Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20]CC(C1C=C(O)C=CC=1O)=O.C(=O)C1C=CC=CC=1>>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[CH:17]([CH3:20])[C:16]2=[O:18]
Reactant: CCC(=O)c1cc(O)ccc1O
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Solvent: O=Cc1ccccc1
Product: CC1C(=O)c2cc(O)ccc2OC1c1ccccc1

Procedure:
6-Hydroxy-3-methyl-2-phenylchroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of 2,5-dihydroxypropiophenone and 1.63 ml of benzaldehyde. The product was purified by column chromatography using heptane-ethyl acetate (3:1) as an eluant. 1H NMR (300 MHz, d6-DMSO) δ: 9.37 (s, 1H), 7.53 (m, 2H), 7.47-7.39 (m, 3H), 7.13 (d, 1H, J 3.1 Hz), 7.02 (dd, 1H, J 8.9, 3.1 Hz), 6.89(d, 1H, J 8.9 Hz), 5.17 (d, 1H, J 12.3), 3.18 (dq, 1H, J 12.3, 6.9 Hz), 0.84 (d, 3H, J 6.9 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([S:18][C:19]2[N:23]4[CH:24]=[C:25]([C:28](=O)[CH3:29])[CH:26]=[CH:27][C:22]4=[N:21][N:20]=2)=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[NH2:31][O:32][CH2:33][CH2:34][OH:35].Cl>CO>[OH:35][CH2:34][CH2:33][O:32]/[N:31]=[C:28](/[C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([S:18][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:17]4)=[N:20][N:21]=2)[CH:24]=1)\[CH3:29]
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CCN(C)CC5)cc4c3)n2c1
Reactant: NOCCO
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(Sc3ccc4ncc(N5CCN(C)CC5)cc4c3)n2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
A solution of (86.2) (120 mg, 0.287 mmol) and 2-(aminooxy)ethanol (44.2 mg, 0.573 mmol) in MeOH (10 ml) was added drops of HCl (3 N) to reach pH about 5 and then stirred at rt for overnight. Solvent was evaporated and the residue was purified by preparative base HPLC (gradient eluent NB from 20/80 to 95/5. mobile phase A: NH4OH/CH3CN 0.05%; mobile phase B: NH4OH/H2O 0.05%) to afford the title compound (20 mg, yield 15%).
Reaction SMILES: [C:1]([C:4](=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:12]([C:11]1[O:3][C:1]([CH3:2])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCC=C(C(C)=O)C(=O)OCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1cc(C(=O)OCC)c(C)o1
Yield: 62.8 %

Procedure:
A mixture of 2.64 g (8.15 mmole) ethyl 2-acetyl-2-hexadecenoate and 1.45 g (8.15 mmole) N-bromosuccinimide in 25 ml of carbon tetrachloride was heated at reflux for 12 hours. After cooling, the succinimide was removed by filtration and the solution concentrated in vacuo. Distillation of the crude product gave 1.65 g (63%) of ethyl 5-dodecyl-2-methyl-3-furoate, bp 160°-163° C. (0.4 mm).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:13][CH:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.N1C=CC=CC=1.[S:31](Cl)(Cl)=[O:32]>C(Cl)Cl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:3]2[CH2:2][O:1][S:31](=[O:32])[N:13]2[CH:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CC(CO)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CC2COS(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
t-Butyl 2-(1-hydroxymethyl-2-(4-methoxyphenyl)ethylamino)-3-methylbutyrate (2.49 g; 7.4 mmol) was dissolved in CH2Cl2 (180 ml). The reaction solution was cooled to −78° C. Then pyridine (3 ml; 37 mmol) was added and subsequently thionyl chloride (0.64 ml; 8.88 mmol) was added dropwise. The reaction mixture was stirred for 1 h, during which the temperature was allowed to reach 0° C. It was taken up in CH2Cl2 and washed with aqueous HCl (1%; 2×) and NaHCO3 solution. The organic phase was dried over Na2SO4 and concentrated in a rotary evaporator. The crude product was purified by filtration through silica gel (100 g). t-Butyl 2-(4-(4-methoxybenzyl)-2-oxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbutyrate (2.35 g; 0.61 mmol) was obtained as a dark yellow oil. MS: 384.20 (M+H); Rt: 1.76 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][C:40]=1[F:48].O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:48][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:39]=1[C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:7]3[O:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:9][N:8]=3)[CH:11]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=1)[C:43]([OH:45])=[O:44]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(=O)O)cc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 90 °C
Yield: 48.8 %

Procedure:
To a solution of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (2.0 g, 3.831 mmol) and 4-bromo-3-fluorobenzoic acid (1.2 g, 5.74 mmol, Sigma-Aldrich) in DME (38 mL)/water (9 mL) was added Na2CO3 (1.35 g, 11.5 mmol) and Pd(PPh3)4 (439 mg, 0.38 mmol) and Ar gas was bubbled for 5 min. The reaction mixture was heated at 90° C. for 4 h. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give crude product (1.0 g), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 535.1 (M+1).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:10][C:8]1[CH:9]=[C:4]([O:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1ccc(CO)cc1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Cl)nc(-c3ccccc3)n2)cc1
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
NaH (60%) (469 mg, 11.73 mmol) was added in portions to a stirred solution of 4,6-dichloro-2-phenyl-pyrimidine (2.2 g, 9.78 mmol) and 4-methoxy benzyl alcohol (1.62 mg, 11.73 mmol) in dry THF (55 ml) at 0° C. After 1.5 h, NaHCO3 (aq) was added. Some solvent was evaporated and the residue was extracted with DCM, dried (MgSO4), filtered and evaporated to give the title compound, (3.19 g, 100%), MS (M+H)+327.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][CH2:21][OH:22])=[CH:16][N:15]([CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[C:27]([CH3:33])=[CH:26][N+:25]=3[O-:34])[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1>CCO.[Cl-].[Cl-].[Zn+2]>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:17]([C:18]#[C:19][CH2:20][CH2:21][OH:22])=[CH:16][N:15]([CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([O:31][CH3:32])[C:27]([CH3:33])=[CH:26][N+:25]=3[O-:34])[C:4]=2[N:5]=1
Reactant: COc1c(C)c[n+]([O-])c(Cn2cc(C#CCCO)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: COc1c(C)c[n+]([O-])c(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C
Yield: 0.9 %

Procedure:
Crude 2-((4-chloro-5-(4-hydroxybut-1-ynyl)-2-pivalamido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-methoxy-3,5-dimethylpyridine 1-oxide (291 mg) was dissolved in 10 mL EtOH. An aliquot of this solution (2 mL) was further diluted with EtOH (5 mL) and treated with ZnCl2 (103 mg) at 120° C. for 20 min in a microwave oven. Reverse-phase preparative HPLC gave the title compound (2.2 mg), as a solid. HPLC Rt=4.88 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(Cl)(C(Cl)=O)=O.[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])=[O:9])[CH:5]=1
Reactant: CCCNCCC
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.6 %

Procedure:
A suspension of 5-nitro-isophthalic acid monomethyl ester (D77) (1.0 g, 4.44 mmol, 1 equiv) in CH2Cl2 (40 ml) was treated with (COCl)2 (655 mg, 5.2 mmol, 1.2 equiv) followed by a few drops of DMF. The resulting mixture was stirred for 1 h at room temperature and then dipropylamine (1.65 g, 15 mmol, 3.4 equiv) was added and the resulting solution stirred for a further 30 min. The solution was then washed with 2N aqueous HCl solution (50 ml), saturated aqueous NaHCO3 solution (50 ml), dried over MgSO4 and concentrated in vacuo to give 5-nitro-N,N-dipropyl-isophthalamic acid methyl ester (D87) (1.5 g, 110%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[NH:19][C:18]3=[O:27])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:28])[CH3:2].C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[OH-].[Na+]>C(O)(=O)C>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:13]([CH:16]=[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[NH:19][C:18]3=[O:27])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:28])[CH3:30]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCN(CC)CCn1ccc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (150 mg, 0.37 mmol) obtained from Example 1 in 4 ml of acetic acid was added with lead acetate (160 mg, 0.37 mmol) in an ice-water bath the control the temperature at 15° C. Upon the completion of the addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with 1N sodium hydroxide (60 ml) and extracted with five to one solvent mixture of dichloromethane, methanol (40 ml×4). The combined organic extracts were washed with brine (50 ml) and water (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (64 mg, 42.6%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[N:48]=[CH:47][N:46]=[C:45]2[C:41]=1[N:42]=[CH:43][N:44]2[CH2:49][C:50](O)=[O:51])=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:44]1[CH:43]=[N:42][C:41]2[C:45]1=[N:46][CH:47]=[N:48][C:40]=2[NH:39][C:37]([O:36][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:38])[CH3:2]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Yield: 79.9 %

Procedure:
The title compound (2.91 g, 80%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [6-N-(benzhydryloxycarbonyl)-adenin-9-yl]-acetic acid (2.02 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.93 (s, 1H), 9.00 (s, 0.6H), 8.60 (s, 0.4H), 8.59 (s, 0.4H), 8.54 (s, 0.6H), 8.33(d, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 7.69 (m, 2H), 7.52–7.29 (m, 10H), 6.83 (s, 1H), 5.47 (s, 1.2H), 5.37 (s, 0.8H), 4.47 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.03 (q, 1.2H), 3.71 (t, 1.2H), 3.61 (q, 1.2H), 3.49 (t, 0.8H), 3.42 (q, 0.8H), 1.24 (t, 1.2H), 1.13 (t, 1.8H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][OH:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-2].[Mg+4].[O-2]>CC(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(Oc2ccccc2)cn1
Agent: [Mg+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1ccc(Oc2ccccc2)cn1
Yield: 73.6 %

Procedure:
(5-Phenoxy-pyridin-2-yl)-methanol (300 mg, 1.5 mmol) described in Manufacturing Example 121-1-2, magnesium (IV) oxide (1.3 g, 15 mmol), and acetone (10 mL) were stirred under reflux for 20 minutes. More magnesium (IV) oxide (1.5 g, 17 mmol) was then added, which was stirred under reflux for another 20 minutes. The reaction solution was filtered through a Celite pad, and then the filtrate was concentrated under a reduced pressure to obtain the title compound (220 mg, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]([S:24]([CH3:23])(=[O:26])=[O:25])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC1CCCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC1CCCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 3 h

Procedure:
To a suspension of 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.68 g) in methanol (30 mL) was added a solution of methylamine (0.83 g) in methanol (3 mL). The reaction mixture was stirred for 72 hours and then sodium borohydride (0.76 g) and molecular sieves were added. After stirring for 2 hours, the reaction mixture was filtered and the filtrate reduced in vacuo. The residue was re-dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (30 mL), brine (30 mL), dried (MgSO4) and reduced in vacuo to give 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.56 g). To a solution of 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g) in dichloromethane (10 mL) was added triethylamine (0.36 mL) followed by methanesulfonyl chloride (0.20 mL). After stirring for 3 hours the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 2-[(methanesulfonyl-methyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (0.63 g). Treatment of this compound with HCl in dichloromethane/methanol yielded N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide hydrochloride (0.49 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]4[C:17]=3[CH2:18][CH2:19][CH2:20]4)[CH:12]=[CH:11][C:10]=2[O:29][CH3:30])=[CH:6][CH:7]=1.C([O-])(=[O:33])C.[Na+]>C(O)(=O)C>[CH3:30][O:29][C:10]1[CH:11]=[CH:12][C:13]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:14][C:9]=1[CH2:8][C:5]1[CH:6]=[CH:7][C:2](=[O:33])[NH:3][N:4]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1Cc1ccc(Cl)nn1
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1Cc1ccc(=O)[nH]n1
Reaction time: 0.5 h
Yield: 284.7 %

Procedure:
A suspension of 3-chloro-6-[2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzyl]pyridazine (760 mg) and sodium acetate (50 mg)in acetic acid (10 mL) was heated at reflux temperature under an argon atmosphere for 2 hours. The reaction mixture was evaporated under reduced pressure to dryness. After adding water (15 mL), the residue was stirred for 30 min. The mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 6-[2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzyl]-2H-pyridazine-3-one (707 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=O)[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[O:32])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)O)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)N5CCN(C)CC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
1-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-4-carboxylic acid and 1-methylpiperazine are used as reactants. Tetrahydrofuran is used instead of N,N-dimethylformamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9]O)=[C:6]([Cl:8])[N:7]=1.S(Cl)([Cl:15])=O>>[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][Cl:15])=[C:6]([Cl:8])[N:7]=1
Reactant: N#Cc1nc(CO)c(Cl)nc1N
Reactant: O=S(Cl)Cl
Product: N#Cc1nc(CCl)c(Cl)nc1N

Procedure:
A suitable method of synthesizing 7-NR1R2 -MTX wherein either both R1 and R2 are hydrogen, or one is hydrogen and the other is C1 -C5 alkyl, is outlined in FIGS. 1A and 1B. A suitable method of synthesizing 7-NR1R2 -MTX wherein both R1 and R2 are hydrogen comprises (a) reacting phosphorus oxychloride with 3-amino-6-(chloromethyl)-2-pyrazinecarbonitrile 4-oxide (1) to yield 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile (2); (b) reacting 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile with thionyl chloride to form 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile (4); (c) reacting 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile with ethyl 4-methylaminobenzoate (3) to form ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate (5); (d) reacting ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate with guanidine to form 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate (6); (e) reacting 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate with ammonia to form 4-[N-(2,4,7-triamino-6-pteridinylmethyl)-N-methylamino]benzoic acid (7a); and (f) coupling 4-[N-(2,4,7-triamino-6-pteridinylmethyl)-N-methylamino]benzoic acid and diethyl L-glutamate hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:12]=[N+]=[N-])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[H][H]>CO.[Pt]=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:10])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(C)N=[N+]=[N-])cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COc1ccc(C(C)(C)N)cc1

Procedure:
1.58 g of platinum oxide were added to a solution of 21.0 g of 1-(4-methoxyphenyl)-1-methylethyl azide [prepared as described in step (a) above] in 100 ml of methanol. The reaction mixture was then stirred for 5 hours under a stream of hydrogen. At the end of this time, the mixture was filtered, diluted with methylene chloride, and washed with an aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure, to give 17.2 g ¢yield 95%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CC1C=CC(S(O[CH2:21][CH2:22][CH2:23][C:24]2[C:32]3[C:27](=[C:28]([C:33]4[N:37]=[C:36]([C:38]5[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:47])[CH3:46])=[C:40]([Cl:48])[CH:39]=5)[O:35][N:34]=4)[CH:29]=[CH:30][CH:31]=3)[N:26]([CH3:49])[CH:25]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:48][C:40]1[CH:39]=[C:38]([C:36]2[O:35][N:34]=[C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:27]=3[N:26]([CH3:49])[CH:25]=[C:24]4[CH2:23][CH2:22][CH2:21][O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:37]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH:45]([CH3:46])[CH3:47]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)cc1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a stirred solution of ethyl hydroxyacetate (90 mg) in DMF (4 mL) at 20° C. was added NaH (69 mg), the mixture was stirred for 15 mins. Then a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propyl 4-methylbenzenesulfonate (D129) (100 mg) in DMF (4 mL) was added dropwise during 1 min. The reaction was stirred at 20° C. for 48 h. The reaction mixture was quenched with water, partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with water and brine, dried over sodium sulphate and evaporated to give the crude product ethyl ({3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propyl}oxy)acetate (D105) (80 mg). MS (ES): C27H30ClN3O5 requires 511; found 512.2 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:7])[CH3:6].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[C:5]([C:8]1[CH:9]=[C:10]([N+:1]([O-:4])=[O:2])[C:11]([O:18][CH3:19])=[C:12]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)=O)c2c1CCCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1c([N+](=O)[O-])cc(C(C)=O)c2c1CCCC2
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
A solution of 100% nitric acid (0.42 ml, 10 mmol) in 2 ml of acetic anhydride was added dropwise with stirring at <10° to <15° C. to a solution of 8-acetyl-1,2,3,4-tetrahydro5-methoxynaphthalene (2.1 g, 10 mmol) in 25 ml of acetic anhydride containing one drop of conc. sulfuric acid. Stirring was continued for 20 min. at the same temperature, then the reaction mixture was poured into 100 ml of icewater. The precipitated crystals were collected by filtration and washed with water and a small amount of cold ethanol to give 1.48 g (59%) of the title compound. M.p. 76°-77° C.; 1H-NMR (CDCl3) 1.60-1.93 (m, 4H, 2CH2), 2.57 (s, 3H, COCH3), 2.67-3.13 (m, 4H, 2CH2), 3.88 (s, 3H, OCH3), 7.97 (s, 1H, H-7).