H); m/z (APCI-neg) M−1=458.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]Br)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:26]=[N+:27]=[N-:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN=[N+]=[N-])c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.867 g, 2.08 mmol) in DMSO (9 mL) was added sodium azide (0.175 g, 2.49 mmol), and the reaction was stirred at 60° C. for 4 hours. The mixture was cooled to room temperature and diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with H2O, then brine, and dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>O>[I:1][C:2]1[C:7]([O:8][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1I
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cccnc2I)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
2-Iodo-pyridin-3-ol (50 mg, 0.226 mmol), K2CO3 (62 mg, 0.452 mmol) and DMF (2 ml) were added with para-methoxybenzyl chloride (46 μL, 0.339 mmol), and the mixture was stirred overnight at 45° C. The resultant was added with water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and the resulting residues obtained after concentration under reduced pressure were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (21 mg, 27%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1C=CC=CC=1N>>[Cl:23][C:24]1[CH:2]=[CH:3][CH:4]=[CH:5][C:1]=1[NH:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1ccccc1Cl
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccccc2Cl)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2-chlorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.13 (s, 3H), 2.38 (s, 3H), 4.75 (d, J=2.8 Hz, 2H), 6.05 (bs, 1H), 6.94 (t, J=6.4 Hz, 1H), 7.06-7.20 (m, 3H), 7.36 (d, J=6.8 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 8.40 (d, J=5.8 Hz, 1H), 8.60 (d, J=3.4 Hz, 1H); MS (ESI) m/z 340.6 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][N:6]=[C:5]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:4]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[F:1][CH:2]([F:19])[C:3]1[C:8]([C:9]([Cl:23])=[O:10])=[CH:7][N:6]=[C:5]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(C(F)(F)C(F)(F)F)nc1C(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 10 ml of dichloromethane, 467 mg of 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylic acid are admixed with two drops of N,N-dimethylformamide and cooled to 0° C. Following the dropwise addition of 167 μl of oxalyl chloride, the reaction mixture is stirred at room temperature for three hours and then concentrated by evaporation. This gives the crude product 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([NH:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:15])[CH3:18]
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1sc(CC)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of methyl 2-amino-5-ethylthiophene-3-carboxylate (7.07 g), ethyl chloroformate (4.4 mL) and toluene (100 mL) was stirred at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as colorless oil (9 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[S:11][C:10]([CH2:12][NH2:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:13][CH2:12][C:10]2[S:11][C:7]([O:6][C:5]3[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)=[O:22])=[CH:19][N:18]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: NCc1ccc(Oc2ccc(F)cc2)s1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NCc2ccc(Oc3ccc(F)cc3)s2)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of C-(5-(4-fluorophenoxy)thiophen-2-yl)methylamine described in Preparation Example 28 (500 mg, 2.24 mmol) and 6-aminonicotinic acid (340 mg, 2.46 mmol) in N,N-dimethylformamide (10 mL) were added benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (1.1 g, 2.46 mmol) and triethylamine (0.6 mL, 4.48 mmol), and the solution was stirred for 30 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed with water three times. The organic layer was passed through a glass filter lined with NH silica gel and silica gel (1:1), and eluted with a mixture solvent of ethyl acetate and methanol (20:1). The solvent was evaporated in vacuo, ethyl acetate and hexane were added to the residue, the generated solid was collected by filtration, and the title compound (560 mg, 1.63 mmol, 72.8%) was obtained as a slightly yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1>CN(C)C=O.O>[OH:10][C:4]1([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8][N:7]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:20]=2)[CH2:6][CH2:5]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: OCCC1(O)CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(N2CCC(O)(CCO)CC2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a solution of compound 26 (517 mg, 3.25 mmol) in anhydrous dimethylformamide (15 mL) under argon were added triethylamine (1.32 g, 13.0 mmol) and 4-fluoro-2-trifluoromethylbenzonitrile (1.80 g, 9.52 mmol). The solution was stirred at 80° C. for 4 hrs. The solution was cooled at room temperature and poured in water (100 mL), extracted with diethyl ether (3×25 mL), washed with brine and finally dried over magnesium sulphate. Purification of the resulting crude product by flash chromatography using ethyl acetate/hexane (7:3) as an eluant gave the desired compound 27a (687 mg, 68%). 1H NMR (400 MHz, Acetone-d6) δ: 1.74 (m, 6H), 3.45 (m, 2H), 3.85 (m, 4H), 7.24 (dd, 1H, J1=6.4 Hz, J2=2.5 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.72 (d, 1H, J=8.8 Hz).