Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:10](=[O:35])[C:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32])=[C:12]([CH3:18])[C:13](=[O:17])[C:14]=1[O:15][CH3:16].Cl>CCOCC.O>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:11]1[C:10](=[O:35])[C:9]([O:8][CH3:7])=[C:14]([O:15][CH3:16])[C:13](=[O:17])[C:12]=1[CH3:18]
Reactant: COC(=O)CCCCCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCO)=C(C)C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
Lithium aluminum hydride (740 mg) is suspended in 80 ml of dried ether, and a solution of 1.06 g of 2,3-dimethoxy-6-(12-methoxycarbonyldodecyl)-5-methyl-1,4-benzoquinone in 100 ml of dried ether is added dropwise with stirring and ice cooling. After 1.5 hours, ice water is added so as to decompose the excess lithium aluminum hydride, then acidified with hydrochloric acid and extracted with ether. The extract is washed with water and concentrated under reduced pressure. The residue is dissolved in 30 ml of methanol, a solution of 12 g of ferric chloride in 60 ml of water is added, and the mixture is stirred at room temperature for 1.5 hours. The liquid reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried, and the solvent is distilled off under reduced pressure. The residue is dissolved in chloroform and subjected to silica gel column chromatography. The crystals recovered from the chloroform-ethanol (99:1) eluate are recrystallized from ether-hexane to give 727 mg of 6-(13-hydroxytridecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (in formula I, n=13) as yellow needles. m.p. 65°-66° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:22][S:23]([C:26]2[CH:31]=[C:30](Br)[CH:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:27]=2[NH:39][C:40](=[O:43])[CH2:41][CH3:42])(=[O:25])=[O:24])[C:12]([CH:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][NH:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.C([O-])=O.[NH4+].[ClH:48]>CO.C(O)(C)C.[Pd]>[ClH:48].[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:27]=2[NH:39][C:40](=[O:43])[CH2:41][CH3:42])(=[O:25])=[O:24])[C:12]([CH:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][NH:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1
Reactant: CCC(=O)Nc1c(-c2ccccn2)cc(Br)cc1S(=O)(=O)N[C@@H](CCCc1ccc(N)nc1)C(=O)C1CNCCC1CC
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CC(C)O
Solvent: CO
Product: CCC(=O)Nc1c(-c2ccccn2)cccc1S(=O)(=O)N[C@@H](CCCc1ccc(N)nc1)C(=O)C1CNCCC1CC
Yield: 75 %

Procedure:
A mixture of 0.2 g (0.3 mmol) of (S)-N-[2-[[[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-4-bromo-6-pyrid-2-ylphenyl]propanamide, 0.02 g of active 10% palladium-on-charcoal and 0.2 g of ammonium formate (3.0 mmol) in 10 ml of methanol is refluxed for 2 h. The reaction mixture is filtered and is then taken up in 100 ml of dichloromethane, washed with 50 ml of saturated sodium hydrogen carbonate solution and 50 ml of saturated sodium chloride solution. The resulting solution is dried over sodium sulphate and then filtered and the resulting product is concentrated. The residue thus obtained is taken up in 40 ml of a 0.1N solution of hydrogen chloride in isopropanol and is then concentrated and purified by chromatography on an RP18 column, eluting with an acetonitrile/water gradient of from 5/95 to 30/70. 0.135 g of (S)-N-[2-[[[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-6-pyrid-2-ylphenyl]propanamide hydrochloride (2:1) is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:15]=2)[N:3]=1.[H-].[Na+].I[CH3:34].[OH-].[K+]>O>[NH2:1][C:2]1[C:7]([N:8]([CH3:34])[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:15]=2)[N:3]=1
Reactant: CI
Reactant: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COC(=O)N(C)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
Prepared in analogy to Example 6 with 310 mg (0.76 mmol) of methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate from Example 5, 27.32 mg (1.14 mmol) of sodium hydride and 215.5 mg (1.52 mmol) of iodomethane. The mixture is worked up by adding water and 2 molar potassium hydroxide solution and extracting with dichloromethane. The combined organic phases are dried with magnesium sulphate and concentrated in a rotary evaporator. The residue is purified by preparative RP-HPLC.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCl.C(OCC)(=O)C>[CH2:7]([C:6]1[CH:5]=[CH:4][C:2]([O:3][C:21](=[O:22])[CH2:20][Br:19])=[C:1]([O:11][CH3:12])[CH:10]=1)[CH:8]=[CH2:9]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCc1ccc(OC(=O)CBr)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of eugenol (500 mg, 3.03 mmol) in dichloromethane (5 mL) were added K2CO3 (1.0 g, 7.57 mmol) followed by bromo acetyl bromide (931 mg, 4.54 mmol) at 0° C. The mixture was allowed to stir at room temperature (25° C.) over a period of 1 hr. The resulting mixture was diluted with ethyl acetate (200 mL), washed with water (2×200 mL) and dried over sodium sulphate. The crude product obtained up on evaporation of the solvent was further purified by silica gel column chromatography to obtain bromo-acetic acid 4-allyl-2-methoxy-phenylester as viscous oil (550 mg, 63%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:67][O:68][C:69]1[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[CH:73][C:70]=1[CH2:71][NH2:72]>O1CCOCC1.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:67][O:68][C:69]1[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[CH:73][C:70]=1[CH2:71][NH:72][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Cc1cc(C)nc(Nc2cc(Br)cnc2C#N)c1
Reactant: COc1ccc(CN)c(OC)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CNc2cnc(C#N)c(Nc3cc(C)cc(C)n3)c2)c(OC)c1
Temperature: 100 °C

Procedure:
To a flask was added 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (PrepEx 1.4) (500 mg, 1.65 mmol), Xantphos (95 mg, 0.17 mmol), Pd2(dba)3 (121 mg, 0.133 mmol) and cesium carbonate (1.08 g, 3.30 mmol). A solution of 2,4-Dimethoxybenzylamine (276 mg, 1.65 mmol) in degassed dioxane (16.5 mL) was added to the flask. The reaction was heated to 100° C. for one hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% ethyl acetate/hexanes, linear gradient) to afford 5-[(2,4-dimethoxybenzyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile. MS ESI calc'd for C22H24N5O2 [M+H]+ 390. found 390. 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.21 (t, J=5.7 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.57 (s, 1H), 6.54 (d, J=2.3 Hz, 1H), 6.53 (s, 1H), 6.45 (dd, J=2.3 Hz, 8.3 Hz, 1H), 4.16 (d, J=5.8 Hz, 2H), 3.73 (s, 3H), 3.70 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[CH:28](B1OC(C)(C)C(C)(C)O1)=[CH2:29].C(=O)([O-])[O-].[K+].[K+]>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]>[CH3:27][N:25]1[CH:26]=[C:22]([C:16]2[CH:17]=[N:18][C:19]3[C:14]([CH:15]=2)=[CH:13][C:12]([CH2:11][C:8]2[N:6]4[N:7]=[C:2]([CH:28]=[CH2:29])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)=[CH:21][CH:20]=3)[CH:23]=[N:24]1
Reactant: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(Cl)nn45)cc3c2)cn1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C=Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Temperature: 135 °C
Yield: 19.3 %

Procedure:
To a degassed (bubbled nitrogen for 15 mins) mixture of water (1 mL) and 1,4-dioxane (2 mL) was added 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)-quinoline (117 mg, 0.31 mmol), vinyl boronic acid pinacol ester (59 μl, 0.35 mmol), potassium carbonate (0.93 mmol, 128 mg) and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (15 mg, 0.02 mmol). The microwave tube was capped and heated in a microwave reactor (Personel Chemistry, Emrys Optimizer) at 135° C. for 1500 seconds. After such time the organic phase was concentrated on silica and purified via flash column chromatography eluting with 0-10% Methanol in dichloromethane to obtain the title compound (22 mgs, 19% yield) as a white solid. Analytical data presented in Table 2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.O>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]#[N:10])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)nn1
Solvent: O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(Cl)nn1
Temperature: -30 °C
Reaction time: 19.5 h
Yield: 39.4 %

Procedure:
A mixture of 6-chloropyridazine-3-carboxamide (described in reference example 3) (15 g, 95.5 mmol) and pyridine (22.6 g, 23.1 ml, 286.6 mmol) were was suspended in dichloromethane and cooled to -30° C. under argon. TFAA was added dropwise to the stirred mixture keeping the internal temperature below -20° C. The reaction was stirred for 19.5 hours allowing to warm to ambient temperature. The mixture was poured into water(500 ml) and washed with water (4×500 ml) until the aqueous phase was pale yellow. The organic phase was dried over MgSO4, filtered through a pad of silica (50 mm diameter, 30 mm deep), and concentrated in vacuo. The resulting solid was purified by MPLC (40% dichloromethane/20%ethyl acetate/hexane) to give 3-chloro-6-cyanopyridazine as a colourless solid (5.25 g, 59%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[NH:16]1[CH2:26][CH2:25][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:16]1[CH2:26][CH2:25][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17]1)=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)c2c(-c3ccccc3)noc2C)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), ethyl isonipecotate (33.8 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C19H22N2O4: 342.1580, found 342.1578.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21](N2CCCC2)=[O:22])[CH2:17][CH2:16]1>CC(OC)(C)C>[Br:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[O:22])[N:8]=1
Reactant: CN1CCC(C(=O)N2CCCC2)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CN1CCC(C(=O)c2cccc(Br)n2)CC1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
Add a solution of n-butyllithium (1.9M in n-hexane, 4 ml, 7.6 mmol) to a solution of 2,6-dibromopyridine (1.81 g, 7.64 mmol) in MTBE (20 mL) dropwise under nitrogen, over 20 min., maintaining the temperature between −72 and −67° C. Stir the yellow heterogeneous solution at −70° C. for 20 min. to provide a green homogeneous solution. Add a solution of 1-methyl-4-(pyrrolidin-1-yl-carbonyl)piperidine (1 g, 5.09 mmol) in 10 mL MTBE dropwise over 20 min., maintaining the temperature below −69° C. Stir the yellow mixture at −75° C. for 1 hr. Quench the reaction mixture with a saturated solution of ammonium chloride (5 mL) between 0 and 10° C. Acidify the mixture to pH 2 with fuming HCl (2 mL). Extract the organic layer. Wash the aqueous phase with MTBE (50 mL), make the aqueous layer basic with a solution of 30% NaOH, and extract with ethyl acetate (2×50 mL). Combine the organic layers, dry over MgSO4, and concentrate under reduced pressure at 40° C. to provide the title intermediate as an oil (1.23 g, 85% yield).
Reaction SMILES: [OH:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][O:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of 195.9 g of 2-hydroxy-3-methyl-4'-chlorobenzophenone [Huston et al., JACS, Vol. 73, (1951), p. 2483] in 1 liter of dimethylformamide was added with stirring to a suspension of 40.8 g of sodium hydride in 200 ml of dimethylformamide and the mixture was stirred for 1 hour with cooling in an ice-water bath. Then a solution of 170.4 g of methyl iodide in 800 ml of dimethylformamide was added thereto over 40 minutes and the mixture was then stirred for 16 hours in the ice-water bath. The mixture was filtered to remove insolubles and the filtrate was treated with activated carbon, filtered and was evaporated to dryness under reduced pressure. The residue was taken up in 1 liter of ether and 200 ml of water and the aqueous phase was reextracted with ether. The combined ether phases were washed with water, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness. The residue was chromatographed over silica and was eluted with methylene chloride to obtain 171 g of 2-methoxy-3-methyl-4'-chlorobenzophenone in the form of colorless crystals melting at 43°C.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]3[CH2:23][CH2:22][CH2:21][C:20]([F:25])([F:24])[C@@H:19]3[NH:26][C:27]([C:29]3[S:30][C:31]([CH:43]([F:45])[F:44])=[C:32]([C:34]4[N:38]5[N:39]=[CH:40][CH:41]=[CH:42][C:37]5=[N:36][CH:35]=4)[CH:33]=3)=[O:28])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C.O>[NH2:17][C@@H:18]1[C@@H:19]([NH:26][C:27]([C:29]2[S:30][C:31]([CH:43]([F:44])[F:45])=[C:32]([C:34]3[N:38]4[N:39]=[CH:40][CH:41]=[CH:42][C:37]4=[N:36][CH:35]=3)[CH:33]=2)=[O:28])[C:20]([F:24])([F:25])[CH2:21][CH2:22][CH2:23]1
Reactant: O=C(N[C@H]1CCCC(F)(F)[C@@H]1NC(=O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNCC1
Product: N[C@H]1CCCC(F)(F)[C@@H]1NC(=O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1
Reaction time: 1 h

Procedure:
To a stirred solution of 9H-fluoren-9-ylmethyl[(1S,2R)-2-({[5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (27 mg, 0.042 mmol) in DMF (0.8 mL) was added piperidine (0.08 mL, 0.83 mmol). The mixture was left to stir for 1 h, diluted with water, and extracted with EtOAc. The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.38 (s, 1H); 8.72 (d, 1H); 8.68 (dd, 1H); 8.43 (s, 1H); 8.27 (dd, 1H); 7.97 (s, 1H); 7.38 (dd, 1H); 7.35 (t, 1H); 4.05 (m, 1H); 2.82 (m, 1H); 1.30-2.10 (m, 6H). LRMS (APCI) calc'd for (C18H18F4N5OS) [M+H]+, 428.1. found 428.1.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].C(O)C.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(OCC)(=O)C.CCCCCC>[CH3:2][C:1]1[S:3][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:4]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Thioacetamide (7.6 g, 100 mmol) was added to ethanol (60 mL), and the resultant suspension was cooled to 0° C. and treated with ethyl bromopyruvate (12.5 mL, 100 mmol). The resultant solution was stirred for five minutes at 0° C. at which time the ice bath was removed and the solution was allowed to warm to ambient temperature. After 0.5 h at ambient temperature, the solution was heated to reflux. After 12 h, the solvents were removed in vacuo, and the resultant crude product was taken up in ethyl acetate (300 mL). The organic phase was washed with saturated aqueous NaHCO3 (50 mL), and the basic aqueous solution was then extracted with additionalethyl acetate (2×50 mL). The combined organic solutions were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford a yellow waxy solid. The crude product was dissolved in a small amount of hot ethyl acetate, diluted with hot hexane, and the resultant solution was allowed to cool to ambient temperature, seeded with a small amount of crude product, and transferred to the freezer. After 16 h the crystalline product was collected, washed with cold 8:1 hexane:ethyl acetate, and allowed to dry under high vacuum to afford ethyl 2-methyl-1,3-thiazole-4-carboxylate (11.76 g, 69% yield) as large brownish crystals. M.p. 56–58.5° C. 1H NMR (CDCl3, 300 MHz) δ 8.06 (s, 1H), 4.43 (q, 2H), 2.78 (s, 3H), 1.42 (t, 3H). MS (EI ionization) 171 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:19]=[C:18]4[CH2:20][O:21][C:22]5[CH:53]=[C:52]6[C:25]([CH:26]=[CH:27][C:28]7[N:32]=[C:31]([C@@H:33]8[CH2:37][CH2:36][CH2:35][N:34]8[C:38](=[O:51])[C@H:39]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:40]8[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=8)[NH:30][C:29]=76)=[CH:24][C:23]=5[C:17]4=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:54][O:55][C:56]([NH:58][C@@H:59]([CH:63]([CH3:65])[CH3:64])[C:60](O)=[O:61])=[O:57].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>[CH3:49][O:48][C:47]([NH:46][C@H:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:38]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:31]1[NH:30][C:29]2[C:52]3[C:25]([CH:26]=[CH:27][C:28]=2[N:32]=1)=[CH:24][C:23]1[C:17]2[C:18]([CH2:20][O:21][C:22]=1[CH:53]=3)=[CH:19][C:14]([C:11]1[NH:10][C:9]([C@@H:6]3[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]3[C:60](=[O:61])[C@@H:59]([NH:58][C:56](=[O:57])[O:55][CH3:54])[CH:63]([CH3:65])[CH3:64])=[N:13][CH:12]=1)=[CH:15][CH:16]=2)=[O:51])=[O:50]
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl {(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (55 mg, 0.077 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (14 mg, 0.077 mmol), HATU (32 mg, 0.085 mmol) and 0.4 mL 10% DIPEA in DMF was stirred at room temperature for 1 hour. The product was purified by reverse phase HPLC. The product was converted to the free base by dissolution in 2 mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported carbonate. The eluent was concentrated, the taken up in 1% TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (30.7 mg)
Reaction SMILES: C[Li].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCC[CH2:21]1.O>CCOCC>[CH3:21][C:14]([C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:12]=1)=[O:16]
Reactant: C1CCOC1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 1.5 h

Procedure:
Over a period of 1.5 hours, methyl lithium (531 ml. of a 2 molar solution, 1.06 M) is added under a nitrogen atmosphere to a rapidly stirring solution of 3-benzyloxybenzoic acid (116 g., 0.532 M) in ether (250 ml.)-tetrahydrofuran (1400 ml.) maintained at 15°-20° C. After stirring an additional 0.75 hour at 10°-15° C., water (600 ml.) is slowly added keeping the reaction temperature below 20° C. The aqueous layer is separated and extracted with ether (3×250 ml.). The organic phases are combined, washed with saturated sodium chloride solution (4×300 ml.), dried over sodium sulfate, and concentrated under vacuum to give the product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN(C=O)C>C(OCC)(=O)C.O>[CH2:11]([N:5]1[CH:4]=[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=[C:2]2[Br:1])=[N:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1cccc2[nH]ncc12
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cccc2nn(Cc3ccccc3)cc12
Temperature: 25 °C
Yield: 65.1 %

Procedure:
4-Bromoindazole of Example 2 (17.4 g, 0.088 M), benzyl bromide (22.7 g, 0.132 M) and DMF (35 mL) were heated to about 50° C. for 25 hours (HPLC: 15:1 ratio of 2-N and 1-N isomers). The mixture was cooled to ambient temperature and diluted with ethyl acetate (160 mL) and water (100 mL). The organic layer was separated, washed with aqueous sodium bicarbonate (5%, 100 mL). The organic layer was separated and concentrated under reduced pressure. The residue was diluted with isopropanol (160 mL) and concentrated under reduced pressure to a volume of about 120 mL. The mixture was heated to 50° C. to dissolve the solid and diluted with water (70 mL) to precipitate the product. The slurry was cooled to 0° C. and the precipitate was filtered off. The solid washed with a mixture of IPA and Water (1:1, 50 mL), and dried at 50° C. to provide the titled compound (16.5 g, 77%, which contained less than 2% of 1-N-isomer by HPLC): 1H NMR (CDCl3, δ, ppm) 5.56 (s, 2H), 7.11 (m, 1H), 7.21 (d, J=7.2 Hz, 1H), 7.24-7.39 (m, 5H), 7.65 (d, J=8.6 Hz, 1H), 7.88 (s, 1H).