Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[N:5]=[CH:4][N:3]=1.[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:19]1([CH2:23][CH2:24][N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:38])[F:39])[CH:31]=3)[N:27]=[C:26]2[CH:41]2[CH2:42][CH2:43][N:44]([C:2]3[C:7]4[O:8][CH2:9][CH2:10][NH:11][C:6]=4[N:5]=[CH:4][N:3]=3)[CH2:45][CH2:46]2)[CH2:20][CH2:21][CH2:22]1.[C:14]([OH:16])([C:13]([F:18])([F:17])[F:12])=[O:15]
Reactant: Clc1ncnc2c1OCCN2
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc5c4OCCN5)CC3)n2)cc1C(F)(F)F
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 4-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (30.0 mg; 0.17 mmol; 1.0 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (109.2 mg; 0.17 mmol; 1.0 eq.) and cesium carbonate (227.8 mg; 0.7 mmol; 4.0 eq.) in 1 ml of DMSO was stirred at 120° C. for 48 hrs. The reaction mixture was purified by pre-HPLC to afford the title compound as TFA salt (48.6 mg, 43% yield); LC-MS (M+H=532, obsd.=532);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]([CH:14]=[CH:15]N(C)C)[C:6]=1[N+:19]([O-])=O)[CH3:2]>CCO.[Ni]>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:19][CH:15]=[CH:14]2)=[O:22])[CH3:2]
Reactant: CCOC(=O)c1c([N+](=O)[O-])ccc(C=CN(C)C)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1c(N)ccc2cc[nH]c12
Reaction time: 2 h

Procedure:
A mixture of 3-(2-dimethylamino-vinyl)-2,6-dinitro-benzoic acid ethyl ester (30 g, 0.097 mol) and Raney Ni (10 g) in EtOH (1000 mL) was stirred under H2 (50 psi) for 2 h. The catalyst was filtered off, and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-1H-indole-7-carboxylic acid ethyl ester (B-19) as an off-white solid (3.2 g, 16%). 1H NMR (DMSO-d6) δ 10.38 (s, 1H), 7.44-7.41 (d, J=8.7 Hz, 1H), 6.98 (t, 1H), 6.65 (s, 2H), 6.50-6.46 (m, 1H), 6.27-6.26 (m, 1H), 4.43-4.36 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[CH:8]([O:10][C@@H:11]1[C@@H:15]([O:16][CH:17]=[O:18])[C@H:14]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([NH:34][CH2:35][CH2:36][C:37]2[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=2)=[N:23][C:24]=3NC(CC)CC)[O:13][C@@H:12]1[C:43]1[O:47][N:46]=[C:45]([CH2:48][CH3:49])[CH:44]=1)=[O:9]>>[CH:17]([O:16][C@@H:15]1[C@@H:11]([O:10][CH:8]=[O:9])[C@@H:12]([C:43]2[O:47][N:46]=[C:45]([CH2:48][CH3:49])[CH:44]=2)[O:13][C@H:14]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([NH:34][CH2:35][CH2:36][C:37]1[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=1)=[N:23][C:24]=2[NH:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])=[O:18]
Reactant: CC(C)(C)CCN
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(NCCc5cn(C)cn5)nc43)[C@H](OC=O)[C@H]2OC=O)on1
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(NCCC(C)(C)C)nc(NCCc5cn(C)cn5)nc43)[C@H](OC=O)[C@H]2OC=O)on1

Procedure:
Example 7 was prepared in an analogous manner to Example 4 using 3,3-dimethylbutylamine (0.006 g, 0.056 mmol) and 2-(1-methyl-1H-imidazol-4-yl)ethylamine (0.035 g, 0.28 mmol; generated as in Example 5) at 90° C. for 5 days. The title compound was afforded after freeze-drying as a brown solid (0.007 g). LC/MS SYSTEM A Rt=3.80 mins, m/z=540 MH+.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]2[C:20]([Cl:21])=[C:19]([CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[CH:11][C:10]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C>[Cl:21][C:20]1[C:15]([NH:14][CH2:13][C:12]2[CH:24]=[CH:25][C:9]([OH:8])=[C:10]([O:26][CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH:11]=2)=[N:16][C:17]([CH3:23])=[N:18][C:19]=1[CH3:22]
Reactant: [H][H]
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OCC3CC3)c2)n1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C)c(Cl)c(NCc2ccc(O)c(OCC3CC3)c2)n1

Procedure:
A solution of 2.0 g (4.7 mmol) of (4-benzyloxy-3-cyclopropylmethoxybenzyl)(5-chloro-2,6-dimethyl-pyrimidin-4-yl)amine (from example A5) in 50 ml of methanol and 20 ml of glacial acetic acid is admixed with 250 mg of Pd-on-carbon catalyst (type 38H, Johnson Matthey) and hydrogenated by circulation with hydrogen until about 1 equivalent of hydrogen (about 190 ml) has been taken up. After filtration to remove the catalyst, the solution is concentrated and the residue is chromatographed on silica gel (mobile phase: toluene/dioxane/ammonia=2:1:0.05). The fractions with Rf=0.35 are collected and concentrated. After crystallization from diisopropyl ether, 550 mg (35%) of the title compound are isolated as a beige powder. m.p.: 123-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:14])([F:13])[O:7][C:8]2([F:12])[F:11])=[CH:4][C:3]=1[OH:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:13][C:6]1([F:14])[C:5]2[C:9](=[CH:10][C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:3]([OH:15])[CH:4]=2)[C:8]([F:11])([F:12])[O:7]1
Reactant: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1
Temperature: 80 °C
Yield: 45.7 %

Procedure:
A mixture of 2.0 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 1.1 g of isonicotinic acid, 2.23 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture. Precipitated solid was filtered and washed with water and dried under reduced pressure to give 1.34 g of N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30](S(C1C=CC(C)=CC=1)(=O)=O)[CH:29]=[C:28]2[C:44]1[CH:49]=[N:48][CH:47]=[C:46](Cl)[N:45]=1.Cl>CN(C=O)C.CCOC(C)=O.O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:44]1[N:45]=[C:46]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:47]=[N:48][CH:49]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(Cl)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5Cl)cc34)n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.7 %

Procedure:
To a slurry of NaH 60% in mineral oil (0.047 g, 1.171 mmol) in 2 mL DMF at 0° C. was added (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.236 g, 1.171 mmol). The reaction was warmed to RT. After 10 min, solid 5-(2-chloro-6-fluorophenyl)-3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indole (0.200 g, 0.390 mmol) was added and the reaction became dark brown. After 30 min, the reaction was sealed and heated to 80° C. overnight. Additional NaH 60% in mineral oil (0.047 g, 1.171 mmol) and (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.236 g, 1.171 mmol) were added, the reaction was sealed, and heated to 120° C. for 1 h. The reaction was cooled and treated with ice, water, and EtOAc, and the aqueous layer was acidified with 1N aqueous HCl. The aqeuous layer was extracted 2×EtOAc, and the combined organics were washed 1× water, 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (40 g column) using 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-tert-butyl 3-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (0.077 g, 0.147 mmol, 37.7% yield) as a light-yellow oil. MS (ESI, pos. ion) m/z: 523 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23]>CC(N(C)C)=O.CCOC(C)=O>[OH:15][CH2:14][C:10]1[CH:9]=[C:8]([S:7][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: OCc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1cncc(Sc2cccc(CO)c2)c1
Temperature: 110 °C
Yield: 99.1 %

Procedure:
Add K2CO3 (6.91 g, 50.0 mmol) to a solution of (3-mercaptophenyl)methanol (2.94 g, 21.0 mmol) and 5-bromonicotinonitrile (3.66 g, 20.0 mmol) in DMA (100 mL). Heat the mixture at 110° C. for 2 h. Cool to room temperature. Dilute with EtOAc. Filter. Wash the residue with EtOAc. Concentrate. Dissolve the residue in EtOAc and filter. Concentrate to afford the title compound (4.80 g, quant.): 1H NMR (CDCl3) δ 2.20 (t, J=5.5 Hz, 1H), 4.74 (d, J=5.5 Hz, 2H), 7.38-7.44 (m, 3H), 7.52-7.53 (m, 1H), 7.62 (dd, J=2.0, 2.3 Hz, 1H), 8.62 (dd, J=2.0, 2.3 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][S:11]([C:14]2[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([Si:27]([O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C@@H:49]2[CH2:51][O:50]2)=[CH:43][CH:42]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24].ClCCl.C(Cl)(Cl)Cl.CO>CO.C1COCC1>[Si:27]([O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C@@H:49]([OH:50])[CH2:51][NH:20][CH2:19][CH2:18][C:17]2[CH:16]=[CH:15][C:14]([S:11]([CH2:10][C:7]3[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=3)(=[O:13])=[O:12])=[CH:22][CH:21]=2)=[CH:43][CH:42]=1)([C:23]([CH3:24])([CH3:26])[CH3:25])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1nc(CS(=O)(=O)c2ccc(CCN)cc2)no1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(CS(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)no1
Temperature: 45 °C
Yield: 37.5 %

Procedure:
A solution of the amine of Example 13 (0.873 g, 2.70 mmol) and tert-butyl{4-[(2S)oxiranylmethoxy]phenoxy}diphenylsilane (0.980 g, 2.42 mmol) in a mixture of methanol (20 mL) and THF (3 mL) was heated to 45° C. for 23 h. TLC shows characteristic product spot at Rf=0.25(silica gel plate; dichloromethane/chloroform/methanol: 20/5/2). The reaction mixture was cooled, silica gel (5 g) was added and the methanol was remove in vacuo. The reaction mixture, preabsorbed onto silica gel was applied to the top of a flash chromatography column (silica gel; dichloromethane/chloroform/methanol: 12/3/1) and purified in the standard manner. This procedure afforded 0.660 g of the title compound as a white foam.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]([N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH2:18][O:17]1)=[O:15]>C(Cl)Cl>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:14]([N:16]3[CH2:22][CH2:21][C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[CH2:18][O:17]3)=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)N1CCc2ccccc2CO1
Solvent: ClCCl
Product: O=C(N1CCN(c2ccccc2)CC1)N1CCc2ccccc2CO1

Procedure:
To a solution of 4.22 g. (26 mmoles) of N-phenylpiperazine in CH2Cl2, 4.24 g. (20 mmoles) of 3-chlorocarbonyl-1,3,4,5-tetrahydro-2,3-benzoxazepine was added and the mixture was refluxed for 2 hours, cooled, washed with NaHCO3 and with H2O, dried over Na2SO4 and the solvent evaporated. Yield 5.5 g. (81.5%), m.p. 123°- 125°C, recrystallized from EtOH.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].BrBr.C(NNC(C#N)(C1CC1)C)(C)(C)C>>[C:1]([N:5]=[N:6][C:7]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC1(C#N)CCCCCCC1
Agent: BrBr
Agent: CC(C)(C)NNC(C)(C#N)C1CC1
Product: CC(C)(C)N=NC1(C#N)CCCCCCC1
Reaction time: 10 h

Procedure:
1-t-Butylazo-1-cyanocyclooctane was prepared in 93% crude yield by oxidizing 1-t-butylhydrazo-1-cyanocyclooctane with bromine using the same procedure described in Example XIIIC for the oxidation of 1-t-butylhydrazo-1-cyano-1-cyclopropylethane. The crude product was chromatographed over alumina and the product eluted with pentane. The infrared spectrum of the purified product was consistent with the structure of the desired azo. The compound has a 10 hour half-life in trichlorobenzene at approximately 55°C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([CH2:12][C:13]2[N:17]4[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]4=[N:15][N:14]=2)=[CH:7][CH:6]=3)[CH:26]=[N:25]1
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(Br)cc4c3)n2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Yield: 3.5 %

Procedure:
A solution of 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (50 mg, 0.141 mmol, 1.0 equiv.) in 1,4-dioxane (1 mL) was degassed with nitrogen and added to a microwave tube containing 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.177 mmol, 1.25 equiv., 37 mg). A degassed solution of potassium carbonate (0.282 mmol, 2 equiv., 39 mg) in water (0.5 mL) was then added to the microwave tube followed by dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5 mg, 0.0071 mmol, 0.05 equiv). The microwave tube was capped and reacted in a microwave reactor at 100° C. for 30 minutes. The reaction mixture was partitioned between dichloromethane and water, and the organic layer was evaporated and the residue directly adsorbed on silica gel. Purification on silica gel with 0-10% gradient of methanol in dichloromethane, followed by trituration with methanol afforded the title compound (1.8 mg, 0.005 mmol, 4% yield) as a white solid. Analytical data presented in Table 2.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[CH3:13][N:14](P(N(C)C)(N(C)C)=O)[CH3:15].CNC>O>[F:9][CH:8]([F:10])[C:4]1[C:3]([CH:11]=[O:12])=[C:2]([N:14]([CH3:15])[CH3:13])[N:6]([CH3:7])[N:5]=1
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: CNC
Solvent: O
Product: CN(C)c1c(C=O)c(C(F)F)nn1C
Temperature: 50 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
To mixture of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (34 g, 0.17 mol) and HMPA (50 mL) was added a 40% aqueous solution of dimethylamine (66.3 mL). The reaction mixture was stirred for at 50° C. for 12 h, diluted with water (1 L), and the product was extracted with dichloromethane (2×100 mL). The combined organic layers were dried with sodium sulfate and evaporated. The liquid residue was purified chromatographically on silica gel using dichloromethane/ethyl acetate as eluent (1:3, Rf=0.25) to give 17.81 g (51.6%) of the title product. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, DMSO-d6): δ 2.93 (s, 6H), 3.72 (s, 6H), 7.07 (t, J=56 Hz, 1H), 9.94 (s, 1H). GC-MS calcd for C8H11F2N3O: 203.09, found (M+): 203 m/z.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:31][OH:32])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH2:31][OH:32])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CO)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CO)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
A solution of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methanol (100.7 mg, 0.174 mmol) and trifluoromethanesulfonic acid (0.07 mL, 0.788 mmol) in 2,2,2-trifluoroacetic acid (3.5 mL) was stirred at 75° C. for 1 h. The mixture was subsequently cooled to 25° C. and concentrated in vacuo. NaOH (1.0N, aq.; 2.0 mL) was added, followed by MeOH (1.0 mL) (final pH>10), and the resulting mixture was stirred at 25° C. for 5 min. MeOH was removed in vacuo, and the resulting mixture was vacuum filtered. The collected solid was sequentially washed with water (20 mL) and ethyl ether (6 mL) and then dried in vacuo. Chromatographic purification of this solid (ISCO, 4 g, 0 to 10% MeOH/DCM) furnished (5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methanol (41.8 mg, 0.123 mmol, 70.9% yield) as a yellow solid. 1H NMR (400 MHz, d4-MeOH) δ 8.94 (d, J=2.54 Hz, 1H); 8.48 (d, J=2.35 Hz, 1H), 8.25 (d, J=2.54 Hz, 1H); 8.07 (dd, J=8.80, 2.74 Hz, 1H); 6.85 (d, J=9.00 Hz, 1H); 4.60 (s, 2H); 3.94 (s, 3H); 3.38 (s, 2H); 2.52 (s, 3H). m/z (ESI, +ve ion) 340.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][N:5]([S:39]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1Cl
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2F)c1Cl
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution (20 mL) of 4-chloro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (270 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 100 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (530 mg) was added dropwise and the mixture was stirred for 30 min. 3-Pyridylsulfonyl chloride (321 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:4), and crystallized from diethyl ether to give the title compound as colorless crystals (yield 358 mg, 81%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:23][C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27](O)=[O:28])=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[NH2:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[CH:39]=[CH:40][CH:41]=1>>[C:43]([NH:42][C:38]1[CH:37]=[C:36]([NH:35][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([N:17]3[CH2:16][C:15]4[CH:14]=[N:13][C:12]5[NH:8][N:9]=[CH:10][C:11]=5[C:20]=4[CH2:19][CH2:18]3)=[O:22])[CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:41]=[CH:40][CH:39]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)O)c2)CC4)cc1
Product: CC(=O)Nc1cccc(NC(=O)c2cccc(NC(=O)N3CCc4c(cnc5[nH]ncc45)C3)c2)c1

Procedure:
The compound N-(3-{[3-(acetylamino)phenyl]carbamoyl}phenyl)-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamide was prepared using 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid and N-(3-aminophenyl)acetamide as described in general procedure J. The compound was obtained as a solid. LCMS [M+H]: 470.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][CH2:8][CH3:9].[CH:15]1([CH2:21][C@H:22]2[C@H:26]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[O:25][C:24]([CH3:34])([CH3:33])[N:23]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(CC2COC(C)(C)N2C(OC(C)(C)C)=O)CCCCC1>O1CCCC1.CO>[CH2:6]([NH:10][S:11]([CH2:14][C:27]([C@@H:26]1[O:25][C:24]([CH3:34])([CH3:33])[N:23]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C@H:22]1[CH2:21][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH2:28][CH2:29][CH2:30][CH3:31])[OH:32])(=[O:13])=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNS(C)(=O)=O
Reactant: CCCCC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Agent: CC(C)(C)OC(=O)N1C(CC2CCCCC2)COC1(C)C
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCCNS(=O)(=O)CC(O)(CCCC)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (4.48 ml., 11.2 mmole, 2.8 eq., 2.5M in hexane) was added to a solution of N-butylmethanesulfonamide [846 mg., 5.6 mmole, 1.4 eq., prepared as described in Example 1(a)] in tetrahydrofuran (16 ml., 0.35M) at -40° and stirred for 10 minutes. The reaction was then warmed to 0°, stirred for 30 minutes and cooled to -40°. (4S-trans)-4-(Cyclohexylmethyl)-2,2-dimethyl-5-(1-oxopentyl)-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester (1.5 g., 3.93 mmole, 1 eq.) in tetrahydrofuran (4 ml., 1.0M) was then added. After 90 minutes at -40°, the reaction was quenched with aqueous saturated NH4Cl, warmed to room temperature and extracted three times with ether. The organic extracts were dried (Na2SO4), filtered through MgSO4, and concentrated. The residue was chromatographed on silica gel (Merck, 80 g.) eluting with hexane:acetone (10:1) to provide 237 mg. of (4S-trans)-5-[2-[butylamino)sulfonyl]-1-butyl-1-hydroxyethyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester, isomer A; [α]D =+4.2° (c=1.0, methanol) and 101 mg. of isomer B; m.p. 138°-140°; [α]D =+5.5° (c=1.0, methanol) and 1.518 g. of a mixture of isomer A and isomer B.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:8]2)C=C.Cl[C:20]1[CH:25]=CC=C[C:21]=1Cl>>[CH2:25]([C:6]1[C:5]([OH:4])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:20]=[CH2:21]
Reactant: C=CCOc1ccc2c(ccn2CC(C)(C)C)c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2c1ccn2CC(C)(C)C

Procedure:
5-Allyloxy-N-neopentylindole (Step B; 1.4 g, 4.93 mmol) was refluxed in 20 mL 1,2-dichlorobenzene for 4 hours. The reaction mixture was cooled and immediately purified by flash chromatography on silica gel (gradient elution: hexane then 10% ethyl acetate/hexane) to provide the title compound.