Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([F:15])[CH:17]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1cccc(F)c1
Product: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(F)c1
Yield: 45.2 %

Procedure:
Following the procedure described above in Example 13, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.300 g, 1.45 mmol) was reacted with 3-fluoroaniline (0.15 mL, 0.18 g, 1.6 mmol). The crude product was purified by flash chromatography over silica gel (10% EtOAc in CH2Cl2) to give pure 6-fluoro-4-(3-fluorophenylamino)-1,7-naphthyridine-3-carbonitrile (0.185 g, 45% yield): 1H NMR (400 MHz, DMSO-D6) δ 7.16 (td, J=8.5, 2.7 Hz, 1 H) 7.22 (ddd, J8.0, 2.0, 0.9 Hz, 1 H) 7.27 (dt, J=10.2, 2.2 Hz, 1 H) 7.43-7.53 (m, 1 H) 8.17 (s, 1 H) 8.72 (s, 1 H) 9.10 (s, 1 H) 10.16 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][C:24]1[CH:25]=[C:26]([C:35](=[O:37])[CH3:36])[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33]Br>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:29]4[CH:28]=[CH:27][C:26]([C:35](=[O:37])[CH3:36])=[CH:25][C:24]=4[Br:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCCCBr)c(Br)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Br)c1
Yield: 68.6 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.1 g, 9.5 mmol ). K2CO3 (2.0 g)-1-[3-bromo-4-(3-bromopropoxy)phenyl]ethanone (3.1 g, 9.2 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (200 ml). The insolubles were filtered off. The dichloromethane was concentrated again. The crude residue was purified by flash chromatography over a silica gel column. (SiO2, 49 g; eluted with dichloromethane, 500 ml; 1% methanol:dichloromethane, 600 ml; 3% methanol; 97% dichloromethane, 600 ml). The material thus obtained (3.26 g, 72%) was recrystallized from ethanol (40 ml) to give 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol -3- yl)-1-piperidinyl]-propoxy]-3-bromophenyl]ethanone as light yellow crystals (3.0 g), m.p.=126°-128° C. ANALYSIS: Calculated for C23H24BrFN2O3: 58.12%C 5.09%H 5.89%N Found: 57.64%C 5.35%H 5.55%N
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]=O.[NH:17]1[CH2:20][CH:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH2:18]1.C(O)(=O)C.[BH3-]C#N.[Na+].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>CO.CC(C)=O>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:17]1[CH2:20][CH:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH2:18]1
Reactant: O=CCc1ccccc1N1CCCCC1=O
Reactant: N#Cc1cccc(C2CNC2)c1
Agent: O=C(O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: N#Cc1cccc(C2CN(CCc3ccccc3N3CCCCC3=O)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To [2-(2-oxopiperidin-1-yl)phenyl]acetaldehyde a3-1 (108.6 mg, 0.5 mmol, 1 eq) and 3-(azetidin-3-yl)benzonitrile a3-2 (97.33 mg, 0.5 mmole, 1 eq) in methanol (4 ml) are added acetic acid (42.9 μl, 0.75 mmol, 1.5 eq) then NaBH3CN (94.3 mg, 1.5 mmol, 3 eq). The reaction mixture is stirred overnight at room temperature. The crude reaction mixture is then loaded on an ion exchange acidic resin cartridge (2 g) prewashed with methanol. The cartridge is washed twice with approximately 3 column volumes of methanol, then eluted with 3 column volumes of 1M NH3 in methanol. This eluate is evaporated to dryness to give 141 mg of a crude material which is purified by reverse phase chromatography (basic mode; gradient: H2O/acetonitrile/NH4OH from 60/40/0.1 to 30/70/0.1 in 10 minutes). The residue obtained is redissolved in acetone (approximately 3 ml), and after addition of oxalic acid (22.7 mg, 0.25 mmol, 1 eq), a precipitate slowly appeared. This precipitate is filtered, washed with diethylether and dried overnight under vacuum at 40° C. to afford 69.6 mg of 3-(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl)benzonitrile oxalate 31.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:15][CH:14]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:25]1([CH2:28][NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([NH:11][CH2:12][C:13]3[S:17][C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[N:15][CH:14]=3)[CH:4]=2)[CH2:27][CH2:26]1
Reactant: O=C(O)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Reactant: NCC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 4-fluoro-3-{[2-(pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-benzoic acid (35 mg, 0.10 mmol) in DMF (1 mL) at RT, cyclopropylmethyl amine (14 mg 0.20 mmol) was added followed by the addition of BOP reagent (53 mg, 0.12 mmol). The above reaction mixture was stirred for 2 h, diluted with EtOAc (10 mL), washed with 10% NaHCO3 (3×5 mL), and 10% LiCl (5 mL). The organic layer was dried over Na2SO4, concentrated and the residue was purified by preparative HPLC to give the title compound as a off-white solid (33 mg, 83%). (M+H)+=398.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:15][C:16]1[O:20][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:18][C:17]=1[CH2:27][CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:15][C:16]1[O:20][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:18][C:17]=1[CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: Oc1ccc(Nc2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(Nc2ccccc2)cc1
Reaction time: 5 h
Yield: 62 %

Procedure:
To a solution of 0.50 g 4-hydrox-phenylaniline, 0.83 g of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethan-1-ol and 1.06 g of triphenylphosphine in 20 ml of THF was added at 0° C. a solution of 0.82 g of diisopropyl azodicarboxylate in 10 ml of THF over 30 min and stirring was continued at 22° C. for 5 h. The mixture was evaporated and the residue purified by chromatography (SiO2, n-hexane/AcOEt 6:1) to give 0.62 g of the title compound as a colorless solid. MS: (M+H)+ 371.4.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][NH:37][C:38]([C:40]1([C:43]2[CH:48]=[CH:47][C:46](Br)=[CH:45][N:44]=2)[CH2:42][CH2:41]1)=[O:39]>>[CH3:36][NH:37][C:38]([C:40]1([C:43]2[CH:48]=[CH:47][C:46]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:45][N:44]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CNC(=O)C1(c2ccc(Br)cn2)CC1
Product: CNC(=O)C1(c2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)cn2)CC1
Yield: 91 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid methylamide following a procedure analogous to that described in Example 1. Yield: 91% of theory; LC (method 1): tR=1.88 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][Li]>C1COCC1>[CH3:12][C:8]1([OH:11])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1
Reactant: [Li]C
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)OCCO2
Temperature: -55 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a cooled solution of 1,4-dioxaspiro[4.5]decan-8-one (7.8 g, 50.0 mmol) in dry THF (75 mL) was added methyllithium solution (1.5 M in ether, 43.3 mL, 65.0 mmol) at −78° C. under argon while keeping inner temperature below −55° C. After addition, the mixture was stirred at −55° C. for additional 4 hours. The reaction was warmed to room temperature and then quenched by saturated NH4Cl solution. The separated organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EA:PE=1:9 to 1:3) to afford the product as a white solid (6.8 g, yield: 80%).
Reaction SMILES: [Cu]C#N.C[Li].B(F)(F)F.CCOCC.[OH:15][C@H:16]1[C@H:20]([CH3:21])[CH2:19][C@@H:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1>C1COCC1>[OH:15][C@@H:16]1[C@@H:20]([CH3:21])[CH2:19][C@H:18]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:17]1
Reactant: C[C@@H]1C[C@@H](C(=O)OCc2ccccc2)C[C@H]1O
Agent: N#C[Cu]
Agent: FB(F)F
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H]1C[C@H](C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A 50 mL three neck round bottom flask equipped with a magnetic stirrer and two addition funnels, which had been flame dried under argon, charged with COPPER(I) CYANIDE (226 mg, 2.52 mmol), and evacuated under high vacuum overnight, was charged with THF (5 mL), and the suspension was cooled to −78° C. The mixture was treated with the dropwise addition of methyllithium (1.6 M in diethylether) (3.15 mL, 5.04 mmol). When the addition was complete, the cooling bath was removed, and the suspension was allowed to slowly warm, until a homogeneous solution was observed. The solution was cooled to −78° C., then treated with the slow dropwise addition of a solution of trans-benzyl 6-oxabicyclo[3.1.0]hexane-3-carboxylate (250 mg, 1.145 mmol) in THF (5 mL) followed by boron trifluoride etherate (0.581 mL, 4.58 mmol) in one portion. The mixture was stirred at −78° C. for 2 h, at which point a precipitate was observed, and the color quickly changed to bright yellow. The reaction was allowed to slowly come to room temperature, during which the color began to turn grey. The reaction was quenched with 30 mL of a 9:1 aqueous solution of saturated NH4Cl and 10% NH4OH, and the mixture was stirred for 30 minutes. The resulting deep blue mixture was filtered to remove a small amount of precipitate, and extracted 3× with ethyl acetate. The combined organic phases were washed with water followed by brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over a 2×15 cm silica gel column, eluting with ethyl acetate/hexanes (25%-50% EtOAc), to yield a racemic mixture of (1R,3R,4R)-benzyl 3-hydroxy-4-methylcyclopentanecarboxylate and (1S,3S,4S)-benzyl 3-hydroxy-4-methylcyclopentanecarboxylate (225 mg, 0.480 mmol, 84% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:13]2[N:9]([CH:10]=[N:11][C:12]=2[CH3:14])[C:8]2[N:7]=[CH:6][S:5][C:4]=2[N:3]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:10]1[N:9]2[C:13]([C:2]([CH3:1])=[N:3][C:4]3[S:5][CH:6]=[N:7][C:8]=32)=[C:12]([CH3:14])[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncn2c1c(C)nc1scnc12
Solvent: CC#N
Product: Cc1nc(Br)n2c1c(C)nc1scnc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
5,6-dimethyl-3-thia-1,4,7,8a-tetraaza-as-indacene (300 mg, 1.469 mmol) was dissolved in acetonitrile (50 ml) and 1-bromopyrrolidine-2,5-dione (131 mg, 0.734 mmol) was added. The resulting mixture was stirred at about 20° C. for about 1 h. After removal of the solvent under reduced pressure, the crude product was purified by prep-HPLC to give 60 mg of the title compound (yield: 15%).
Reaction SMILES: Br[C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[CH:4][N:3]=1.C([Mg]Br)C.[CH2:14]([O:17][C:18]([C:20](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:21]1[C@@H:24]([C@H:25]([C:27](C2C=CC=CN=2)=S)[CH3:26])[C@@H:23]([C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH3:36])[C:22]1=[O:45])=[O:19])[CH:15]=[CH2:16]>C1COCC1.[Cl-].[NH4+].C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1(C=CC(O)=CC=1)O>[Si:38]([O:37][C@@H:35]([C@H:23]1[C:22](=[O:45])[N:21]2[C:20]([C:18]([O:17][CH2:14][CH:15]=[CH2:16])=[O:19])=[C:26]([C:2]3[N:9]4[C:5]([S:6][CH:7]=[CH:8]4)=[CH:4][N:3]=3)[C@H:25]([CH3:27])[C@H:24]12)[CH3:36])([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccccn1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ncc2sccn12
Agent: CC[Mg]Br
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(c2ncc3sccn23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
To an ice-cooled solution of 0.61 g of 5-bromoimidazo[5,1-b]thiazole in 6 ml of THF was added 3.2 ml of 1 M solution of ethyl magnesium bromide in THF. After stirring at room temperature for 2 hours, the mixture was cooled to −50° C., and a solution of 2.23 g of (3S,4R)-1-[(allyloxycarbonyl)(triphenylphosphoranylidene)methyl]-3-((1R)-1-t-butyldimethylsilyloxyethyl)-4-[(1R)-1-[(pyridin-2-yl)thiocarbonyl]ethyl]azetidin-2-one in 6 ml of THF was added. The mixture was stirred for 1 hour during which the temperature was raised up to 10° C. The reaction mixture was diluted with 12 ml of a saturated aqueous ammonium chloride solution, extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2) to give 0.67 g of crude product. A 0.63 g portion of the crude product and a solution of 4.5 mg of hydroquinone in 7 ml of xylene were stirred under heating at 140° C. for 6 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, and saturated aqueous saline in this sequence, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 0.35 g of allyl (1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+].[CH2:22](O)[CH3:23]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:22][CH3:23])=[O:6]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cccc(N)c1
Temperature: 25 °C

Procedure:
To 3-aminobenzoic acid (7.00 g, 0.52 mol) dissolved in 300 mL of absolute ethanol was added ~3.5 mL of concentrated sulfuric acid. The reaction mixture was heated at reflux for 2 days and then cooled to ambient temperature. Potassium carbonate (8.9 g) was added and then most of the ethanol was removed under reduced pressure. The solution was partitioned between chloroform and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was filtered through silica gel eluting with ethyl acetate to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.40 (t, 3H), 3.85 (bs, 2H), 4.35 (q, 2H), 6.90 (m, 1H), 7.25 (m, 1H), 7.45 (m, 2H). MS (DCl/NH3) m/e 166 (M+H)+, 183 (M+H+NH3)+.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:13][CH2:14][OH:15])[C:11]=1[NH2:12].[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](ON1C(=O)CCC1=O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[NH2:12][C:11]1[N:10]([CH2:13][CH2:14][OH:15])[N:9]=[CH:8][C:7]=1[NH:6][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: Nc1cnn(CCO)c1N
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cnn(CCO)c1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To a suspension of 4,5-diamino-1-(2-hydroxyethyl)pyrazole sulfuric acid salt (1.20 g) and N-[2-(tert-butoxycarbonylamino)acetoxy]succinimide (1.35 g) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (2.1 ml) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with water (40 ml), saturated aqueous sodium hydrogen carbonate solution (40 ml) and brine (40 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with 10% methanol/chloroform to give 5-amino-4-[2-(tert-butoxycarbonylamino)acetyl]amino-1-(2-hydroxyethyl)pyrazole (1.20 g) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:21])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:10]([CH3:11])=[C:6]2[C:5]([CH3:22])=[N:4][N:3]=1.[CH3:23][O-:24].[Na+].[Na]>CO>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]3[C:7]([C:2]([O:24][CH3:23])=[N:3][N:4]=[C:5]3[CH3:22])=[C:8]2[CH3:21])=[CH:13][CH:14]=1)[CH3:20]
Reactant: C[O-]
Reactant: CCOc1ccc(-n2c(C)c3c(C)nnc(Cl)c3c2C)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(OC)c3c2C)cc1
Temperature: 100 °C

Procedure:
A solution of 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine (EXAMPLE 85) (100 mg, 0.32 mmol) and MeOH (5 mL) was treated with a solution of NaOMe (freshly prepared from MeOH (5 mL) and sodium metal (22 mg, 0.96 mmol)). The resulting mixture was placed in a resealable reaction vessel and heated at 100° C. for 12 h. The reaction was allowed to cool to rt, and poured into ice water (100 mL) to give 6-(4-ethoxyphenyl)-1-methoxy-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine: 1H NMR (CDCl3, 500 MHz) δ 7.11-7.25 (m, 4H), 4.16 (q, 2H), 2.71 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 1.43-1.46 (t, 3H); MS (ESI) 312 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1([CH3:30])[CH2:8][O:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)=[CH:11][CH:10]=2)=[N:5]1.[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40]Br)([CH3:34])([CH3:33])[CH3:32]>CS(C)=O>[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40][O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3[O:7][CH2:8][C:4]([CH3:30])([CH3:3])[N:5]=3)=[CH:14][CH:13]=2)([OH:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CC1(C)COC(c2ccc(C(O)(c3ccccc3)c3cccc(O)c3)cc2)=N1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC1(C)COC(c2ccc(C(O)(c3ccccc3)c3cccc(OCCCNC(=O)OC(C)(C)C)c3)cc2)=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of powdered KOH (45 mg, 0.8 mM) in anhydrous DMSO (2.5 mL) at room temperature was added 3-{[4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-hydroxy-phenyl-methyl}-phenol (2, 150 mg, 0.4 mM) and (3-Bromo-propyl)-carbamic acid tert-butyl ester (96 mg, 0.4 mM). The reaction mixture was stirred at room temperature for 3 h. Then the reaction mixture was extracted with ethyl acetate (3×25 mL) and the combined extract was dried over anhydrous Mg2SO4. The residue obtained on evaporation of the solvent was purified by silica gel chromatography using hexane/EtOAc (1:1) as an eluent. Evaporation of the solvent gave 3. Yield: >220 mg (quantitative yield). Mass: 531 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:8]=[CH:7][C:6]=1[OH:20])([O:3][CH3:4])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]#[N:32].[I-].[K+]>C(#N)C>[C:1]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:8]=[CH:7][C:6]=1[O:20][CH2:28][CH2:29][CH2:30][C:31]#[N:32])([O:3][CH3:4])=[O:2]
Reactant: N#CCCCBr
Reactant: COC(=O)c1cc(OCc2cccc(Cl)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(OCc2cccc(Cl)c2)ccc1OCCCC#N
Yield: 79 %

Procedure:
2-Carbomethoxy-4-(m-chlorophenylmethyloxy)-phenol, 1 gram (3.32 mmoles), was treated with 1 gram potassium carbonate, 0.4 ml 4-bromobutyronitrile, and 70 mg potassium iodide in 18 ml acetonitrile under reflux for 64 hours. Then the mixture was filtered and the filtrate was stripped in vacuo. The residue was chromatographed on silica gel using 1.3 ethyl acetate/hexanes to give 0.97 grams of the title product at 79% yield. Mp 97°-98° C. Elemental analysis. Calculated for C19H18ClNO4 : C 63.42, H 5.04, N 3.89, Cl 9.85; found: C 63.38, H 5.01, N 3.81, Cl 9.77.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[O:14][C@H:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1)C3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCCNC1)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
A mixture of (S)-3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (288 mg; 0.53 mmol; 1 eq.) and TFA (3 mL) in DCM (3 mL) was stirred at room temperature for 1 hour then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting solid was triturated in water and filtered off to afford the title compound (82 mg, 35%) as an off-white solid. 1H NMR (CDCl3) δ 7.36-7.29 (m, 1H), 6.78-6.68 (m, 2H), 5.01-4.99 (m, 2H), 4.66 (s, 2H), 4.29-0.23 (m, 1H), 3.13-3.06 (m, 1H), 2.91 (s, 2H), 2.86 (s, 1H), 2.84-2.75 (m, 2H), 2.71-2.65 (m, 2H), 2.62 (s, 2H), 2.03-1.91 (m, 1H), 1.78-1.56 (m, 3H), 1.51-1.36 (m, 1H). HPLC (max plot) 98.7%, Rt 2.82 min. UPLC/MS: (MS+) 444.4 ([M+H]+).
Reaction SMILES: [C:1](CC(N)=O)(=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18]>>[C:17]([N:19]=[C:1]([NH:15][CH:16]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH3:16]
Reactant: NC(=O)CC(=S)c1ccccc1
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Product: CC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C)CC1)c1ccccc1

Procedure:
The title compound was prepared starting from thiobenzoyl acetamide and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 1, step b. MS, m/z 438=M+1.