Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[ClH:1].[CH3:29][S:30]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:35]=1)(=[O:31])=[O:32]
Reactant: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Product: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5ccc(CS(C)(=O)=O)cc5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(4-methyl-benzyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) as a white solid (141 mg, 97%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.21 (s, 1H), 7.76-7.79 (M, 3H), 7.50 (br s, 1H), 7.22-7.30 (m, 5H), 7.09-7.14 (M, 3H), 6.86 (d, J=8.4 Hz, 1H), 5.64 (d, J=6.0 Hz, 1H), 4.55 (d, J=5.4 Hz, 2H), 4.34 (s, 2H), 3.58 (s, 3H), 3.43 (s, 3H), 2.85 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z=542 [M+H].
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[C:3]#[N:4].[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C1COCC1.C(OCCCC)CCC.CO>[CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH:3]([NH2:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C#N)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C(N)c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-2-(1-pyrrolidinyl)propanenitrile D4 (40 g; 289.85 mmol) in dry THF (0.8 L) under nitrogen, cooled at −78° C., was added dropwise a solution of phenyl lithium in dibutyl ether over 40 minutes (305.1 mL of a 1.9M solution; 579.70 mmol). After 2 h the reaction was allowed to reach room temperature and then stirred overnight at this temperature. The mixture was quenched at 0° C. with a saturated solution of NaHCO3 (0.8 L) and stirred for 15 minutes and diluted with water (ca. 0.6 L). The phases were separated and the aqueous back extracted with diethylether (2×1 L). The collected organics were dried over Na2SO4 and evaporated in vacuo to get 90 g of crude material as a yellow oil that was dissolved in methanol (1 L) at 0° C. and treated portionwise with sodium borohydride (21.93 g; 579.70 mmol). After 1 hour at 0° C. and then overnight at room temperature the mixture was cooled and quenched with water (ca. 0.5 L). Methanol was evaporated in vacuo and the aqueous phase, diluted with water (200 mL), was extracted with DCM (3×800 mL). The collected organics were dried over Na2SO4 and evaporated in vacuo to get the title product (51 g) as a yellow solid, used in step 2 without further purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[O:15]=[C:16]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][N:17]1[CH2:33][C:34](O)=[O:35].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:34](=[O:35])[CH2:33][N:17]3[CH2:18][CH2:19][C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:16]3=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(4-fluorobenzyl)piperazine (0.081 g, 0.416 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.165 g, 0.436 mmol) and 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.135 g, 0.457 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (0.109 mL, 0.623 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated and loaded onto a silica gel column (Analogix® SF25-25) and eluted with a gradient of 5% to 100% ethyl acetate/hexanes to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.20-7.37 (m, 12H), 6.97-7.04 (m, 2H), 4.18 (s, 2H), 3.59 (t, J=4.7 Hz, 2H), 3.51 (t, J=6.5 Hz, 2H), 3.44 (s, 2H), 3.39-3.44 (m, 2H), 2.81 (t, J=6.5 Hz, 2H), 2.38 (t, J=4.9 Hz, 2H), 2.28-2.32 (m, 2H); MS (ESI+) m/z 472 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:6]2[O:11][CH:10]=[CH:9][C:7]=2[N:8]=1.ClC1N=C(Cl)C2[O:27][CH:26]=[CH:25]C=2N=1.N1CCNCC1.C(Cl)(=O)C>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:26](=[O:27])[CH3:25])[CH2:14][CH2:13]2)[C:6]2[O:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: Clc1nc(N2CCNCC2)c2occc2n1
Agent: C1CNCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CC(=O)N1CCN(c2nc(Cl)nc3ccoc23)CC1
Temperature: 35 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a flask was added 2-chloro-4-(piperazin-1-yl)furo[3,2-d]pyrimidine, hydrochloride salt (0.325 g, 1.18 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [Ark Pharm] with piperazine), DMF (10 mL), TEA (0.543 mL, 3.90 mmol) and acetyl chloride (0.185 mL, 2.60 mmol). The mixture was warmed to about 35° C. and stirred overnight. The mixture was cooled to rt and diluted with DCM (50 mL). The organic layer was washed with water (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, filtered, concentrated in vacuo and dried in a vacuum oven at about 40° C. to give 1-(4-(2-chlorofuro[3,2-d]pyrimidin-4-yl)piperazin-1-yl)ethanone (0.214 g, 64%): LC/MS (Table 2, Method a) Rt=1.04 min; MS m/z 281.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])#[CH:20].C1(C)C=CC=CC=1>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:19]#[C:20][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C#Cc1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1nc(C#Cc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
6-Chloro-3-nitro-pyridin-2-ylamine (1254 g, 7.23 mol), triethylamine (1510 mL, 10.84 mol) and acetonitrile (10 L) are charged into a 20 L, 4-neck round bottom flask equipped with a mechanical stirrer under nitrogen. To the resulting yellow suspension, copper(I) iodide (13.9 g, 72.3 mmol) and bis(triphenylphosphine)palladium (II) chloride (50.72 g, 72.3 mmol) are added. The resulting pale orange suspension is cooled to 0-5° C. and then degassed during 10 min with nitrogen. A solution of 1-ethynyl-2,4-difluoro-benzene (1100 g, 7.95 mol) dissolved in acetonitrile (2.5 L) is added dropwise during 60 min. The resulting mixture is left stirring at RT (30° C.) overnight. The mixture is cooled to 0-5° C. Toluene (6 L) is added to the suspension and the mixture is stirred for 45 min and filtered though a frit. The solid is washed with toluene (3×3 L), water (2×3 L) and is dried overnight in a vacuum oven, to obtain the title compound as a yellow solid (1750 g, 92%). LC-ES/MS m/z 276 (M+1).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:12]=O.C([CH2:29][C:30]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=[O:36])=[O:31])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:29]/[C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])=[O:31])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCCCC#CCCOc1ccc(C=O)cc1OC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCCCC#CCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 79.1 %

Procedure:
Piperidine (95 μL, 0.96 mmol) was added to a suspension of 3-methoxy-4-(oct-3-ynyloxy)benzaldehyde (0.25 g, 0.96 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.20 g, 0.90 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(3-methoxy-4-(oct-3-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.30 g, 79%) as a colourless crystalline solid; mp 169-170° C.; δH (400 MHz, DMSO-d6) 0.85 (t, J=7.2 Hz, 3H, CH3), 1.31-1.42 (m, 4H, CH3CH2CH2), 2.13 (t, J=7.2 Hz, 2H, CH2), 2.60 (t, J=7.2 Hz, 2H, CH2CH2O), 3.83 (s, 3H, OCH3), 4.05 (t, J=7.2 Hz, 2H, OCH2), 6.76 (d, J=15.6 Hz, 1H, CH═CHCO), 7.00 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.15 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.37 (d, J5′,6′=1.6 Hz, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.30 (s, 1H, NH), 13.55 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 13.4, 17.7, 19.2, 21.3, 30.4, 55.7, 67.0, 76.7, 81.6, 110.9, 113.0, 116.7, 120.1, 120.3, 122.5, 122.6, 127.6, 131.1, 133.9, 141.0, 141.5, 149.1, 149.5, 164.1, 169.4; HRMS (ESI) calculated for C25H27NO5 [M+H]+ 421.1962. found 421.1962; vmax 757, 1143, 1220, 1514, 1601, 1652, 1690, 2939 cm−1.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=1.[OH-].[Na+].O.CO>O1CCCC1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:15])=[O:2])[CH:11]=[CH:10][C:9]=1[CH3:12]
Reactant: COC(=O)C=Cc1ccc(C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=CC(=O)O)ccc1C
Temperature: 50 °C
Yield: 93.2 %

Procedure:
A mixture of 3-methoxy-4-methylbenzaldehyde (19.3 g, 0.129 mol), carbomethoxy methylene triphenylphosphorane (51 g) in toluene (250 ml) was refluxed for 24 h. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate and concentrated in vacuo to give a residue. The residue was purified by flash chromatography using ethyl acetate-heptane (1:1) to give 3-(3-methoxy-4-methyl-phenyl)acrylic acid methyl ester (27 g, 0.126 mol). A mixture of 3-(3-methoxy-4-methylphenyl)acrylic acid methyl ester (27 g), sodium hydroxide (14 g), water (70 ml), methanol (140 ml) and tetrahydrofuran (70 ml) was refluxed at 50° C. for 1 h. The mixture was concentrated in vacuo and then water added. The mixture was filtered and 5 M HCl was added until precipitation occurred. The mixture was filtered and the solid precipitate washed with water and dried in-vacuo to give 3-(3-methoxy-4-methylphenyl)acrylic acid (23.5 g, 0.122 mol).
Reaction SMILES: [C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:17][O-:18].[Na+]>CO>[C:1]([NH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[O:18][CH2:17]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC=Cc1ccc(OC(C)=O)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC=Cc1ccc(OCC2CO2)cc1
Temperature: 50 °C

Procedure:
13.0 g (0.05 mol) of p-(2-acetylaminovinyl)-acetoxybenzene are suspended in 100 ml of absolute methanol, a solution of 2.8 g (0.05 mol) of sodium methoxide in 20 ml of absolute methanol is added and thereafter the mixture is warmed to 50° C. for 15 minutes. It is then evaporated to dryness in vacuo. The resulting crude phenolate of p-(2-acetylaminovinyl)-phenol is heated with 65 ml of epichlorohydrin to the boil for 18 hours, under a reflux condenser and whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and ethyl acetate and the organic phase is siphoned off, dried over sodium sulphate and evaporated. After crystallisation of the crude product, thus obtained, from acetone-ether, 1-[p-(2-acetylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 135°-137° C. is obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[N:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14]([CH3:17])=[CH:15][CH:16]=1>ClCCCl>[CH3:17][C:14]1[N:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:12]([CH3:11])=[CH:16][C:15]=1[CH:8]=[O:9]
Reactant: COC(=O)Cn1c(C)ccc1C
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)Cn1c(C)cc(C=O)c1C

Procedure:
17 ml (0.18 mol) of phosphorus oxychloride, 14 ml (0.18 mol) of anhydrous dimethylformamide and 30 g (0.18 mol) of methyl (2,5-dimethyl-pyrrol-1-yl)-acetate are reacted in 140 ml of 1,2-dichloroethane as described above.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2C=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COP([C:39](=[CH2:44])[C:40]([O:42][CH3:43])=[O:41])(OC)=O.[C:45]([O-])([O-])=O.[Cs+].[Cs+].C([O-])(=O)C=C>CN(C=O)C.C(OCC)(=O)C>[C:40]([C:39]1[CH2:44][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:8]2=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:15]3[CH:14]=[CH:13][C:12]([C:16]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[O:17])=[CH:11][C:10]=3[N:9]2[CH:45]=1)([O:42][CH3:43])=[O:41]
Reactant: C=C(C(=O)OC)P(=O)(OC)OC
Reactant: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: C=CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cn2c(c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)C)cc32)-c2ccccc2C1
Reaction time: 8 h
Yield: 58.4 %

Procedure:
A mixture of 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formylphenyl)-1H-indole-6-carboxamide (1.06 g, 2.1 mmol), methyl 2-(dimethoxyphosphoryl)acrylate (0.4 mL, 3.2 mmol), and Cs2CO3 (1.04 g, 3.2 mmol) in DMF (4 mL) was stirred at 60° C. for 18 hr, at which time additional Cs2CO3 4 g, 0.32 mmol) and methyl dimethoxyphosphoryl)acrylate (0.4 mL, 3.2 mmol) were added. The mixture was stirred for an additional 8 hr, cooled and diluted with ethyl acetate. The resulting mixture was washed with dilute HCl (3×) followed by brine (3×). The solution was concentrated to leave the crude product as a yellow solid (1.2 g). The crude product was purified utilizing a Biotage apparatus with a prepacked silicic acid column and using gradients of hexanes: ethyl acetate:acetic acid of from (100:2:.0.5) to (64:36:0.5). The product containing fractions were combined and concentrated to dryness to afford the titled compound as a pale yellow solid (640 mg, 59%). MS m/z 522 (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:27])[CH2:5][C:6]1[N:17](S(C2C=CC=CC=2)(=O)=O)[C:9]2=[N:10][CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1.O.C(OCC)(=O)C>C1COCC1>[CH3:3][N:4]([CH3:27])[CH2:5][C:6]1[NH:17][C:9]2=[N:10][CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1
Reactant: CN(C)Cc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 70 °C
Yield: 81.1 %

Procedure:
Sodium hydroxide (1.11 mL, 1.11 mmol, 1M in water) was added to a solution of N,N-dimethyl-1-(5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanamine (0.10 g, 0.28 mmol) in THF (1.5 mL). The reaction mixture was heated at 70° C. for 16 hours. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were then separated. The aqueous layer was extracted once with ethyl acetate. The organic layers were dried over sodium sulfate, filtered, and evaporated to afford N,N-dimethyl-1-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)methanamine (0.05 g, 82%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH2:21][C:22]([CH3:58])([CH3:57])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][CH:39]=3)[C:33]([CH2:52][CH2:53][CH3:54])=[N:32][C:31]=2[CH2:55][CH3:56])=[CH:26][CH:25]=1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[CH2:55]([C:31]1[N:32]=[C:33]([CH2:52][CH2:53][CH3:54])[N:34]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[C:50]3[NH:3][C:4](=[O:7])[O:5][N:51]=3)=[CH:42][CH:43]=2)[C:35](=[O:36])[C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:22]([CH3:58])([CH3:57])[CH2:21][OH:20])=[CH:25][CH:26]=1)[CH3:56]
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)c(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)(C)CO)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogen carbonate (1.31 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C. for 30 min, 4′-{[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.99 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (12 mL). N,N′-carbonyldiimidazole (0.38 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride tetrahydrofuran solution (1 mol/L, 2.6 mL) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated from the reaction mixture under reduced pressure. The residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.38 g, 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][C:36]1[O:40][C:39](B(O)O)=[CH:38][CH:37]=1.C>COCCOC.O.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.C(OCC)(=O)C>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:39]4[O:40][C:36]([CH3:35])=[CH:37][CH:38]=4)=[C:3]([F:28])[CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: Cc1ccc(B(O)O)o1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)c(F)c1
Temperature: 25 °C

Procedure:
A stirred suspension of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-3-fluorobenzenesulfonamide (3.4 g, 7.2 mmol) in 1,2-dimethoxyethane (80 ml) was treated with a solution of sodium carbonate (3.8 g, 36 mmol) in water (20 ml). (5-Methyl-2-furanyl)boronic acid (1.4 g, 10.8 mmol) and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.2 mol %) were added with some water and the mixture was stirred at reflux for 3 hours. Additional (5-methyl-2-furanyl)boronic acid (420 mg, 3.3 mmol) was added and the mixture was heated at reflux for a further 30 minutes. After cooling to room temperature, ethyl acetate (50 ml), water (50 ml) and charcoal (3 g) were added and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered through celite, the ethyl acetate layer separated and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate extracts were combined washed with water and brine dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography on a 100 g column eluting with 1:40 to 1:10 2M ammonia in methanol: dichloromethane. Residue was then triturated in ether, dissolved in ether/pentane and evaporated. Residue was then triturated in pentane, washed in pentane, air dried and then dried at 50° C. under argon and high vacuum to give the title compound (E248). MS (ES+) m/e 474 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:11])[O:7][CH2:8][C:9]#[CH:10])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[I-:14].[Na+].ClCl>O.CO>[CH2:1]([NH:5][C:6](=[O:11])[O:7][CH2:8][C:9]#[C:10][I:14])[CH2:2][CH2:3][CH3:4]
Reactant: C#CCOC(=O)NCCCC
Reactant: [I-]
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCNC(=O)OCC#CI
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
At 5° C., 19.0 g of propargyl butylcarbamate (0.122 mol), 12.2 g of sodium hydroxide (0.305 mol) and 18.5 g of sodium iodide (0.123 mol) are introduced as initial charge in 50 g of water and 48 g of methanol. Chlorine (11.7 g, 0.165 mmol) is then slowly introduced so that the temperature remains below 5° C. When the metered addition is complete, the mixture is stirred at this temperature for 1 h, then slowly heated to room temperature and stirred for 1 hour. After adding 100 g of water, the precipitated solid is isolated by filtration, washed with water and dried in vacuo. This gives 29.1 g of 3-iodo-2-propynyl N-butylcarbamate (purity: 94.7% (HPLC), polyiodized compounds: <0.1% (HPLC), yield: 80%).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C1COCC1>[C:26]([O:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[NH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=NOC(C)=O
Temperature: 0 °C
Yield: 89.3 %

Procedure:
A solution of 0.8 g (3.3 mmol) of methyl 3-(hydroxyiminomethyl)-4,7-dimethylindole-2-carboxylate in 15 ml of anhydrous THF was cooled to 0° C., and then 0.5 ml (3.6 mmol) of triethylamine was added. While the reaction mixture was stirred at 0° C., a solution of 0.25 ml (3.6 mmol) of acetyl chloride in 5 ml of THF was added dropwise over a period of 15 minutes. The reaction mixture was stirred at room temperature for 1 hour and then poured into 100 ml of ice water. The crystals were separated by filtration and dried to provide 0.85 g of yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]#[N:17])[C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]#[N:17])[C:13]=1[O:14][CH3:15])[C:8]([Cl:27])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C#N)cc(C(=O)O)cc1C(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C(C)(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-t-butyl-5-cyano-4-methoxybenzoic acid (586 mg), toluene (10 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.27 mL) was added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (630 mg) as a brown oily substance.