Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18]C(=O)C(F)(F)F)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:25]2[CH:26]=[CH:27][C:28]([Cl:40])=[C:29]3[C:33]=2[N:32]([CH3:34])[N:31]=[C:30]3[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CCO>[NH2:18][C@H:8]([C:6]1[C:5]([C:25]2[CH:26]=[CH:27][C:28]([Cl:40])=[C:29]3[C:33]=2[N:32]([CH3:34])[N:31]=[C:30]3[NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@@H](N)Cc3cc(F)cc(F)c3)c21
Temperature: 130 °C

Procedure:
To a solution of (S)—N-(1-(6-chloro-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2,2,2-trifluoroacetamide (57D, 870 mg, 1.40 mmol) in EtOH (16 mL) was added 2M aqueous LiOH (7.0 mL, 13.98 mmol). The reaction was heated in a microwave reactor at 130° C. for 10 minutes. Upon cooling, the reaction mixture was acidified with 2N aqueous HCl until at pH 5. The reaction mixture was then concentrated in vacuo and taken in EtOAc. To the solution was added saturated aqueous NaHCO3 until the aqueous layer was at pH 10. The organic layer was collected, and the aqueous layer was extracted an additional time with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and used without further purification. MS (m/z) 526.06 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]3([C:29]([O:31][C@@H:32]([CH:49]([CH3:51])[CH3:50])[C:33]([NH:35][C@@H:36]([CH3:48])[C:37]([N:39]4[CH2:44][CH2:43][CH2:42][C@@H:41]([C:45]([OH:47])=[O:46])[NH:40]4)=[O:38])=[O:34])=[O:30])[CH2:28][O:27][CH2:26][CH2:25][O:24]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=O)(C)(C)C.[ClH:52]>O1CCOCC1>[ClH:52].[NH2:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]3([C:29]([O:31][C@@H:32]([CH:49]([CH3:51])[CH3:50])[C:33]([NH:35][C@@H:36]([CH3:48])[C:37]([N:39]4[CH2:44][CH2:43][CH2:42][C@@H:41]([C:45]([OH:47])=[O:46])[NH:40]4)=[O:38])=[O:34])=[O:30])[CH2:28][O:27][CH2:26][CH2:25][O:24]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10]
Reactant: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)COCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)N)nc3c2)COCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of crude (S)-1-{(S)-2-[(S)-2-(2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-[1,4]dioxane-2-carbonyloxy)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (0.081 mmol) in 4 M hydrogen chloride in 1,4-dioxane (2 mL) was stirred at room temperature for 1 h. The solvent was evaporated and the residue was co-evaporated with diethyl ether (2×) and the resulting solid was dried to afford (S)-1-{(S)-2-[(S)-2-(2-{(E)-2-[2-((R)-1-amino-ethyl)-quinolin-7-yl]-vinyl}-[1,4]dioxane-2-carbonyloxy)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid hydrochloride (0.081 mmol) as an off-white solid and as a 1:1 mixture of diastereoisomers which was used crude in the next reaction. LCMS (m/z) 612.1 [M+H], Tr=1.38 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:11]([OH:13])=O)=[C:7]([CH3:10])[S:8][CH:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][CH3:62])=[CH:57][CH:56]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1.C(N(CC)CC)C>ClCCl>[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:56]=[CH:57][C:58]([N:61]([CH3:62])[C:11]([C:6]5[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:9][S:8][C:7]=5[CH3:10])=[O:13])=[CH:59][CH:60]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: CC(=O)Nc1csc(C)c1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1csc(C)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
A mixture of 4-acetylamino-2-methyl-thiophene-3-carboxylic acid (45 mg, 0.17 mmol) in dichloromethane (3 mL) at 25° C. was treated with triphenylphosphine (71 mg, 0.22 mmol). This mixture was cooled to 0° C. and then was treated with N-chlorosuccinimide (36 mg, 0.22 mmol). This mixture was stirred at 0° C. for 15 min and then was warmed to 25° C. for 15 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (75 mg, 0.17 mmol). This solution was then cooled to 0° C. and was treated with triethylamine (38 μL, 0.22 mmol). The reaction was warmed to 25° C. and was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 4-acetylamino-2-methyl-thiophene-3-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (27.8 mg, 26.1%): EI-HRMS m/e calcd for C32H31N6O4SF (M+Na)+ 637.2004, found 637.2018.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[Na].[C:10]([C:12](=[N:21][OH:22])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])#[N:11]>C1C=CC=CC=1.ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:22][N:21]=[C:12]([C:10]#[N:11])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])(=[O:7])=[O:6]
Reactant: N#CC(=NO)c1c(Cl)cccc1Cl
Reactant: O=S(=O)(Cl)CCCCl
Agent: [Na]
Solvent: ClCCl
Solvent: c1ccccc1
Product: N#CC(=NOS(=O)(=O)CCCCl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5.0 g (0.0281 mol) sample of 3-chloropropylsulfonyl chloride was added slowly at about 0° C. (ice bath) to a suspension of 6.7 g (0.0281 mol) of the sodium salt of alpha-cyano-2,6-dichlorobenzaldoxime in 60 ml benzene. The reaction was exothermic. The reaction mixture was stirred at 25° C. for 2 hours during which time a solid product formed. The reaction mixture was then diluted with 200 ml dichloromethane, washed with water, dried over magnesium sulfate and silica gel, and evaporated under reduced pressure to give a yellow oil. The oil was crystallized from ether/hexane to give the product as white crystals, m.p. 86°-88° C. This product is tabulated in Table I as compound No. 12.
Reaction SMILES: [CH3:1][C:2]1([CH3:54])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH:10]2[CH2:14][CH:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:11]2[C:31](=[O:53])[CH2:32][NH:33][C:34](=[O:52])[NH:35][C:36]2[CH:37]=[C:38]([CH:49]=[CH:50][CH:51]=2)[C:39]([O:41]CC2C=CC=CC=2)=[O:40])=[O:9])[CH2:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:54])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH:10]2[CH2:14][CH:13]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:11]2[C:31](=[O:53])[CH2:32][NH:33][C:34](=[O:52])[NH:35][C:36]2[CH:37]=[C:38]([CH:49]=[CH:50][CH:51]=2)[C:39]([OH:41])=[O:40])=[O:9])[CH2:3]1
Reactant: CC1(C)CCCN(C(=O)C2CC(S(=O)(=O)c3ccccc3)C(c3ccccc3F)N2C(=O)CNC(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)C1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCCN(C(=O)C2CC(S(=O)(=O)c3ccccc3)C(c3ccccc3F)N2C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)C1
Yield: 34.7 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 2A, but from 3.6 g of benzyl (2RS,4SR,5RS)-3-{3-[2-(2-(3,3-dimethylpiperidino)carbonyl-5-(2-fluorophenyl)-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoate and 0.35 g of 10% palladium-on-charcoal in 200 cm3 of ethanol. After treatment, there are obtained 1.1 g of (2RS,4SR,5RS)-3-{3-[2-(2-(3,3-dimethylpiperidino)carbonyl-5-(2-fluorophenyl)-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid [Rf =0.21; eluent: methylene chloride/methanol (90/10)].
Reaction SMILES: C(OC([N:6]([CH2:13][C@@H:14]([OH:24])[CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[O:7]C(OCC)=O)=O)C.C[Si](C)(C)Br.C1OC1C.C(O)C>ClCCl.O.CO>[OH:24][C@H:14]([CH2:13][NH:6][OH:7])[CH2:15][P:16](=[O:17])([OH:23])[OH:20]
Reactant: CCOC(=O)ON(C[C@@H](O)CP(=O)(OCC)OCC)C(=O)OCC
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: CO
Solvent: CCO
Product: O=P(O)(O)C[C@H](O)CNO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18.1 %

Procedure:
Diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2(R)-hydroxypropylphosphonate (13.8 g) was dissolved in dichloromethane (25 ml). To the solution was added trimethylbromosilane (25 g) under ice-cooling. The reaction mixture was stirred at the same temperature for 30 minutes and at ambient temperature for 1.5 hours. Subsequently, the resultant mixture was concentrated under reduced pressure to give a residue, which is dissolved in water (50 ml). The aqueous solution was stirred at ambient temperature for an hour, washed three times with chloroform (20 ml) and then the aqueous layer was separated. After 1 N hydrochloric acid (140 ml) was added to the aqueous layer, the mixture was heated to reflux for 15 hours. The resultant mixture was concentrated under reduced pressure to give a residue, which was dissolved in a mixture of water (10 ml) and methanol (20 ml). The solution was adjusted to pH 3-4 with propyleneoxide (20 ml) and ethanol (200 ml) was added to the solution to precipitate an oil, which was separated by decantation, washed with ethanol (20 ml) and dissolved in water (20 ml). After the aqueous solution was treated with activated charcoal (100 ml), the activated charcoal was removed by filtration. The filtrate was evaporated to dryness under reduced pressure and dried over phosphorus pentoxide to give powdery 2(R)-hydroxy-3-(N-hydroxyamino)propylphosphonic acid (1.15 g).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:26]([C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:40]=1[OH:41])[CH:33]=[CH:34][C:35](O)=[O:36])([CH3:29])([CH3:28])[CH3:27].[NH2:46][C:47]1[CH:48]=[N:49][C:50]2[C:55]([C:56]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:63])=[CH:54][C:53]([CH3:64])=[CH:52][C:51]=2[CH3:65]>CN(C=O)C>[C:42]([C:39]1[CH:38]=[C:32]([CH:31]=[C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])[C:40]=1[OH:41])[CH:33]=[CH:34][C:35]([NH:46][C:47]1[CH:48]=[N:49][C:50]2[C:55]([C:56]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:63])=[CH:54][C:53]([CH3:64])=[CH:52][C:51]=2[CH3:65])=[O:36])([CH3:44])([CH3:45])[CH3:43]
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C)c2ncc(NC(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
1-Hydroxybenzotriazole (154 mg) and dicyclohexylcarbodiimide (272 mg) were added to a solution of 3,5-di-tert-butyl-4-hydroxycinnamic acid (331 mg) in DMF (5 ml). The mixture was stirred at room temperature for 30 minutes, and then, 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (288 mg) was added thereto. The resultant mixture was further stirred at room temperature for 24 hours. The insoluble materials were filtered off, while the filtrate was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed, and the residue was purified by a silica gel chromatography with benzene-acetone (9:1), then, crystallized from isopropyl ether to give 3-(3,5-di-tert-butyl-4-hydroxycinnamoylamino)-4-(2-chlorophenyl)-6,8-dimethylquinoline (257 mg, 47.5%) as colorless needles.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[C:4]([CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]4)=[C:4]([CH3:18])[CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: Cc1cc(I)ccc1NCCN1CCC(C)CC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1NCCN1CCC(C)CC1

Procedure:
The product was prepared analogously to Example 7.1e starting from (4-iodo-2-methylphenyl)-[2-(4-methylpiperidin-1-yl)ethyl]amine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 60 mg (20% of theoretical); C28H30ClN3 (M=444.011); calc.: molpeak (M+H)+444/446 (Cl); found molpeak (M+H)+: 444/446 (Cl); HPLC-MS: 5.53 minutes (method B).
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1)(OC(C)(C)C)=O>Cl.C(O)C>[ClH:20].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[N:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(Cl)nn1
Agent: Cl
Solvent: CCO
Product: Clc1ccc(OC[C@@H]2CCN2)nn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 811 mg sample of 3-(1-BOC-2(S)-azetidinylmethoxy)-6-chloro-pyridazine, prepared as in Example 13a above, was dissolved in 10 mL of satd HCl in ethanol cooled to 0° C., and the reaction was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and the oily residue was dried under high vacuum for 4 hours to provide a solid. The solid was triturated with ether, collected, and recrystallized three times from ethanol/ether to give 118 mg of the title compound. mp 150-151° C. MS (DCI/NH3) m/e: 200 (M+H)+. 1H NMR (DMSO 4,300 MHz) δ: 9.31 (br s, 1H), 7,87 (d, J=9.2 Hz, 1H), 7.44 (d, J=9.2 Hz, 1H), 4.84-4.63 (m, 3H), 3.98-3.83 (m, 2H), 2.59-2.36 (m, 2H). Anal. Calc. for C8H11N3OCI2 : C, 40.70; H, 4.70; N, 17.80; Found C, 40.58; H, 4.59; N, 17.58.
Reaction SMILES: P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)([O-:12])=[O:11].[O:22]=[C:23](N1CCCC1)[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])O.[Na+]>CO>[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:23](=[O:22])[C:24]([O:26][CH3:27])=[O:25])=[CH:16][NH:17]2)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: COC(=O)C(=O)N1CCCC1
Agent: O=C([O-])O
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C

Procedure:
9.4 mL (68 mmol) diphosphoryl chloride were slowly added dropwise to 10 g (62 mmol) 4-nitroindole and 11 g (68 mmol) methyl oxo-pyrrolidin-1-yl-acetate with stirring and while cooling with ice. The reaction mixture was heated to RT and stirred for 3 h at RT. Then first of all 10 mL MeOH were added dropwise at 0° C. and then saturated sodium hydrogen carbonate solution was added dropwise at 0° C. After repeated extraction with DCM the organic phase was dried and evaporated down to 100 mL. This residue was left to stand at RT and the precipitate formed was suction filtered, washed and dried in the air.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:8][CH:7]=[CH:6][N:5]2[C:20]=1[CH3:21].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[CH3:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:20]([CH3:21])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[CH:7][C:8]=1[N+:22]([O-:24])=[O:23]
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cccc(C)c1CNc1c([N+](=O)[O-])ccn2c(C)c(C)nc12
Temperature: 82.5 °C
Reaction time: 3 h
Yield: 17.2 %

Procedure:
2,3-dimethyl-8-(2,6-dimethylbenzylamino)-imidazo[1,2-a]pyridine (2.0 g, 7.16 mmol) was dissolved in acetic acid (30 ml) and nitric acid (0.53 g, 7.57 mmol) was added. The mixture was heated to 80-85° C. and stirred for 3 h at this temperature. After evaporation of the major part of the acetic acid, the residue was partitioned between methylene chloride and water. The organic layer was washed with a solution of sodium carbonate and the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride (100 ml) and filtered through silica gel (10 g) whereupon the methylene chloride was removed under reduced pressure. Chromatography with methylene chloride (100%) gave 0.4 g (17%) of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=O)[CH3:19])=[CH:13][CH:12]=1.C(O)(=O)C>C(O)C.C(N(CC)CC)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])[CH3:19])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCN
Reactant: CC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(C)Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a solution of β-alanine ethyl ester hydrochloride (1.00 g) in ethanol (13.5 mL), triethylamine (907 μL), 4-chlorophenylacetone (1.32 g), acetic acid (1.5 mL) and borane-2-picoline complex (1.39 g) were added successively and the mixture was stirred at 60° C. for 30 minutes. After being cooled to room temperature, the mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with chloroform twice. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to give the titled compound as a yellow oil (1.70 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([N:10]2[CH2:14][CH:13]3[C@@H:15](CS([O-])(=O)=O)[CH2:16][CH2:17][N:12]3[C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([N:10]2[CH2:14][C@@H:13]3[C@H:15]([N:25]=[N+:26]=[N-:27])[CH2:16][CH2:17][N:12]3[C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N2CC3[C@@H](CS(=O)(=O)[O-])CCN3C2=O)ccc(C#N)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(N2C[C@@H]3[C@H](N=[N+]=[N-])CCN3C2=O)ccc(C#N)c1Cl
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A solution of compound 90A (400 mg, 1.18 mmol) and sodium azide (309 mg, 4.75 mmol) in anhydrous DMF (3.2 mL) was placed in a pre-heated bath (75° C.) and stirred at 75° C. for 3 h. The solution was cooled, quenched with H2O (6.0 mL) and extracted with EtOAc (2×80 mL). The organic phase was washed with H2O (6.0 mL), brine (6.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The syrup was chromatographed (silica gel; CH2Cl2/CH3OH gradient) to yield the title compound (339.3 mg, 90.8%) as a white solid foam from CH2Cl2/Hexane. HPLC: 97.7% at 2.22 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. MS (ES+): m/z 317 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH3:27])[C:5]2[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[NH:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[N:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:4]([CH3:27])[C:5]2[C:6]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[NH:28][N:29]=[CH:30]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc2[nH]ncc2c1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)C3CC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (300 mg, crude) in dioxane (10 mL), 1H-indazol-5-ylboronic acid (430 mg, 1.76 mmol), K3PO4 (370 mg, 1.76 mmol), and Pd(PPh3)4 (51 mg, 0.04 mmol). The resulting solution was stirred for 1 h at 90° C. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%-50% ethyl acetate in petroleum ether to afford methyl 3-(cyclopropyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylate as a yellow solid (40 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([NH2:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:20](Cl)(Cl)=[S:21]>ClCCl>[CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N:14]=[C:20]=[S:21])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(C2CC2)c2ccccc12
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: S=C=Nc1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 149.7 %

Procedure:
Compound 2 (440 mg, 2.6 mmol) was dissolved in 14 mL of dichloromethane. Sodium bicarbonate (7 mL, sat. solution) and thiophosgene (0.2 mL, 2.6 mmol) were added and the mixture stirred at room temperature for 1 h. Then, the organic layer was separated, dried over sodium sulfate and concentrated to afford 877 mg, 99% yield of 1-cyclopropyl-4-isothiocyanatonaphthalene (3) which was used in the next step without further purification