Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCCCC1[C:14]1[N:22]2[C:17]([CH:18]=[N:19][C:20]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:21]2)=[CH:16][CH:15]=1)=O)(C)(C)C.F[C:37](F)(F)[C:38](O)=O>C(Cl)Cl>[N:30]1([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:20]3[N:19]=[CH:18][C:17]4=[CH:16][CH:15]=[C:14]([C:16]5[CH2:17][CH2:18][NH:19][CH2:37][CH:38]=5)[N:22]4[N:21]=3)=[CH:29][CH:28]=2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)CCNC1
Temperature: 25 °C

Procedure:
Into a 8 dram vial, [2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.150 g, 0.315 mmol), Methylene chloride (5 mL) and Trifluoroacetic Acid (1 g, 9 mmol) were added and stirred at room temperature over night. The reaction was partitioned with Sat. NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The desired product was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded (4-Morpholin-4-yl-phenyl)-[7-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:39]1([CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:42]3[CH2:41][CH2:40][N:39]([CH2:45][CH2:46][N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)[CH2:44][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCN2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-(2-piperazin-1-yl-ethyl)-morpholine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H54N5O3Cl2 [(M+H)+] 734.3598, observed 734.3600.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:6]2[C:7](=[O:9])[CH:8]=1.[Br:15]N1C(=O)CCC1=O.C(O)(=O)C>O>[Br:15][C:8]1[C:7](=[O:9])[N:6]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:5]2=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(CCl)nc2ccc(F)cn12
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(Br)c(CCl)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(chloromethyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (8.310 g, 39.09 mmol), N-bromosuccinimide (8.055 g, 42.99 mmol), and acetic acid (110.3 mL) was stirred at rt. After 6 h, the mixture was poured into water (300 mL) and the resulting precipitate was collected by filtration, washed with water (400 mL), and dried to give 3-bromo-2-(chloromethyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (1 H, td), 8.19 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.86-7.94 (1 H, m), 4.81 (2 H, s); Mass Spectrum (ESI) m/e=292.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Br[CH2:18][CH3:19]>>[CH2:18]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH2:13][CH2:12]1)[CH3:19]
Reactant: Cc1ccc(N2CCNCC2)cc1[N+](=O)[O-]
Reactant: CCBr
Product: CCN1CCN(c2ccc(C)c([N+](=O)[O-])c2)CC1

Procedure:
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and 1-bromoethane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 249 (M+, 53), 234 (47), 84 (36), 57 (bp), 56 (46).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([C:26]#[N:27])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:28].CO>>[ClH:28].[C:26]([C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cccc3cncc(C#N)c23)CC1
Agent: Cl
Solvent: CO
Product: N#Cc1cncc2cccc(O[C@H]3CC[C@H](N)CC3)c12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 122 (34.9 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (22.4 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[O:23]COC)=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:27])=[CH:4][N:3]=1.Cl>C1COCC1.C(=O)(O)[O-].[Na+].ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[OH:23])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:27])=[CH:4][N:3]=1
Reactant: COCOc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 8.4 %

Procedure:
Treat a solution of 2-chloro-5-fluoro-4-[7-(3-methoxymethoxy-pyridin-4-yl)-benzo[b]thiophen-2-yl]-pyrimidine (4 g, 10 mmol) in THF (10 mL) with 5 N HCl (3 mL). Stir the mixture at room temperature for 6 hours. Concentrate the reaction in vacuo and dilute with saturated aqueous sodium bicarbonate and dichloromethane. Separate the layers and filter each layer. Wash the solid from the organic phase with dichloromethane to give the title compound (300 mg) as a tan solid. Wash the solid from the aqueous layer with water and dry to give the title compound (300 mg) as a tan solid. Combine the solids to give the title compound (600 mg, 17%) as a tan solid. MS (ES) m/z 358 [M+1]+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25](=[O:44])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](=[O:43])[NH:33][CH2:34][CH:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:23][O:24][C:25](=[O:44])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](=[O:43])[NH:33][CH2:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)CCCCCCC(=O)NCC(O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)CCCCCCC(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Add Dess-Martin periodinane (16.5 g, 38.7 mmol) to a solution of 7-(2-hydroxy-2-phenylethylcarbamoyl)heptanoic acid methyl ester (10.2 g, 33.3 mmol) in methylene chloride (360 mL) at 0° C. under nitrogen, stir and warm the mixture to room temperature for 4 hours. Filter the mixture through Celite, wash with ethyl acetate (3×100 mL) and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (60:40), to provide 7-(2-oxo-2-phenylethylcarbamoyl)heptanoic acid methyl ester (7.33 g, 72%).
Reaction SMILES: CO[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[ClH:10].Cl.[NH2:12][CH2:13][CH2:14][SH:15]>C(O)(=O)C>[ClH:10].[ClH:10].[NH2:12][CH2:13][CH2:14][S:15][CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9]
Reactant: COCc1nc[nH]c1C
Reactant: NCCS
Agent: Cl
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CSCCN
Yield: 80 %

Procedure:
4-Methoxymethyl-5-methylimidazole as the hydrochloride (4.5 g, 0.03 mole) and 3.4 g (0.03 mole) of cysteamine hydrochloride were dissolved in a minimum amount of acetic acid and the mixture was refluxed for 18 hours. After cooling in an ice bath, the mixture was filtered to give 5.8 g (80%) of 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride salt (thioamine salt).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[S:39]([CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][N:28]([S:39]([CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])(=[O:41])=[O:40])[CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)n1
Reactant: COC(=O)CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5nc(C(C)C)no5)CC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of 3-isopropyl-5-(4-(6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-2-yloxy)piperidin-1-yl)-1,2,4-oxadiazole (95 mg, 0.223 mmol) and triethylamine (0.078 ml, 0.558 mmol) in CH2Cl2 (2 ml) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (67.2 mg, 0.335 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt overnight. The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) and extracted with CH2Cl2 (3×3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 50% EtOAc) to afford methyl 4-(4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoate (68 mg, 0.107 mmol, 48% yield) as an off white solid. 1H NMR (500 MHz, chloroform-d) δ 7.64 (d, J=1.9 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.5, 1.9 Hz, 1H), 6.07 (dt, J=3.2, 1.8 Hz, 1H), 5.45 (tt, J=7.0, 3.6 Hz, 1H), 4.03 (q, J=2.8 Hz, 2H), 3.90-3.82 (m, 2H), 3.69 (s, 3H), 3.65 (ddd, J=13.5, 7.2, 4.1 Hz, 2H), 3.58 (t, J=5.6 Hz, 2H), 3.12-3.06 (m, 2H), 2.90 (spt, J=6.9 Hz, 1H), 2.67 (s, 2H), 2.53 (t, J=7.0 Hz, 2H), 2.23-2.12 (m, 4H), 2.06 (dtd, J=13.8, 7.1, 4.0 Hz, 2H), 1.29 (d, J=6.9 Hz, 6H). LCMS (m/z)=590 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:13])=O>>[C:1]([Cl:13])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCC(=O)O
Product: CCCCCCCC(=O)Cl
Temperature: 40 °C

Procedure:
144.2 g of Octanoic Acid is charged at room temperature and heated to 40° C., then 154.64 g of Thionyl Chloride is added over a period of 1 hour and the reaction mixture is heated to reflux at 110° C. for 1½ hour to obtain crude Octanoyl Chloride.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10]O)[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][Cl:14])[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CO)sn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCl)sn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.61 g of (3-t-butyl-isothiazol-5-yl)methanol was dissolved in 50 ml of dichloromethane, and 3.2 ml of thionyl chloride was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain 1.12 g of 3-t-butyl-5-(chloromethyl)isothiazole. The crude product was subjected to the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:20]([O:22][C:23]([CH3:25])=[CH2:24])=[O:21]>C1COCC1>[CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:6][C:20](=[O:21])[O:22][C:23]([CH3:25])=[CH2:24])=[O:5]
Reactant: COC(C)(C)C(N)=O
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C(C)(C)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
A −78° C. solution of 2-methoxy-2-methylpropanamide (0.25 g, 2.134 mmol) in THF (6 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1M in THF, 2.77 mL, 2.77 mmol) stirred for 0.5 h. A solution of isopropenyl chloroformate (0.257 mL, 2.347 mmol) in THF (1 mL) was added drop-wise and the mixture was stirred at −78° C. for 1 h. The mixture was warmed to RT, stirred for 1 h, quenched with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl (2-methoxy-2-methylpropanoyl)carbamate (440 mg, 102%). MS (ESI) m/z: 202.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(COC)OC.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH3:10])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Cl)nc(N)n1
Yield: 63.2 %

Procedure:
4,6-dichloropyrimidin-2-ylamine (1.0 g, 6.13 mmol) and 2-methoxyphenylboronic acid (0.775 g, 5.1 mmol) were added to a solution of dimethoxyethane (20 mL) and water (3 mL), followed by the addition of NaHCO3 (1.03 g, 12.26 mmol) and (PPh3)2PdCl2 (0.2 g) to this and the reaction mixture was allowed to reflux for 4 h, and then the solvent removed under reduced pressure. The residue was taken up in ethyl acetate (50 mL), and the resulting solution washed with water, dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chropatography on silica gel (eluent CH2Cl2) and recrystallized from hexanes yielding 4-chloro-6-(2-methoxyphenyl)-pyrimidin-2-ylamine (0.76 g; 63%) as light yellow powder.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(C(F)(F)F)cn4)CC2)C3)CC1
Temperature: 25 °C

Procedure:
A mixture of (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned; 110 mg}, 2-chloro-5-trifluoromethyl-pyrimidine (76 mg), K2CO3 (100 mg), and dimethyl sulfoxide (1.5 mL) is stirred at 110° C. for 3 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 30:70→10:90) to give the title compound. LC (method 5): tR=1.32 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[F:33][C:34]([F:45])([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](Cl)=[O:36].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH:25][C:35](=[O:36])[C:34]([F:33])([F:45])[O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Reactant: O=C(Cl)C(F)(F)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CN(C)c1cccc(C(=NOCc2cccc(NC(=O)C(F)(F)Oc3ccccc3)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 88 %

Procedure:
To a stirred solution of 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine (90 mg, 0.26 mmol) in dry 1,4-dioxane (10 mL) were added pyridine (31 μL, 0.38 mmol) and 2,2-difluoro-2-phenoxyacetyl chloride (105 mg, 0.51 mmol). The reaction mixture was stirred at room temperature for 25 h, then poured into aq. NaHCO3 (10 g/L, 30 mL). After extraction with ethyl acetate (50 mL), the organic layer was dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded N-(6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-yl)-2,2-difluoro-2-phenoxyacetamide as an oil [123 mg, yield 88%; HPLC/MS:m/z=523 (M+H); log P(HCOOH)=4.14].
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1([C:9]2[CH:10]=[C:11]([C:19]([O:21]C)=O)[C:12](=[CH:17][CH:18]=2)[C:13](OC)=[O:14])[CH:8]=[CH:7][CH:6]=[N:5]1>C(O)C>[N:4]1([C:9]2[CH:10]=[C:11]3[C:12](=[CH:17][CH:18]=2)[C:13](=[O:14])[N:3]=[N:2][C:19]3=[O:21])[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: NN
Reactant: COC(=O)c1ccc(-n2cccn2)cc1C(=O)OC
Solvent: CCO
Solvent: O
Product: O=C1N=NC(=O)c2cc(-n3cccn3)ccc21

Procedure:
22 ml hydrazine monohydrate was added to a mixture of 77 g dimethyl 4-(1H-1-pyrazolyl)phthalate and 500 ml ethanol, and heated under reflux for 6 hr. After cooling, the resulting precipitates were collected by filtration to give 36 g of 6-(1H-1-pyrazolyl)-1,4-phthalazine dione.
Reaction SMILES: [C:1]([O:5][P:6](=[O:13])([O-:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:32][CH2:33][CH2:34][OH:35]>COCCOC>[OH:35][CH2:34][CH2:33][CH2:32][O:13][P:6](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COCCOC
Product: CC(C)(C)OP(=O)(OCCCO)OC(C)(C)C
Temperature: 25 °C
Yield: 100 %

Procedure:
To a 100 mL flask was added tetra-n-butyl ammonium phosphoric acid di-tert-butyl ester salt (3.08 g, 6.8 mmol), ethylene glycol dimethyl ether (10 mL), and 3-bromo-1-propanol (freshly distilled from potassium carbonate). The reaction mixture was heated to reflux for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl ether (60 mL) and cooled in a refrigerator until a white solid precipitated. The solid was filtered through Celite and the filtrate was evaporated in vacuo, affording the title compound as a clear oil (1.85 g, ˜100%). 1H NMR (CDCl3, 500 MHz) δ 4.10 (m, 2H), 3.73 (m, 2H), 1.84 (m, 2H), 1.46 (s, 18H).
Reaction SMILES: IC.[Cl:3][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[OH:18])[N:5]=1.[OH-].[K+].[CH3:21]S(C)=O>O>[Cl:3][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[O:18][CH3:21])[N:5]=1
Reactant: O=[N+]([O-])c1ccc(-n2cnc(Cl)n2)c(O)c1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
Step E (2): Iodomethane (0.860 mL, 13.82 mmol) was added to a mixture of 2-(3-chloro-1H-1,2,4-triazol-1-yl)-5-nitrophenol (1.33 g, 5.53 mmol), potassium hydroxide (0.388 g, 6.91 mmol), and DMSO (25 mL). The mixture was left to stir at rt for 24 h. The reaction mixture was poured into water (250 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified using silica gel column chromatography (0-1% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min). The pure fractions were combined and concentrated to afford 3-chloro-1-(2-methoxy-4-nitrophenyl)-1H-1,2,4-triazole (0.924 g, 3.63 mmol, 65.6% yield) as a light yellow solid. LC-MS (M+H)+=255.0. 1H NMR (500 MHz, chloroform-d) δ ppm 8.35 (s, 1 H) 7.36 (d, J=8.55 Hz, 1 H) 6.29-6.34 (m, 2 H) 3.80 (s, 3 H) 2.46 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][CH:7]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:5]=2.[C:21]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22].N1CCCCC1>CO>[C:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10](/[CH:11]=[CH:22]/[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:23])=[C:2]([CH3:1])[NH:3]2)=[CH:8][CH:7]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1[nH]c2cc(C(=O)c3ccccc3)ccc2c1C=O
Reactant: CC(=O)c1ccncc1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1[nH]c2cc(C(=O)c3ccccc3)ccc2c1/C=C/C(=O)c1ccncc1
Reaction time: 24 h
Yield: 74.7 %

Procedure:
In a dried 100 mL round bottom flask under argon, compound 29 (50 mg, 0.19 mmol) was dissolved in anhydrous methanol (3 mL). 4-Acetyl-pyridine (21 μL, 0.19 mmol) and piperidine (19 μL, 0.19 mmol) were added and the reaction was refluxed. After 24 hours, the reaction was cooled, filtered and rinsed with cold hexanes and dried under vacuum, yielding 52 mg (74%) of pure yellow solid. 1H NMR (600 MHz, d6-DMSO): δ 12.350 (s, 1H, N—H), 8.832-8.222 (d, J=6.0, 2H, pyr-2,6H), 8.255-8.241 (d, J=8.4, 1H, indole-4H), 8.125-8.099 (d, J=15.6, 1H, C═CH), 8.008-7.999 (d, J=5.4, 2H, pyr-3,5H), 7.801 (s, 1H, indole-7H), 7.766-7.754 (d, J=7.2, 2 H, phenyl-2,6H), 7.683-7.642 (m, 2H, phenyl-4H, indole-5H), 7.585-7.563 (m, 3H, C═CH, phenyl-3,5H), 2.659 (s, 3H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 195.5, 188.2, 150.6, 148.5, 144.6, 138.7, 138.2, 135.4, 132.0, 130.6, 129.4, 129.2, 128.4, 123.1, 121.5, 119.9, 114.5, 114.1, 109.6, 12.3. Melting point: 267-270° C. TLC (ethyl acetate:hexanes 4:1) Rf=0.29. Elemental analysis calculated for C24H1N2O2.0.05H2O: C, 78.48; H, 4.97; N, 7.63. found: C, 78.08; H, 5.01; N, 7.50.