Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1>CS(C)=O.C(OCC)(=O)C>[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:8][CH2:7][CH2:6][CH2:5][NH:4][CH3:3])=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:29])([F:30])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1
Reactant: CNCCCO
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2N[C@@H](C)C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To sodium hydride (60% in mineral oil, 2.3 g, 57.6 mmol) in 20 mL of dimethylsulfoxide at room temperature is added a solution of 3-(methylamino)propan-1-ol (5.14 g, 57.6 mmol) in 10 mL of dimethylsulfoxide. The solution is stirred at room temperature for 1 h, and 5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (5.7 g, 14.4 mmol) is added. The mixture is heated at 60° C. for 3 h, and cooled to room temperature. The reaction mixture is diluted with ethyl acetate, and washed with water and saturated sodium chloride. The organic layer is dried over magnesium sulfate, and concentrated to a residue. The residue is triturated with small amount of acetone, then hexanes, and chromatographed over silica gel, eluting with a gradient of 100% ethyl acetate to 100% methyl alcohol. Concentration provides 5-chloro-6{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a white solid (2.7 g). MS: m/z 465.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl.[CH3:13]O>>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(O)c(O)c1
Yield: 86.5 %

Procedure:
A solution of 3,4-dihydroxy benzoic acid (2.8 g) in methanol (150 ml) was refluxed in presence of concentrated hydrochloric acid (0.5 ml) for 12 hrs. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate (150 ml) and washed with water (50 ml) 10% sodium bicarbonate solution (50 ml), brine solution (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 2.64 g of 3,4-dihydroxybenzoic acid methyl ester. (Yield 86.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([NH2:31])[C:12](=[O:30])[NH:13][C:14]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:15]=1[O:16][CH2:17][O:18][CH3:19])=[O:5])[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([NH:31][S:39]([C:36]1[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=1)(=[O:41])=[O:40])[C:12](=[O:30])[NH:13][C:14]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([C:26]([CH3:27])([CH3:29])[CH3:28])[C:15]=1[O:16][CH2:17][O:18][CH3:19])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCCCN(N)C(=O)Nc1cc(OC)cc(C(C)(C)C)c1OCOC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCN(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1cc(OC)cc(C(C)(C)C)c1OCOC
Yield: 57.3 %

Procedure:
A mixture of 5 g of {2-[3-(5-ethoxycarbonylpentyl)-3-aminoureido]-4-methoxy-6-tert-butylphenoxy}methoxymethane, 5 g of 4-chlorobenzenesulfonyl chloride, 7.24 g of triethylamine and 20 ml of chloroform was refluxed for 4 hours. The solvent was removed under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed and dried, and the solvent was removed under reduced pressure to give 4 g of {2-[3-(5-ethoxycarbonylpentyl)-3-(4-chlorobenzenesulfonylamino)ureido]-4-methoxy-6-tert-butylphenoxy}methoxymethane (yield: 57%, state: oily product, IR (film): 3400, 1732, 1710, 1610, 1590 cm-1).
Reaction SMILES: C([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])(OC(C)(C)C)=O.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23](F)[CH:24]=1>[OH-].[Na+].C(O)C>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:21]1[CH:20]=[C:19]([O:18][CH3:17])[CH:24]=[CH:23][C:22]=1[N+:26]([O-:28])=[O:27])[C:14]([OH:16])=[O:15]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NCCC[C@H](N)C(=O)O)c1
Reaction time: 12 h

Procedure:
A solution of 696 mg (3.0 mmol) of Nα -BOC-L-ornithine and 513 mg (3 mmol) of 5-methoxy-2-nitrofluorobenzene in 3 mL of 1N NaOH and 3 mL of ethanol were heated at reflux for 20 hours, then concentrated in vacuo to a yellow oil. The oil was dissolved in 21 mL of 4N HCl in 33% acetic acid and stirred for 12 hours, then suspended in 50 mL of water and washed with 30 mL of dichloromethane and concentrated in vacuo to give a yellow powder. This was recrystallized twice from acetic acid/water to afford the title product as yellow crystals. mp 245°-246°; MS M/Z (DCl/NH3) 284 [M+H]; 1H NMR (300 MHz, D2O/NaOD) δ: 8:1.45 (m, 4H), 2.81 (m, 2H), 3.10 (d, J=1 Hz, 4.2H), 3.52 (d, J=3 Hz, 5.7H), 5.52 (d, J=1 Hz, 3.0H), 5.69 (m, 1H), 7.33 (dd, J=1, 8.4 Hz, 5.7H); 13C NMR (75.5 MHz, D2O/NaOD) δ: 185.47, 168.65, 150.74, 131.00, 127.20, 108.64, 96.78, 58.48, 45.27, 35.37, 27.37; Analysis calc'd for C12H17N3O5.0.2 H2O: C, 50.24; H, 6.11; N, 14.65; found: C, 50.09; H, 6.03; N, 14.60.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([SH:9])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][C:17]=1[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([Cl:10])[C:5]=1[S:9][C:15]1[N:14]=[N:13][C:12]([Cl:11])=[C:17]([CH:18]([CH3:20])[CH3:19])[CH:16]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: Nc1cc(Cl)c(S)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(Sc2c(Cl)cc(N)cc2Cl)nnc1Cl
Temperature: 90 °C
Yield: 71.1 %

Procedure:
A solution of 4-amino-2,6-dichloro-benzenethiol (82) (1.0 g, 5.2 mmol) in N,N-dimethylformamide at 25° C. was treated with 3,6-dichloro-4-isopropyl-pyridazine (7) (990 mg, 5.2 mmol) and potassium carbonate (2.16 g, 15.6 mmol). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C., poured onto a mixture of ice water and a 1N aqueous hydrochloric acid solution (10 mL). The resulting solution was brought to pH=7 with additional 1N aqueous hydrochloric acid solution and then was extracted with ethyl acetate (2×100 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 petroleum ether/ethyl acetate) afforded 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenylamine (83) (1.29 g, 72%) as an off-white foam; ES(+)-HRMS m/e calcd for C13H12Cl3N3S (M+H)+ 347.9891, found 347.9889. Exact Mass=346.9817; Molecular weight=348.68
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])#[N:2].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].C(O)(=O)C.[Na]>ClCCl>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:19])[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])#[N:2]
Reactant: CC(C)C=O
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCCN2
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCCN2CC(C)C

Procedure:
To the material isolated in Step A in 2 mL of dichloromethane was added 0.041 mL (0.90 mmol) of iso-butyraldehyde, followed by 0.026 mL (0.45 mmol) of acetic acid and 0.10 g (0.45 mmol) of sodium tracetoxyborohydride. After 16 h at ambient temperature the reaction was diluted with 30 mL of dichloromethane and washed twice with equal volumes of saturated aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative reversed phase BPLC afforded the tide compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][CH2:11][CH2:12][CH2:13][NH2:14].O>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][C:4]([CH:1]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccncc1
Reactant: NCCCN
Solvent: Cc1ccccc1
Solvent: O
Product: CC(NCCCN)c1ccncc1
Reaction time: 16 h

Procedure:
4-Acetylpyridine (30.3 g) was added portionwise over 40 minutes to a solution of 1,3-diaminopropane (85 cm3) in toluene (250 cm3) under reflux, with continuous removal of water using a Dean and Stark trap. When no more water was observed in the toluene layer (3 hours) the mixture was concentrated in vacuo and the residue was taken into methanol (200 cm3) and treated with sodium borohydride (12.0 g) added portionwise over 20 minutes at 0° C. After stirring for 16 hours concentrated hydrochloric acid (10 cm3) was slowly added and the mixture was concentrated in vacuo. The residue was dissolved in water (100 cm3) and basified to pH11 with 5M sodium hydroxide solution. The mixture was extracted with chloroform (3×300 cm3) and the dried (MgSO4) extracts were evaporated in vacuo. Distillation gave N-[1-(4-pyridyl)ethyl]-1,3-diaminopropane (22.7 g) as a colourless oil, b.p. 108°-114°/0.03 mm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:14]3[C:15]4[C:16](=[O:36])[N:17](CCCBr)[C:18](=[O:31])[C:19]=4[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])=[CH:21][C:22]=3[O:23][C:8]=2[CH:7]=1.[CH3:37][NH:38][CH3:39]>O1CCCC1>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:20]1[C:19]2[C:18](=[O:31])[NH:17][C:16](=[O:36])[C:15]=2[C:14]2[C:9]3[CH:10]=[C:11]([O:12][CH3:13])[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:38]([CH3:39])[CH3:37])=[CH:7][C:8]=3[O:23][C:22]=2[CH:21]=1
Reactant: CNC
Reactant: COc1cc2c(cc1OCCCBr)oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)N(CCCBr)C3=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCCN(C)C)oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reaction time: 24 h
Yield: 84 %

Procedure:
Reaction of dibromide (331) (100 mg, 0.16 mmol) prepared as described in example 385 with aqueous dimethylamine solution (40%, 5.0 mL) according to The procedure described in example 179, except that the reaction was performed in tetrahydrofuran (50 mL) at room temperature for 30 hours, gave the crude diamine (LXXX; Ar=2-chlorophenyl, n=3, Z═N(CH3)2), which was used without further purification as a tetrahydrofuran solution. To this solution was added SN potassium hydroxide (2.5 mL), then the procedure outlined in example 328 was followed except that the HCl treatment was for 24 hours and the chromatography was performed eluting with methanol/dichloromethane/concentrated ammonia (15:85:trace). Trituration from ethyl acetate gave amine (332) (64 mg, 84%) as a yellow powder, mp 251–253° C. 1H NMR δ [(CD3)2SO] 11.37 (br s, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.59 (m, 1H), 7.55 (s, 1H), 7.52–7.43 (m, 3H), 4.18 (t, J=6.4 Hz, 2H),3.93 (s, 3H), ˜2.5 (obscured m, 2H), 2.23 (br s, 6H), 1.96 (m, 2H). Found: C, 65.03; H, 4.79; N, 6.00. C26H23ClN2O5 requires: C, 65.21; H, 4.84; N, 5.85.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[CH3:11][NH:12][NH2:13]>C(O)C>[NH2:8][C:7]1[N:12]([CH3:11])[N:13]=[C:4]([CH3:5])[C:6]=1[C:9]#[N:10]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: CNN
Solvent: CCO
Product: Cc1nn(C)c(N)c1C#N
Temperature: 25 °C
Yield: 68 %

Procedure:
2-(1-Ethoxy-ethylidene)-malononitrile 1a (10 g, 73.45 mmol) was added portionwise to a mixture of N-methylhydrazine (1 equiv., 3.88 ml) in ethanol (50 ml) and the reaction mixture was refluxed for 1 hour, cooled to room temperature, precipitate filtered, washed with ethanol and dried to give 5-amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile 2a as white crystalline solid (9.85 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:29])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:29])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[N:17]=2)[CH:14]=1
Reactant: O=C(NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F
Yield: 55.6 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-2,2,2-trifluoroacetamide (0.160 g), KOH (0.050 g), water (2 mL) and THF (10.0 mL) to afford 0.070 g of the desired product.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH3:5][N:6]([C:14]1[S:15][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:18]=1)[C:7](=[O:13])[CH2:8][CH2:9][C:10](=O)[CH3:11].C([O-])(=O)C.[Na+]>C(O)C>[CH3:5][N:6]([C:14]1[S:15][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:18]=1)[C:7](=[O:13])[CH2:8][CH2:9]/[C:10](=[N:4]/[O:3][CH3:2])/[CH3:11]
Reactant: CC(=O)CCC(=O)N(C)c1nnc(-c2cccnc2)s1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CO/N=C(\C)CCC(=O)N(C)c1nnc(-c2cccnc2)s1
Yield: 37.1 %

Procedure:
4-[(E)-methoxyimino]-pentanoic acid methyl-(5-pyridin-3-yl-[1,3,4]thiadiazol-2-yl)-amide was prepared as described in J F W Keana et al. in J. Org. Chem., 1985, 50, 2346. A suspension of O-methylhydroxylamine hydrochloride (0.065 g, 0.9 mmol), 4-oxo-pentanoic acid methyl-(5-pyridin-3-yl-[1,3,4]thiadiazol-2-yl)-amide (0.18 g, 0.6 mmol) and sodium acetate (0.076 g, 0.9 mmol) in anhydrous ethanol was refluxed under nitrogen for 14 hours, cooled, concentrated under reduced pressure and chromatographed on silica to afford the title compound as an amorphous yellow solid (0.071 g, 36%): mp 114-121° C.; 1H NMR (400 MHz, CDCl3) δ 9.15 (d, J=1.8 Hz, 1H), 8.70 (dd, J=4.8, 1.8 Hz, 1H), 8.29 (dt, J=5.9, 1.8 Hz, 1H), 7.43 (dd, J=7.7, 5.2 Hz, 1H), 3.92 (s, 3H), 3.86, 3.83 and 3.77 (all s, 1H), 2.95 (q, J=7.0 Hz, 2H), 2.71 (q, J=7.4 Hz, 2H), 2.11, 1.98 and 1.89 (all s, 3H); ESIMS m/z 320 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[CH:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:30]([CH:27]3[CH2:29][CH2:28]3)(=[O:32])=[O:31])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)C1CC1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (150 mg, 0.383 mmol) and cyclopropanesulfonyl chloride (0.039 mL, 0.383 mmol) the title compound of Step A was obtained as a yellow solid (125 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 8.27-8.39 (m, 1H), 7.54 (td, J=7.6, 1.7 Hz, 1H), 7.22-7.42 (m, 2H), 6.62-6.72 (m, 1H), 5.30 (s, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.52 (t, J=4.6 Hz, 4H), 2.59-2.70 (m, 1H), 0.75-0.93 (m, 3H).
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[Cl:25]N1C(=O)CCC1=O>C(OC(C)=O)(C)C.O>[Cl:25]/[C:3](=[N:2]\[OH:1])/[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(/C=N/O)cc1)C1CCOCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc(/C(Cl)=N/O)cc1)C1CCOCC1
Temperature: 20 °C
Yield: 88.8 %

Procedure:
A suspension of (E)-tert-butyl 4-((hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4) (1662 g, 4.97 mol) in i-PrOAc (16.6 L) is stirred at 20° C. in a reactor. N-chlorosuccinimide (730 g, 5.47 mol) is added maintaining about 20° C. The suspension is stirred at about 20° C. to complete the reaction. The suspension is diluted with water (8.3 L) and stirred to dissolve the solid. The phases are separated and the organic phase is washed with water (8.3 L). The organic phase is concentrated then diluted with i-PrOAc (831 mL). Heptane (13.3 L; 8 V) is slowly added to induce crystallization. The thick suspension is then stirred for 1 h. The solid is collected by filtration; the filter-cake is washed with heptane (2×1.6 L; 2×1 V) and dried to afford (Z)-tert-butyl 4-(chloro(hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4-i) (1628 g 89%, 98.0 area % purity by HPLC) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13]
Reactant: CC(=O)OC1CC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)NC1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC1CC(N2Cc3c(N)cccc3C2=O)C(=O)NC1=O

Procedure:
A solution of 3-(4-nitro-1-oxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (0.9 g, 3.1 mmol) and Pd/C (10%, 0.1 g) in methanol (100 mL) is shaken under hydrogen (50–60 psi) for 3 hours, The suspension is filtered through a pad of Celite and washed with methanol to give 3-(4-amino-1-oxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(I)cc2c1O
Product: CCCCOC(=O)c1nc(Cl)c2ccc(I)cc2c1O

Procedure:
Analogously to Example D-43 d), 0.150 g of 4-hydroxy-6-iodo-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester was allowed to react with 5 ml of POCl3 to afford 0.057 g of a pale white solid: Proton NMR (200 MHz, chloroform-d): δ 11.9 (s, 1H), 8.89 (m, 1H), 8.1 (m, 1H), 7.97 (m, 1H), 4.5 (t, J=7 Hz, 2H), 2.0-1.8 (m, 2H), 1.65-1.4 (m, 2H), 1.00 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[CH3:12][C:3]1[C:2]2[C:7]([CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[N:8][C:14](=[O:15])[C:13](=[O:17])[N:1]=2
Reactant: Cc1cc([N+](=O)[O-])cc(N)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: Cc1cc([N+](=O)[O-])cc2c1=NC(=O)C(=O)N=2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9.3 g (55.63 mmol) of 2,3-diamino-5-nitro-toluene and 14 g of oxalic acid in 93 ml of 6N HCl is heated at reflux for 30 minutes and then stirred at room temperature overnight to complete the reaction. The suspension is filtered and then washed with water, taken up in 250 ml of 2N NaOH and heated at reflux until a homogeneous solution is formed. After cooling, the mixture is acidified to pH 3 and the resulting 5-methyl-7-nitro-quinoxaline-2,3-dione is filtered off.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[C:28]=2[CH:33]=[O:34])=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:33]([C:28]2[C:29]([CH3:32])=[N:30][O:31][C:27]=2[C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=2)[OH:34])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(Cc2ccccc2)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1-Benzyl-3-bromo-benzene (0.811 g, 3.3 mmol) was dissolved in THF (2 mL), cooled to −78° C. and then n-butyllithium (2.0 M in THF, 1.65 mL, 3.3 mmol) was added dropwise. The reaction was stirred for 15 minutes then warmed to 0° C. and 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (1.05 g, 3.96 mmol) was added. The reaction was allowed to warm to room temperature while stirring for 1 hour. The reaction was quenched with aqueous ammonium chloride then submitted to standard aqueous workup and silica gel chromatography to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].C[NH:30][CH2:31][CH2:32][OH:33].[I-].[Na+]>COCCOC>[OH:33][CH2:32][CH2:31][NH:30][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: CNCCO
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCNCCO
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 375.6 mg (5.0 mmol) of 2-(methylamino)-ethanol and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME was heated at 135° C. for 15 hr. The work up gave 116.4 mg (54.0%) of the product as a yellow solid, m.p. 179° C. (dec.), mass (electrospray, m/e): M+H 433.0.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:16][C:13]1[N:12]=[CH:11][C:10]([C:7]2[S:6][C:5]3=[N:4][CH:3]=[C:2]([C:25]4[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=4)[N:9]3[N:8]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(-c2nn3c(I)cnc3s2)cn1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)cn1
Temperature: 110 °C
Yield: 1.9 %

Procedure:
A mixture of 5-Iodo-2-(6-methyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (226 mg, 0.661 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (228 mg, 0.793 mmol, 1.2 eq), PdCl2(PPh3)2 (95 mg, 0.132 mmol, 0.2 eq) and 2M aq Na2CO3 (1.6 mL) in dioxane (7 mL) was heated at 110° C. for 90 min. The solvent was removed under reduced pressure and the residue was suspended in water and filtered. The solid was washed with diethylether, methanol and acetone. The residue was purified by HPLC to afford the desired product (4.7 mg, 2%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.23 min, [M+H]+ m/z 377.0; 1H NMR (300 MHz, DMSO) δ 9.02 (s, 1H), 8.87 (s, 1H), 8.36 (s, 1H), 8.25 (dd, J=8.1, 2.2 Hz, 1H), 7.81 (s, 1H), 7.52 (d, J=8.2 Hz, 1H), 6.75 (s, 2H), 2.59 (s, 3H).