Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[C:8]1([CH2:14][O:15][C:16]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[NH:21][C:20]2=[O:36])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][N:21]1[C:22]2[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=2[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:25][CH:19]([NH:18][C:16]([O:15][CH2:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:17])[C:20]1=[O:36])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Product: CCOC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The procedure of Example 4 was employed using equimolar amounts of ethylbromoacetate and 1,3-dihydro-3(R,S)-(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one. The chromatographed product (ethyl acetate-hexane) was dried in vacuo at room temperature over P2O5 : m.p. 65°-66° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH:3]=1.[C:15]([O:19][C:20]([NH:22][C:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=S)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:29]([O:28][C:26]([NH:25][C:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[N:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH:9]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: Cc1ccnc(-c2cccc(N)c2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2.5 h
Yield: 62.1 %

Procedure:
To a suspension of 3-(4-methylpyridin-2-yl)aniline (276 mg), N,N′-bis (tert-butoxycarbonyl )thiourea (539 mg) and diisopropylethyl-amine (0.601 ml) in dichloromethane (15 ml) was added 1-methyl-2-chloropyridinium iodide (498 mg), and the mixture was stirred for 2.5 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 45 g, n-hexane:ethyl acetate=9:1) to give N,N′-bis(tert-butoxycarbonyl) -N″-(3-(4-methylpyridin-2-yl)phenyl)guanidine (397 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16](C)[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C(C(NC)=O)=C([Cl:61])C(C2C=NN(CCCO)C=2)=CC=1>>[Cl:61][C:18]1[C:14]([C:15](=[O:20])[NH:16][CH3:17])=[C:13]([NH:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:23]=2)[CH:12]=[CH:11][C:10]=1[C:8]1[CH:7]=[N:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:9]=1
Reactant: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1Cl
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(Cl)c3C(=O)NC)n2)c(OC)c1)OCC
Yield: 3 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 6-amino-2-chloro-3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylbenzamide (Compound 28C, 274 mg, 887 μmol) to afford 21 mg of the title compound (3%). 1H NMR (400 MHz, CD3OD) δ=8.31 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 6.94 (t, J=2.0 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 4.34 (t, J=6.8 Hz, 2H), 3.95-4.05 (m, 4H), 3.89 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 3.20 (s, 1H), 3.14 (s, 1H), 2.86 (s, 3H), 2.11 (quin, J=6.6 Hz, 2H), 1.22 (t, J=7.1 Hz, 6H). MS (ESI): m/z=726.19 [M+H]+. UPLC: tR=1.32 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:28]#[N:29])[CH2:25][CH2:24][C:23]3[N:22]=[C:21]([CH3:26])[NH:20][C:19](=[O:27])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33](=[O:36])[CH2:34]Br)[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:28]([C:16]1([C:6]2[C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25][CH2:24][C:23]2[N:22]=[C:21]([CH3:26])[N:20]=[C:19]([O:27][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:36])[C:18]=2[CH2:17]1)#[N:29]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C2(C#N)CCc3nc(C)[nH]c(=O)c3C2)c2c1oc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1nc(C)nc2c1CC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in example 21 (150 mg, 1.76 mmles) in dry DMF (5 ml) was added ethylbromoacetate (322.3 mg, 1.93 mmol) and cesium carbonate (688 mg, 2.11 mmol). The reaction mass was stirred at room temperature for 1 hr, diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine and dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography to get both pure compounds.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1>C1COCC1.C(OCC)(=O)C>[CH3:29][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:9]([C:17]([NH2:19])=[O:18])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:5]=[CH:6][CH:7]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: NC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2cccc(-c3cc4ccccc4n3C(N)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 2-(3-aminophenyl)-1H-indole-1-carboxamide (50.2 mg, 0.2 mmol, 1 eq) in anhydrous THF (2 mL) was added m-tolyl isocyanate (25 μL, 1 eq) and the reaction solution was stirred at room temperature for one hour. It was then diluted with ethyl acetate, washed with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated and the oily residue was treated with small amount of dichloromethane. The white solid appeared during this process was filtered to yield 2-[3-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-1-carboxamide in amount of 36 mg.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([CH3:29])[CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f54) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(OC([NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1)([CH3:14])[CH3:13])=O)C1C=CC=CC=1.[H][H]>CO.C(Cl)(Cl)Cl.[C].[Pd]>[NH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1)([CH3:13])[CH3:14]
Reactant: CC(=O)NCc1ccc(C(C)(C)NC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)(C)N)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of N-(4-(1-benzyloxycarbonylamino-1-methylethyl)phenylmethyl)acetamide (9.57 g) in methanol (200 ml) and chloroform (200 ml) was added 10% palladium-carbon (5.0 g) and the mixture was stirred for 5 hr while introducing a hydrogen gas. The reaction mixture was passed through Celite and the solvent was evaporated to give the title compound (5.8 g) as a pale-yellow amorphous solid.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:39][CH2:40][CH2:41][CH:42]([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:44]([O:43][CH:42]([O:46][CH2:47][CH3:48])[CH2:41][CH2:40][NH:39][C:14](=[O:16])[C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:13])[CH3:45]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(CCN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1)OCC
Yield: 84.8 %

Procedure:
By using an analogous procedure to that described for Reference Example 13, carbobenzyloxy-L-alanine (2 g, 8.99 mmol), hydroxybenzotriazole (1.2 g, 8.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.72 g, 8.99 mmol), 1-amino-3,3-diethoxypropane (1.25 g, 8.53 mmol) and N,N-diisopropylethylamine (1.56 ml, 8.99 mmol) were reacted in anhydrous tetrahydrofuran (40 ml) at room temperature for 16 h, to provide benzyl (1S)-2-[(3,3-diethoxypropyl)amino]-1-methyl-2-oxoethylcarbamate (2.55 g, 85%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([SH:8])[CH:7]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13]>>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([S:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH3:10])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13]
Reactant: COc1ccc(F)cc1S
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Product: COc1ccc(F)cc1Sc1ccc(S(C)(=O)=O)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the is product from step (ii) and the product from example 7 step (ii), yield 0.8 g.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[C:31]([CH2:37][CH2:38][CH3:39])=[N:30][C:29]([OH:40])=[CH:28]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[OH:40][C:29]1[N:30]=[C:31]([CH2:37][CH2:38][CH3:39])[C:32]2[C:27]([C:28]=1[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]3[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[CH:26][C:25]([O:24][CH3:23])=[C:34]([O:35][CH3:36])[CH:33]=2
Reactant: COc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(2-((3-(chloromethyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide hydrochloride SLA 41090 (128 mg, 0.372 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (103 mg, 0.417 mmol) followed by a 2 N aq. LiOH solution (0.21 mL, 0.42 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 19.4 mg of N-(2-(3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afforded N-(2-((3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide dihydrochloride 55 as a yellow solid (20 mg, 9% yield).
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][C:17]#[CH:18].[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][C:28]#[C:29][CH2:30]I.S(=O)(=O)(O)O>CCOCC.O1CCCC1>[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][C:28]#[C:29][CH2:30][C:18]#[C:17][CH2:16][C:15]#[C:14][CH2:13][C:12]#[C:11][CH2:10][O:9][C:8]1[CH:19]=[CH:20][CH:21]=[C:6]([CH3:5])[CH:7]=1
Reactant: COC(=O)CCCC#CCI
Reactant: C#CCC#CCC#CCOc1cccc(C)c1
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCC#CCC#CCC#CCC#CCOc1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.61 ml (751 mg, 5.6 mmol) of 3.6N ethylmagnesium bromide in ether was added dropwise, under argon to a solution of 1.34 g (6 mmol) of 9-(m-methylphenoxy)-1,4,7-nonatriyne in 20 ml of anhydrous tetrahydrofuran. The temperature was maintained at 0° C. The reaction mixture was stirred for one hour further at 0° C., then allowed to warm to room temperature, and then 50 mg of cuprous cyanide wasadded. The mixture was stirred for 20 minutes, heated to 40° C. and then 1 g (3.75 mmol) of 7-iodo-5-heptynoic acid methyl ester was added. The resulting mixture was stirred during 4 hours at 40° C. The reaction mixture was then poured into 60 ml of 1N sulfuric acid and ice and the product extracted with ether (3×100 ml). The combined organic extract was concentrated to about 1/5 its original volume and washed several times with EDTA and water, dried over sodium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on 75 g of silica gel, using hexane:ethyl acetate (85:15) as eluant, to obtain 16-(m-methylphenoxy)hexadeca-5,8,11,14-tetraynoic acid methyl ester, as an oil. The product was stored in dry ice.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[N:17]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[N:18]=[CH:19][C:11]=2[CH:10]=1.[Cu][C:29]#[N:30]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:29]#[N:30])=[CH:4][C:3]=1[C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[N:17]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[N:18]=[CH:19][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2cc(I)ccc2Cl)cc2cnn(-c3c(F)cccc3F)c21
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2cc(C#N)ccc2Cl)cc2cnn(-c3c(F)cccc3F)c21
Temperature: 140 °C

Procedure:
A mixture of 5-(2-chloro-5-iodophenyl)-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (60 mg, 0.12 mmol) and copper(I) cyanide (54 mg, 0.6 mmol) in DMF (1.5 mL) were heated in a microwave at 140° C. for 1 h. LC-MS indicates ˜60% conversion to the desired product. Additional copper(I) cyanide (100 mg) was added and the reaction mixture was heated for another 1 h in the microwave at 140° C. The reaction mixture was diluted in DCM (20 mL), washed with brine (2×15 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO 12 g column (15-50% EtOAc in hexanes) affording the title compound as a white amorphous solid. MS (ESI, pos.ion) m/z: 397.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12](O)=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:3]1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:13])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)=[CH:3]1
Reactant: O=C(O)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.1 %

Procedure:
A mixture of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromene-8-carboxylic acid 35 (0.5 g, 1.5 mmol), 3-aminopyridine 36 (0.28 g, 3 mmol), HATU (1.14 g, 3 mmol) and DIPEA (0.78 g, 6 mmol) in DMF (4 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered and the solid was washed with H2O and dried under vacuum to give Compound 224 as a yellow solid (0.13 g, 23% yield). MS (ESI) calcd for C22H13F3N2O3: 410.09. found: 411 [M+H].
Reaction SMILES: [CH:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[Cl:9][C:10]1([Cl:19])[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]1[Cl:18]>>[Cl:15][C:14]12[C:10]([Cl:9])([Cl:19])[C:11]([Cl:18])([CH:3]3[CH:4]1[CH2:5][CH2:6][CH:1]([C:7]#[N:8])[CH2:2]3)[C:12]([Cl:17])=[C:13]2[Cl:16]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: N#CC1CC=CCC1
Product: N#CC1CCC2C(C1)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
3-Cyclohexene-1-carbonitrile (Aldrich Chemical Corp.) (56 g.), and 200 g. of hexachlorocyclopentadiene were mixed, heated at 160°-170° C. for 6 hours, and then allowed to cool to room temperature. The reaction mixture was then vacuum distilled. Unreacted hexachlorocyclopentadiene was first removed and then the crude adduct produced was collected, 175°-170° C. at 0.3 m.m. Hg. The thick liquid was crystallized very slowly in Skelly "B". The crude solid melted at 140°-150° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([CH2:21]Cl)[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:23][NH:24][CH3:25]>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([CH2:21][N:24]([CH3:25])[CH3:23])[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Reactant: CNC
Product: CN(C)Cc1nnc2ccc3nc(Cl)c(-c4ccccc4)nc3n12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-chloro-9-(chloromethyl)-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine (10-2) (840 mg, 0.254 mmol) and dimethylamine (2M in THF, 5 mL, 10 mmol) was stirred at room temperature for 2 hours. The solvent was evaporated to give 1-(3-chloro-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-9-yl)-N,N-dimethylmethanamine (10-3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:15]=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[CH2:18]([NH2:28])[C:19]1[CH:27]=[CH:26][C:25]2[O:24][CH2:23][O:22][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[N:15]=[C:14]([NH:28][CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[O:24][CH2:23][O:22][C:21]=3[CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)c2cc(Cl)ccc2n1
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Yield: 92.3 %

Procedure:
2.72 g (0.0100 mol) of 2-ethoxycarbonyl-4,6-dichloroquinazoline, 1.75 g (0.0116 mol) of piperonylamine and 1.60 g (0.0151 mol) of sodium carbonate were mixed with 100 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography and recrystallized from chloroform/n-hexane to give 3.56 g of the title compound as a colorless needle.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N:20]=[C:19]([NH:30][CH2:31][CH2:32][OH:33])[N:18]=1)[CH2:27][CH2:26][CH2:25]3.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N+:20]([O-:4])=[C:19]([NH:30][CH2:31][CH2:32][OH:33])[N:18]=1)[CH2:27][CH2:26][CH2:25]3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(NCCO)nc2cc3c(cc21)CCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(NCCO)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
H2O2 (70%, 0.5 mL, ca. 10 mmol) was added dropwise to a stirred solution of TFAA (1.4 mL, 10 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 24 (246 mg, 1.0 mmol) and TFA (0.28 mL, 2.0 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 1 h and then at 20° C. for 30 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-4%) of MeOH/DCM, to give 1,4-dioxide 25 (106 mg, 40%) as a red solid: mp (MeOH/DCM) 187-188° C.; 1H NMR [(CD3)2SO] δ 7.99 (s, 1H, H-9), 7.92-7.98 (m, 2H, NH, H-5), 4.84 (t, J=6.0 Hz, 1H, OH)), 3.61 (q, J=6.0 Hz, 2H, CH2O), 3.46 (q, J=6.0 Hz, 2H, CH2N), 2.98-3.10 (m, 4H, H-6, H-8), 2.05-2.14 (m, 2H, H-7); 13C NMR [(CD3)2SO] δ 154.5, 149.4 144.9, 137.6, 129.0, 115.0, 110.9, 59.1, 43.1, 32.6, 31.7, 25.1. Anal. calcd for C12H14N4O3: C, 55.0; H, 5.4; N, 21.4. Found: C, 54.8; H, 5.4; N, 21.1%.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([OH:16])=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[OH:19][N:18]1[C:14](=[O:13])[C:7]2[CH:6]=[C:5]([OH:16])[CH:4]=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12]
Reactant: O=C1OC(=O)c2cc(O)cc3cccc1c23
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3cc(O)cc(c23)C(=O)N1O
Yield: 130.2 %

Procedure:
3-Hydroxy-1,8-naphthalic anhydride (1.4 g, 6.7 mmol) and hydroxylamine hydrochloride (0.9 g, 12.9 mmol) were reacted in pyridine (30 mL) following the procedure of Example 1 to give 2.0 g of the title compound, mp 285-288/C.;
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 72.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S,2R)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (130 mg, 0.20 mmol) prepared in Example 102d, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (70 mg, 99%) as a colorless solid.