Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C@H:20]1[O:25][C@@H:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:21][C@@H:20]([CH3:19])[O:25][C@@H:24]([CH3:26])[CH2:23]2)[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2OCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: C[C@@H]1CN(c2nc(Cl)nc3c2COC3c2ccc(F)cc2)C[C@H](C)O1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) was reacted as described in Preparation Xa with (2R,6S)-2,6-dimethylmorpholine to give 2-chloro-4-((2S,6R)-2,6-dimethylmorpholino)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation Mh). LC-MS (M+H)+=364.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.39 (dd, J=8.70, 5.34 Hz, 2 H) 7.07 (t, J=8.70 Hz, 2 H) 5.90 (br. s., 1 H) 5.34-5.42 (m, 1 H) 5.24-5.34 (m, 1 H) 4.14 (q, J=7.02 Hz, 2 H) 3.67 (ddd, J=10.38, 6.41, 2.44 Hz, 4 H), 1.20 (m, 6 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[CH2:8][NH:9][CH2:10][C:4]=2[C:3]=1[C:11]#[N:12].[NH3:13].[CH3:14]O>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]2[CH2:8][NH:9][CH2:10][C:4]=2[C:3]=1[C:11]#[N:12].[CH3:14][N:7]([CH3:6])[C:2]([NH2:13])=[NH:1]
Reactant: N
Reactant: CO
Agent: N#Cc1c(N)ncc2c1CNC2
Product: CN(C)C(=N)N

Procedure:
Two 6,7-dihydropyrrolo[3,4-c]pyrido[2,3-d]pyrimidines which contain a novel tricyclic ring system of potential bilogical interest were sythesized. 6-(2,5-Dimethoxphenyl)-6,7-dihydropyrrolo[3,4-c]pyrido[2,3-d]pyrido[2,3-d]pyridmidine-2,4(1H,3H)-dione (3a) [throughout the Experimental Detail section, numbers in parenthesis () refer to numbered compounds in FIGS. 1 to 4] was prepared from a pyrido[2,3-d]pyrimidine. 6-Acetoxymethyl-5-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4) was oxidized with SeO3 to the corresponding 5-formyl derivative (5) which was condensed with 2,5-dimethoxyaniline to form the Schiff base. Reduction of the exocyclic azomethine double bond of the Schiff base with NaBH3CN to (6) followed by thermal cyclization afforded (3a). 2,4-Diamino-6-(4-methoxyphenyl)-6,7-dihydropyrrolo[3,4-c]pyrido[2,3-d]pyrimidine (3b) was synthesized by addition of a pyrimidine ring to the dihydropyrrolo[3,4-c]pyridine system. 1-(4-Methoxphenyl)pyrrolidine- 3-one (18) was condensed with malononitrile to give a Knoevenagel adduct (19). Treatment of (19) with N,N-dimethylaminomethylene chloride in the presence of LDA afforded the 4-N,N-dimethylaminomethylenepyrrolidine derivative (20) which was converted into 6-amino-7-cyano-2,3-dihydropyrrolo[3,4-c]pyridine (21) by treatment with NH3 /MeOH. Cyclization of (21) with N,N-dimethyl-guanidine afforded the desired product (3b) in high yield.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][NH:17][C:18](=O)[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:15])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>O1CCCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[O:15][C:18]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:17][N:16]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCCC(c2nnc(-c3ccc(F)cc3)o2)C1
Yield: 85 %

Procedure:
A mixture of 4-fluoro-benzoic acid N′-[(S)-1-(4-fluoro-benzoyl)-piperidine-3-carbonyl]-hydrazide (100 mg, 0.26 mmol), 4-toluenesulphonyl chloride (60 mg, 0.31 mmol), solid supported 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphorine (PS-BEMP, ex Fluka, 586 mg, 1.3 mmol, loading 2.2 mmol/g) in dry tetrahydrofuran (6 mL) was irradiated by microwaves under the following conditions: MW cycle: t=1 min, P=100 W, cooling time=2 min. After 5 MW cycles, the resin was filtered off and washed repeatedly with dichloromethane. The solvent was evaporated under reduced pressure to give a crude solid that was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 1:1). The title compound was obtained as a white solid (82 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[S:30]1[CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[C:33]1[CH2:34][CH2:35][S:30][CH2:31][CH:32]=1
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(C3=CCSCC3)c(Cl)cc21
Temperature: 85 °C

Procedure:
Palladium tetrakistriphenylphosphine (41.7 mg, 0.036 mmol) was added to a stirred suspension of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-hexahydrofuro[3,2-b]furan-3-ol (Intermediate 3, 100.0 mg, 0.181 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 45, 61.2 mg, 0.270 mmol), and potassium phosphate tribasic (115.0 mg, 0.542 mmol) in degassed 20% water in dioxane (1.85 mL). The reaction mixture placed under N2 and heated at 85° C. for 10 h. The reaction mixture was cooled to room temperature. The lower aqueous layer drawn off and discarded. The remaining reaction mixture was evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 12 g silica RediSep Rf® Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C23H32ClN3O5SSi 525.15 observed m/e: 526.17 (M+H)+ (Rt 1.64/2.0 min)
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:6][CH:5]=[N:4][CH:3]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cncs1
Product: Fc1ccc(-c2cncs2)cc1

Procedure:
Using 5-bromothiazole (1.0 g, 6.09 mmol) and (4-fluorophenyl)boronic acid (1.0 g, 7.31 mmol) and following the procedure described in example 7 step 1, the title compound was obtained after purification by purified by Biotage IsoleraOne® column (10% ethyl acetate in hexane) as yellow viscous liquid (0.4 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.25 (s, 1H), 7.73-7.69 (m, 2H), 7.27 (t, 2H); LC-MS m/z calculated for [M+H]+180.02. found 180.1.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:10]=2)[N:5]=[CH:4][NH:3]1.Cl>CCOC(C)=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]([OH:15])=[O:14])[CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: CC(C)(C)OC(=O)Cc1ccc2nc[nH]c(=O)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc2nc[nH]c(=O)c2c1

Procedure:
A solution of tert-butyl 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetate (0.25 g, 0.96 mmol) in 10 mL of satd. HCl in EtOAc was stirred at rt for 4 hours. The mixture was concentrated in vacuo at rt, and the residue was used in the next reaction without further purification. MS (ESI, pos. ion) m/z: 205.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[C:8]=2[CH:7]=1>C(Cl)Cl.CCCCCC>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[C:8](=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=1
Reactant: COCCOc1ccc2c(c1)C(=O)c1ccccc1C2=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COCCOc1ccc2cc3ccccc3cc2c1
Yield: 50.6 %

Procedure:
Using the procedure outlined in Example 1B, 2-[2-(methoxy)ethoxy]anthraquinone (12A) gave a 50.6% yield of 2-[2-(methoxy)ethoxy]anthracene, mp 131°-134°, (C,H), (CH2Cl2 /hexane).
Reaction SMILES: [CH2:1]([C:3]1(O)[CH:27]=[C:26]2[C@:21]([CH3:29])([CH2:22][CH2:23][C@H:24]([OH:28])[CH2:25]2)[C@@H:20]2[C@@H:4]1[C@H:5]1[C@:17]([CH3:30])([CH2:18][CH2:19]2)[C@@H:8]([C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:6]1)[CH3:2]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C@@H:4]2[C@@H:20]([C@:21]3([CH3:29])[C:26]([CH:27]=1)=[CH:25][C:24](=[O:28])[CH2:23][CH2:22]3)[CH2:19][CH2:18][C@@:17]1([CH3:30])[C@H:5]2[CH2:6][CH2:7][C@@H:8]1[C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CCC1(O)C=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]21
Solvent: Cc1ccccc1
Product: CCC1=CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@H]12

Procedure:
The above Grignard product 2, 5.13 g (11.9 mmol) was dissolved in 50 ml toluene and cyclohexanone and about 40 ml of solvent distilled off under vacuum. To this was added 7.2 g aluminum isopropoxide and the reaction mixture refluxed overnight for 15 hours. The mixture was cooled, diluted with ethyl acetate, washed with sodium potassium tartarate, brine, and the organic layer was concentrated under vacuum and the residue steam distilled. The residue was extracted with ethyl acetate, the ethyl acetate layer, washed with brine, dried and purified by column chromatography on silica gel, eluting with 5% EtOAc/hexane to yield the title compound 3. Rf=0.58 (20% EtOAc/hexane). Mass spec: 412(M=1) by FAB, Calc'd. 411.9.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:38])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[C:30]([F:37])[CH:29]=1.CCN(CC)CC>ClCCCl>[CH3:23][O:24][C:25](=[O:38])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:36])=[C:30]([F:37])[CH:29]=1
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)COc1ccc(N=C=O)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)COc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with (3-fluoro-4-isocyanato-phenoxy)-acetic acid methyl ester in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 days under reflux conditions to give the title compound as yellow solid. MS: m/e=516.8 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:11]3[C:18]([C:19](O)=[O:20])=[C:17]([CH2:22][CH3:23])[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:5][CH2:4]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.[F:58][C:59]1[CH:60]=[N:61][CH:62]=[CH:63][C:64]=1[NH2:65]>CN(C=O)C>[CH3:24][N:2]([CH3:1])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:11]3[C:18]([C:19]([NH:65][C:64]4[CH:63]=[CH:62][N:61]=[CH:60][C:59]=4[F:58])=[O:20])=[C:17]([CH2:22][CH3:23])[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:5][CH2:4]1
Reactant: Nc1ccncc1F
Reactant: CCc1sc2ncnc(OC3CCC(N(C)C)CC3)c2c1C(=O)O
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: CCc1sc2ncnc(OC3CCC(N(C)C)CC3)c2c1C(=O)Nc1ccncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a solution of 4-[[4-(dimethylamino)cyclohexyl]oxy]-6-ethylthieno[2,3-d]pyrimidine-5-carboxylic acid (100 mg, 0.29 mmol, 1.00 equiv) in distilled DMF (5 mL) was added HATU (217 mg, 0.57 mmol, 2.00 equiv), DIEA (110.9 mg, 0.86 mmol, 3.00 equiv) and 3-fluoropyridin-4-amine (32 mg, 0.29 mmol, 1.00 equiv) under nitrogen. The resulting solution was stirred for 1 h at room temperature. After evaporation under reduced pressure, the crude product (120 mg) was purified by Prep-HPLC with the following conditions (Waters): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (7.0% CH3CN up to 48.0% in 10 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 4-[[4-(dimethylamino)cyclohexyl]oxy]-6-ethyl-N-(3-fluoropyridin-4-yl)thieno[2,3-d]pyrimidine-5-carboxamide (40 mg) as a white solid. MS (ES, m/z): 444 [M+H]+. 1H NMR: (400 MHz, CD3OD): 8.55-8.59 (2H, m), 8.50 (1H, d), 8.40 (1H, d), 5.19-5.24 (1H, m), 3.07 (2H, q), 2.28 (6H, s), 2.10-2.19 (3H, m), 1.89-1.92 (2H, m), 1.27-1.43 (5H, m), 1.22-1.25 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][CH:24]([C:20]3[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=3)[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: ClCCCOc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-bromo-4-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.37 (d, 2H, J=7.6 Hz), 7.26 (m, 3H), 6.97 (d, 1H, J=7.7 Hz), 6.79 (d, 2H, J=7.7 Hz), 4.01 (t, 2H, J=5.6 Hz), 3.08 (d, 2H, J=9.4 Hz), 2.53 (m, 4H), 2.05 (m, 4H), 1.84 (m, 4H), 1.24 (d, 6H, J=5.9 Hz); Anal. Calcd for C24H31BrN2O2.HCl+0.34CHCl3: C, 54.5; H, 6.08; N, 5.22. Found: C, 54.5; H, 6.22; N, 5.22; ESMS m/e: 459.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:20])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([Cl:19])[CH:11]=3)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].CC(S(Cl)(=O)=O)C>CN(C=O)C>[Cl:19][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([C:17]#[N:18])=[C:8]([C:4]3[CH:3]=[C:2]([N:1]=[CH:8][N:9]([CH3:20])[CH3:10])[CH:7]=[N:6][CH:5]=3)[N:9]2[CH3:20])=[CH:14][CH:13]=1
Reactant: Cn1c(-c2cncc(N)c2)c(C#N)c2ccc(Cl)cc21
Agent: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C=Nc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 211, 85 mg, 0.3 mmol) in DMF (5 mL) is added 60% NaH in mineral oil (48 mg, 1.2 mmol), followed with propane-2-sulfonyl chloride (86 mg, 60.6 mmol). The mixture is stirred at room temperature for 5 h. The mixture is filtered and the filtrate is purified on Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give N′-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N,N-dimethyl-formamidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.98 (s, 3H), 3.06 (s, 3H), 3.79 (s, 3H), 7.35 (dd, J=8.3, 1.8 Hz, 1H), 7.62 (t, J=2.1 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 7.96 (s, 1H), 8.37-8.39 (m, 2H). HRMS (ESI) m/z 338.1182 [(M+H)+ Calcd for C18H17ClN5: 338.1173].
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH:18]=[CH2:19])[C:4]=1[C:20]([O:22][CH3:23])=[O:21].OO.C(=O)(O)[O-:28].[Na+]>C(O)C>[F:24][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH:18]2[CH2:19][O:28]2)[C:4]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C([O-])O
Reactant: C=Cc1c(C(=O)OC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1C1CO1
Temperature: 70 °C
Yield: 19 %

Procedure:
A stirred mixture of 14.0 g (0.039 mole) of product of Example 99, 105 ml of ethanol, 70 ml (0.60 mole) of 30% hydrogen peroxide, and 2.9 g (0.033 mole) of sodium bicarbonate is heated at 70° C. for 3 hours. The reaction mixture is cooled and concentrated in vacuo to approximately 30 ml then extracted with 75 ml of methylene chloride. The methylene chloride solution is washed with 300 ml of water. The aqueous layer is extracted twice with 75 ml of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and concentrated. The residue is purified by HPLC using 8% ethyl acetate/cyclohexane as eluent to give a yellow solid which after recrystallization from hexane/ether gave 2.32 g of the desired product as a white solid; m.p. 57.5°-59° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:19][N:18]=4)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37].[OH-].[Na+]>CN1C(=O)CCC1>[CH:23]([NH:22][C:20]1[O:21][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH:36]([CH3:38])[CH3:37])[N:7]=2)=[N:18][N:19]=1)([CH3:25])[CH3:24]
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccnc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nccc(-c2c[nH]c3ccc(-c4nnc(NC(C)C)o4)cc23)n1
Temperature: 100 °C
Yield: 39.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(2-chloropyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (100 mg, 0.196 mmol) and isopropylamine (16.88 μl, 0.196 mmol) in NMP (2.0 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 135° C. for 1 h. aq. NaOH (0.5 mL, 5 M) was added to the mixture and the reaction was heated in the microwave at 100° C. for 20 min. The mixture was purified with preparative HPLC (eluting with 10-50% MeCN in water with 0.1% TFA in each solvent) and the fractions containing the product were combined and concentrated in vacuo to remove MeCN. The resulting mixture was extracted with CHCl3/iPrOH (4:1) and the combined organic layers were dried (MgSO4), filtered and concentrated to give N-isopropyl-5-(3-(2-(isopropylamino)pyrimidin-4-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (29 mg, 0.077 mmol, 39.1% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 378.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, s), 8.99 (1H, br. s.), 8.30 (1H, s), 8.17 (1H, d, J=5.1 Hz), 7.64 (1H, dd, J=8.5, 1.5 Hz), 7.57 (1H, d, J=8.6 Hz), 7.45 (1H, d, J=7.2 Hz), 7.00 (1H, d, J=5.3 Hz), 6.70 (1H, br. s.), 4.17-4.29 (1H, m), 3.71-3.83 (1H, m), 1.20-1.30 (12H, m).
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].C(O[C:15](=[O:36])[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[C:29]#[C:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH3:18])[CH3:17])C>CN(C=O)C.O1CCOCC1>[OH:9][C:29]1[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][C:21]=2[C:25]([F:27])([F:28])[F:26])[C:16]([CH3:17])([CH3:18])[C:15](=[O:36])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)C#Cc1c(C(F)(F)F)cccc1C(C)(C)C(=O)OCC
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2c(C(F)(F)F)cccc2C(C)(C)C1=O
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
Benzaldehyde oxime (112 mg, 0.92 mmol) in 6 mL dry DMF under argon, was added via syringe to a suspension of NaH (22 mg, 0.92 mmol) in dry dioxane (6 mL) under argon at room temperature. The mixture was stirred for 30 minutes, and ethyl 3-(2-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-6-(trifluoromethyl)phenyl)propiolate (275 mg, 0.77 mmol) was added as a solution in dry DMF (6 mL) via syringe. The reaction was stirred at room temperature for 11 hours. The dioxane was removed under vacuum, and the remaining DMF was partitioned between EtOAc and water. The layers were separated, and the organic layer was washed with twice with water and once with brine. The combined aqueous extracts were back extracted twice with EtOAc, and these organic layers were added to the organic layer already obtained. The combined extracts were dried over MgSO4, concentrated under vacuum, and the resulting residue was purified by column chromatography to give the product as a light yellow oil (50 mg). MS (m/z)=329 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23]C(C)(C)C)=O)[C@@H:17]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:32][C:33]1[C:41](C)=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](O)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.C(N(CC)CC)C.CN(C)C=O>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:23])[C:41]2[CH:40]=[CH:39][CH:38]=[C:34]([CH3:35])[C:33]=2[CH3:32])[C@@H:17]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: Cc1cccc(C(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)c1cccc(C)c1C
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4.5 mL) was added to a solution of 4-benzyl-1-tert-butoxycarbonyl-2(S)-n-butylpiperazine (0.507 g, 1.52 mmol) in methylene chloride (9 mL), and the reaction stirred for 2 h at 20° C. The volatiles were removed in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was dissolved in dry, degassed dimethylformamide (18 mL) and 2,3-dimethylbenzoic acid (0.229 g, 1.53 mmol), HOBT (0.222 g, 1.45 mmol), and EDC.HCl (0.307 g, 1.60 mmol) added. The pH was adjusted to 8 by the addition of triethylamine. The reaction was stirred at 20° C. overnight, and the dimethylformamide removed in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([CH3:35])[CH3:34])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl.[NH4+].[OH-].O>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([CH3:35])[CH3:34])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: CC(C)Oc1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(6-isopropoxypyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (185 mg, 379 μmol) in dichloromethane (5.9 mL) was added trifluoroacetic acid (865 mg, 585 μL, 7.59 mmol) and the mixture stirred at r.t. for 16 h. The mixture was diluted with 25% aqueous NH4OH, dichloromethane, and water. The organic phase was separated and washed with water (2×), then concentrated in vacuo and purified by chromatography (silica, 3 to 10% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxamide (68 mg, 176 μmol, 46%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 8.38 (s, 1H), 7.62 (m, 3H), 6.76 (d, J=7.7 Hz, 1H), 6.54 (d, J=7.8 Hz, 1H), 6.35 (d, J=8.2 Hz, 1H), 5.18 (m, 1H), 4.07 (br. s, 1H), 3.80 (d, J=11.3 Hz, 1H), 3.67 (dd, J=11.6, 3.8 Hz, 1H), 3.50 (dd, J=11.9. 2.3 Hz, 1H), 3.39 (m, 2H), 2.96 (s, 1H), 1.78 (m, 1H), 1.68 (m, 2H), 1.33 (dd, J=6.3, 1.7 Hz, 6H); MS (EI/CI) m/z: 388.3 [M+H].