Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([CH:18]=O)[C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][OH:28])=[NH:26])=[CH:23][CH:22]=1.C([N+]#[C-])C1C=CC=CC=1>>[C:9]([O:8][C:6]([CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:16][C:15]([Cl:17])=[CH:14][C:13]=1[CH:18]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=[NH:26])[NH:27][OH:28])=[CH:23][CH:22]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: N=C(NO)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)COc1c(Cl)cc(Cl)cc1C=O
Agent: [C-]#[N+]Cc1ccccc1
Product: COC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(Cl)cc(Cl)c1OCC(=O)OC(C)(C)C

Procedure:
In analogy to Example 1.1., tert-butyl (2,4-dichloro-6-formyl-phenoxy)-acetate was reacted with 4-amino-N-hydroxybenzamidine and benzyl isonitrile. There was obtained methyl (RS)-(2-tert-butoxycarbonylmethoxy-3,5-dichloro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate; MS (ISP) m/z 498.2 (M+H)+, 520.2 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[C-]#N.[Na+]>CCO.O>[OH:8][CH:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:7]([C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:8]
Reactant: COc1ccc(C=O)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Yield: 65.4 %

Procedure:
To a stirred solution of 4-methoxybenzaldehyde (2 g, 14.6 mmol) in EtOH (50 mL) was added a solution of NaCN (0.8 g, 16.3 mmol) in water (5 mL) and the reaction mixture was refluxed for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and then concentrated in vacuo to yield a crude material which was purified via silica gel column chromatography eluting with 40% EtOAc in hexanes to afford 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone (1.3 g, 65%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH2:1])=[CH:11][CH:10]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CN)cc1
Yield: 92 %

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (300 g, 1.98 mol) in methanol (5 L) was added thionylchloride (473 g 3.97 mol). The reaction mixture was refluxed for 6 h, followed by the removal of the solvent under reduced pressure to obtain the crude product. The crude was purified by acid-base work up to afford methyl-4-(aminomethyl)benzoate (300 g, 92%) as a liquid.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.N1C=CC=CC=1.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>ClC(Cl)C.ClCCl>[O:7]=[C:6]1[NH:8][C@@H:9]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:21][O:22]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C(C[C@H]1COC(=O)N1)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of the alcohol (95.7 g) from Step 7 in dichloroethane (925 mL) was added pyridine (625 mL) and the mixture was cooled to 0-5° C. Anhydrous p-toluenesulfonic anhydride (105.7 g) was added and the mixture was warmed to room temperature and stirred for 1 hour and then heated to 90° C. for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 mL) and washed with 1N HCl (3×600 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes in a 1:1 ratio followed by ethyl acetate to yield benzyl [(4S)-2-oxo-1,3-oxazolidin-4-yl]acetate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[I:21]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[C:15]([I:21])[CH:16]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: Clc1ccc(CBr)c(I)c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2I)c1

Procedure:
1-(4-Chloro-2-iodo-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 1-Bromomethyl-4-chloro-2-iodo-benzene following General Procedure A.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][CH:10]=3)[CH2:3]2)=[O:28])=[CH:22][CH:21]=1
Reactant: OC1CCN(CCc2c[nH]c3ccccc23)C1
Reactant: COc1ccc(N=C=O)cc1
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)OC2CCN(CCc3c[nH]c4ccccc34)C2)cc1

Procedure:
A stirred suspension of 3.5 g. (0.015 mole) of 3-[2-(3-hydroxypyrrolidinyl)ethyl]indole in 50 ml. of dry benzene was treated dropwise with 2.3 g. (0.015 mole) of p-methoxyphenylisocyanate in 15 ml. of dry benzene. After addition (0.5 hour) the mixture was refluxed for 12 hours after which time only a small amount of solid remained suspended. The residue was filtered off and the filtrate was evaporated under vacuum to an orange gum. The product was dissolved in benzene and chromatographed on 200 g. of 60-100 mesh magnesium silicate, eluting first with benzene then benzene with increasing amounts of acetone. At 20% acetone-benzene pure product was obtained from the column; yield 3.5 g. (60%). The glassy solid would not crystallize.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])[CH:18]=1
Reactant: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2cccnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 12.1 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (0.350 g, 2.4 mmol), 5-methyl-2-nitro-benzenesulfonyl chloride (Intermediate 449) (0.86 g, 3.6 mmol), pyridine (1 ml) DMAP (cat) and DCM (5 ml) gave the title compound (100 mg, 12%) after purification by column chromatography with n-hexane/EtOAc (10:90) as the eluent. The structure was confirmed by 1H NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][C:16]([CH3:23])([CH3:22])/[CH:17]=[CH:18]/[C:19]([Cl:21])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:21].[CH3:15][C:16]([CH3:23])([CH3:22])/[CH:17]=[CH:18]/[C:19]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: CC(C)(C)/C=C/C(=O)Cl
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
To a solution of (E)-4,4-dimethyl-2-pentenoic acid (Gream, G. E.; Serelis, A. K. Aust. J. Chem. 1978, 31, 863) (200 mg, 1.6 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-4,4-dimethyl-2-pentenoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (150 mg, 0.81 mmol) and (E)-4,4-dimethyl-2-pentenoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate yielded the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>CO.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([C@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(COc1ccccc1)N1CCCC[C@@H]1c1nc(-c2cccc([N+](=O)[O-])c2)n[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cccc(-c2n[nH]c([C@H]3CCCCN3C(=O)COc3ccccc3)n2)c1
Reaction time: 0.5 h

Procedure:
(R)-1-{2-[5-(3-Nitro-phenyl)-2H-[1,2,4]triazol-3-yl]-piperidin-1-yl}-2-phenoxy-ethanone were dissolved in 100 ml MeOH. 50 ml sat. NH4Cl and Zn-powder were added. The suspension was briefly heated to reflux and stirred for 30 min. After filtration the MeOH was evaporated and the product isolated via extraction ethylacetate/water.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:3]=1.C(N(CC)CC)C.[CH3:35][C:36]1([CH3:43])[C:40]([CH3:42])([CH3:41])[O:39][BH:38][O:37]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([N:11]4[CH2:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH2:12]4)[C:10]=3[C:2]([B:38]3[O:39][C:40]([CH3:42])([CH3:41])[C:36]([CH3:43])([CH3:35])[O:37]3)=[CH:3]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(N4CCCC(C)C4)ncnc32)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3c(N4CCCC(C)C4)ncnc32)cc1
Temperature: 95 °C

Procedure:
5-Bromo-7-[(4-methylphenyl)sulfonyl]-4-(3-methylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (racemic version of C15, see Example 7) (1.44 g, 3.20 mmol) was added to a solution of triethylamine (1.3 g, 13 mmol) in 1,4-dioxane (15 mL). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.64 g, 12.8 mmol) was then slowly added, and the mixture was degassed by bubbling nitrogen through it for 5 minutes. 2-Dicyclohexylphosphino-2′,6′-triisopropylbiphenyl (XPhos, 137 mg, 0.287 mmol) and tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.160 mmol) were then introduced, and the reaction mixture was heated at 95° C. for 18 hours. After cooling, the mixture was filtered through cotton and the filtrate was concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 75% ethyl acetate in heptane) afforded the product as a solid. Yield: 1.25 g, 2.52 mmol, 79%. 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.10 (br d, J=8.4 Hz, 2H), 7.95 (s, 1H), 7.30 (brd, J=8.6 Hz, 2H), 4.28 (brd, J=13 Hz, 1H), 4.18-4.24 (m, 1H), 2.99 (ddd, J=13, 11, 4 Hz, 1H), 2.70 (dd, J=12.9, 10.9 Hz, 1H), 2.40 (s, 3H), 1.77-1.85 (m, 1H), 1.56-1.70 (m, 4H), 1.35 (s, 12H), 0.88 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH2:11])[CH2:5]2.[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH:20]=O)([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)Cl>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][CH2:20][CH2:19][NH:18][C:17](=[O:22])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]2
Reactant: NC1Cc2ccc(Br)cc2C1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-Bromo-2,3-dihydro-1H-inden-2-amine (0.21 g, 1.0 mmol) in 16 mL of DCM/MeOH (7/1, v/v) was added tert-Butyl(2-oxoethyl)carbamate (160 mg, 1.0 mmol) and NaBH(OAc)3 (297 mg, 1.4 mmol), and the mixture was stirred at RT for 3 hours. DCM was added to the mixture, and then washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give the title product.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:7]=[C:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH3:4].[O:33]([C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]Br)[C:34]([CH3:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:48]([O:47][C:45](=[O:46])[C:44]1[CH:43]=[CH:42][C:39]([CH2:40][N:11]([CH2:10][C:9]2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:7][C:8]=2[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:38][C:37]=1[O:33][C:34](=[O:35])[CH3:36])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(=O)Oc1cc(CBr)ccc1C(=O)OC(C)(C)C
Reactant: CCCCn1c(-c2ccccc2)nc(-c2ccc(OC)cc2)c1CNCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1c(-c2ccccc2)nc(-c2ccc(OC)cc2)c1CN(Cc1ccc(C(=O)OC(C)(C)C)c(OC(C)=O)c1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amine (4.0 g, 9.31 mmol) and 3-acetoxyl-4-tert-butoxycarbonyl-benzyl bromide (3.37 g, 10.24 mmol, 1.1 eq.) in 50 ml anhydrous acetonitrile is added anhydrous potassium carbonate (2.82 g, 20.5 mmol, 2.2 eq.), the resulting mixture is stirred at room temperature for 1 h, then raised to 50° C., stirred overnight. The solid precipitate is filtered off, washed with ethyl acetate, the combined organics is concentrated to dryness, purified through silica gel flash chromatography to give 3.99 g of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]cyclohexylmethyl-amino}-methyl)-2-acetoxy-benzoic acid tert-butyl ester MS (+VE) m/z 680 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C.O.C([O-])(O)=O.[Na+]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2
Reactant: CCOC(=O)C(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)c1cc2cc(N)ccc2[nH]1
Temperature: 120 °C
Yield: 99.7 %

Procedure:
To a solution of ethyl 2-(5-nitro-1H-indol-2-yl)propanoate (0.10 g, 0.38 mmol) in ethanol (4 mL) was added tin chloride dihydrate (0.431 g, 1.91 mmol). The mixture was heated in the microwave at 120° C. for 1 h. The mixture was diluted with ethyl acetate before water and saturated aqueous NaHCO3 were added. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give ethyl 2-(5-amino-1H-indol-2-yl)propanoate (0.088 g, 99%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C@@H:19]([CH3:20])[CH2:18][NH:17][CH2:16][C@@H:15]2[CH3:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C@@H:19]([CH3:20])[CH2:18][N:17]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:16][C@@H:15]2[CH3:21])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CNC[C@H](C)N1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ncccc2Cl)C[C@H](C)N1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 27.7 %

Procedure:
To a solution of (2S,6S)-1-[(4-tert-butylphenyl)sulfonyl]-2,6-dimethylpiperazine (120 mg, 0.39 mmol) and 2,3-Dichloropyridine (115 mg, 0.78 mmol) in anhydrous 1,4-Dioxane (0.2 mL) was added diisopropylethylamine (0.201 mL, 1.16 mmol). The mixture was subject to microwave irradiation at 200° C. for 1 hour. Reaction was half complete as determined by TLC. The reaction mixture was diluted with ethyl acetate and washed with saturated NH4Cl (aq.), 10% HCl (aq.), water and brine. Organic layer was dried over MgSO4. Solvent evaporation followed by flash column chromatography afforded (2S,6S)-1-[(4-tert-butylphenyl)sulfonyl]-4-(3-chloropyridin-2-yl)-2,6-dimethylpiperazine in 27.7% yield (45 mg) as off white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:37]([O:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]([C:45]([O:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:46])[CH2:9][CH:10]([OH:29])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CNCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOCC(O)CN(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
21.4 g of 3-benzylamino-1-hexadecyloxy-propan-2-ol are dissolved in 100 cc. of anhydrous chloroform. At first 5.4 g of triethylamine and then a solution of 9 g of chloroformic acid benzyl ester in 50 cc. of chloroform is added dropwise with cooling and the mixture is stirred for 3 hours. The chloroform solution is washed with 5% hydrocholoric acid and water, dried over sodium sulfate, evaporated and the residue is purified by column chromatography (silicic acid gel//chloroform).
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.[CH3:19][O:20][C:21]([CH:23](P(OC)(OC)=O)[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22].CN(C)C(=N)N(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([CH:55]=[C:56]([Cl:58])[CH:57]=1)[CH:53]=O>C1COCC1>[CH2:28]([O:27][C:25]([NH:24]/[C:23](=[CH:53]\[C:52]1[CH:51]=[C:50]([Cl:49])[CH:57]=[C:56]([Cl:58])[CH:55]=1)/[C:21]([O:20][CH3:19])=[O:22])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cc(Cl)cc(Cl)c1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 85.6 %

Procedure:
Step BF (1): To a slurry of N-(Benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester (76.37 g, 230.5 mmol) in THF (210 mL) just thawed from a −78° C. bath was added tetramethylguanidine (28.85 mL, 230.0 mmol) dropwise. A cold solution of 3,5-dichlorobenzaldehyde (36.70 g, 209.7 mmol) in THF (52.5 mL) was added via cannula. The cold yellow solution was stirred for 1 hour, at which time TLC revealed no aldehyde remained. The THF was removed in vacuo, and EtOAc and 1M HCl was added. The mixture was extracted three times into EtOAc, and the combined organic layers were washed with water, brine, and then dried over MgSO4. Concentration in vacuo followed by recrystallization of the desired olefin isomer from EtOAc/hexane yielded pure product. Concentration of the mother liquor and recrystallization of the residue yielded, over 4 crops, 68.22 g (86% yield) of (Z)-methyl 2-(benzyloxycarbonylamino)-3-(3,5-dichlorophenyl)acrylate. 1H NMR (500 MHz, CDCl3) δ 7.28-7.42 (m, 7H) 7.16 (s, 2H) 6.55 (s, 1H) 5.10 (s, 2H) 3.79-3.90 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li]CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: C=Cc1ccccc1
Agent: [Li]CCCC
Product: Fc1ccc(N2CCN(CCc3ccccc3)CC2)cc1

Procedure:
According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and 2.22 mmol (=0.23 g=0.25 ml) of styrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (3:1) gives the product 1-(4-fluorophenyl)-4-(2-phenyl-1-ethyl)piperazine as a light-brown solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:6]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:16]=[CH:15][C:7]=2[N:8]=[C:9]([NH:11]C(=O)C)[N:10]=1>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:16]=[CH:15][C:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:5]([O:2][CH3:1])[C:6]=3[N:18]=2)=[CH:24][CH:23]=1
Reactant: CC(=O)Nc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
Sodium methoxide (0.32 mL, 0.158 mmol; 0.5 N in MeOH) was added to a solution of N-[4-chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-yl]-acetamide (20 mg, 0.063 mmol) in THF (1.5 mL). After stirring at room temperature for 20 minutes, solvents were concentrated in vacuo and the residue was purified by RP HPLC using a C18 column with a gradient of H2O and 0.1% TFA-acetonitrile, to provide the pure title compound as a white solid (14 mg, yield 50%) which was characterised as follows: MS (m/z) 271.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[NH2:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(N)ccc1O
Reaction time: 8.5 h

Procedure:
A mixture of 5-aminosalicylic acid (15 g), absolute ethanol (250 ml) and concentrated sulphuric acid (7.5 ml) was boiled under reflux with stirring for 8.5 hours. The reaction mixture was evaporated to dryness. Water (20 ml) was added to the residue and the mixture filtered. The filtrate was basified with saturated bicarbonate solution and the solid collected by filtration. The solid was extracted into dichloromethane and the extract evaporated to dryness. The residue was triturated with petroleum ether b.p. 40°-60° C. and filtered to give ethyl 5-aminosalicylate, m.p. 44° C.
Reaction SMILES: O.[SH-].[Na+:3].C([S:11]([C:14]1[N:19]=[C:18]([N:20]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[S:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:17]=[C:16]([NH:38][C@H:39]([CH3:42])[CH2:40][OH:41])[N:15]=1)(=O)=O)C1C=CC=CC=1>CS(C)=O>[OH:41][CH2:40][C@H:39]([NH:38][C:16]1[CH:17]=[C:18]([N:20]([S:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)(=[O:22])=[O:23])[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=[C:14]([S-:11])[N:15]=1)[CH3:42].[Na+:3]
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCOCC2)nc(S(=O)(=O)Cc2ccccc2)n1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCOCC2)nc([S-])n1
Reaction time: 1.25 h

Procedure:
Sodium hydrosulfide hydrate (0.62 g) was added to a solution of the subtitle product of step iii) (2.5 g) in DMSO (5 ml) and the green solution stirred for 1.25 h. A further aliquot of sodium hydrosulfide hydrate (0.28 g) was added and stirred for 45 min. A further aliquot of sodium hydrosulfide hydrate (0.32 g) was added and stirred for 1.25 h before the addition of a final aliquot of sodium hydrosulfide hydrate (0.10 g) in DMSO (1 ml). The resulting reaction solution was diluted with DMSO (10 ml) and used directly in the following step. The subtitle compound was also kept as a stock solution for further reaction with alkyl halides, described in Examples 107-110.