Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[N+:31]([O-:54])[CH:32]=[C:33]([Cl:53])[C:34]=1[CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:47])[F:46])=[C:40]([O:48][CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([O:18][CH2:19][C:20]([O:22][C@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:46])[F:47])=[C:40]([O:48][CH2:49][CH:50]2[CH2:51][CH2:52]2)[CH:39]=1)[CH2:35][C:34]1[C:33]([Cl:53])=[CH:32][N+:31]([O-:54])=[CH:30][C:29]=1[Cl:28])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)OCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A mixture of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoyloxy)acetic acid (0.192 g, 0.476 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), EDC (0.274 g, 1.428 mmol), and DMAP (0.058 g, 0.476 mmol) in DCM (20 ml) was stirred at RT for 2 hours. The mixture was washed with HCl 1N and with NaHCO3 5%; the organic layer was dried over Na2SO4, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1) to afford (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.296 g, 0.367 mmol, 77% yield, MS/ESI+ 805.0 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1ccccc1F
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2F)cc1
Yield: 69.4 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.048 g (69%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][C:50]1[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[C:51]=1[NH2:52]>C(O)(=O)C>[CH3:49][C:50]1[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[C:51]=1[N:52]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: Cc1cccc(C)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: Cc1cccc(C)c1-n1cnc2c(-c3ccccc3)csc2c1=O
Yield: 56 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (43 mg, 0.18 mmol), triethyl orthoformate (0.34 ml), 2,6-dimethylaniline (0.04 ml, 0.33 mmol), and acetic acid (0.042 ml) were used to give 34.8 mg (0.10 mmol, 56% yield) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.[F:15][C:16]([F:20])([F:19])[CH:17]=O.[BH3-]C#N.[Na+]>>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:16]([F:20])([F:19])[F:15])[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: O=CC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2CC(F)(F)F
Yield: 90.8 %

Procedure:
This compound was prepared by General Method 7 from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (388 mg, 2.1 mmol), 2,2,2-trifluoroacetaldehyde monohydrate (2.51 g, 21.6 mmol) and NaBH3CN (656 mg, 10.4 mmol) to afford 500 mg (88%) of 3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine, a yellow solid. Data for 3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf 0.59 (3:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.81 (dd, 1H, J=8.8, 2.6), 7.72 (d, 1H, J=2.6), 6.72 (d, 1H, J=9.1), 4.27 (t, 2H, J=4.5), 3.94 (2H, J=8.6), 3.61 (t, 2H, J=4.5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.CI.[OH-].[Na+].Cl[CH2:18]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: Brc1ccc(-c2nn[nH]n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1nnc(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3.5 mmol of 5-(4-bromo-phenyl)-2H-tetrazole, 0.2 mmol of tetrabutyl ammonium bromide, 4.4 mmol of methyl iodide, 6 ml of 1M aqueous sodium hydroxide and 6 ml of dichloromethane were stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried, evaporated and the product purified by column chromatography (SiO2; cyclohexane/ethyl acetate 7:3). MS (m/e): 239.1 (MH+, 29%)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.CO>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[N+:1]([O-:3])=[O:2])[C:9]2=[O:14])=[CH:18][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc(F)cc1

Procedure:
5-Nitro-isochromen-1-one (1 g, 0.005 mol) and 4-fluoro-benzene methanamine, (2 g, 0.02 mol) were refluxed in methanol (20 mL, 0.5 mol) for 2 hours. The volatiles were removed via rotovapor, and the residue was purified via flash column chromatography (40 g of silica gel, 0-50% EtOAc/Hexane) gave a bright yellow solid. MS m/z (M+H) 299.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:29])[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([O:27][CH3:28])[CH:18]=1)C(OC)=O>CCO.Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: COC(=O)C(C(=O)c1cc(OC)ccc1OC)c1ccc(C(F)(F)F)c(OC)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(OC)c(C(=O)Cc2ccc(C(F)(F)F)c(OC)c2)c1
Temperature: 130 °C
Yield: 107.1 %

Procedure:
To a solution of methyl 3-(2,5-dimethoxyphenyl)-2-(3-methoxy-4-(trifluoromethyl)phenyl)-3-oxopropanoate (30.1 g, 73 mmol) in EtOH (400 mL), concentrated HCl (100 mL) was added. The reaction mixture was heated at 130° C. for 3 h, cooled to room temperature, and concentrated. The residue was dissolved in dichloromethane (150 mL) and washed with brine (3×100 mL). The organic layer was dried (Na2SO4), concentrated and purified by silica gel column chromatography (1:10 EtOAc/petroleum ether) to afford the title compound (27.7 g). 1H NMR (DMSO-d6): δ 7.48 (d, 1H), 7.26-7.25 (m, 1H), 7.07-7.03 (m, 1H), 6.93-6.84 (m, 3H), 4.33 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=C[CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C=C2C=NN(C(OC(C)(C)C)=O)C2=[N:22]C=1.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO.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.O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[CH:11]=[N:12][NH:13][C:14]3=[N:22][CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)cnc21
Reactant: Clc1ncccc1-c1ccc2[nH]ncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Clc1ncccc1-c1cnc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine was prepared in the similar to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of tert-butyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (2.0 g, 6.7 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.9 g, 8.0 mmol), Pd(PPh3)4 (770 mg, 67 mmol), 1,4-dioxane (40 mL) and 2M aq.Na2CO3 (9 mL, 18 mmol) under argon atmosphere. After 12 h, the reaction mixture was cooled to room temperature and concentrated. The crude concentrate was diluted with EtOAc/water (200 mL/100 mL), allowed to stir for 30 min and the heterogeneous solution was filtered. The filter cake was washed with EtOAc (200 mL) and water (75 mL) successively. The filter cake thus obtained was analyzed as the desired product (0.55 g) and dissolved in a mixture of THF/MeOH (2:1, 50 mL). The homogeneous solution was passed through a pad of Celite® and the filtrate concentrated to provide desired product as a crystalline solid (0.45 g). Organic layer from combined filtrates was separated, stirred with MgSO4/Celite® for 20 min and filtered. The filtrate was concentrated and subjected to flash silica gel column purification (Combiflash® companion System® with RediSep® silica gel column 12 g, 30-50-90EtOAC/hexanes eluting solvent gradient upon dry loading the sample by absorbing on silica gel) to obtain another 0.4 g of 5-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine. Total yield: 52%. 1H NMR (DMSO-d6): δ 13.83 (s, 1H), 8.59 (d, 1H, J=2.0 Hz), 8.45 (dd, 1H, J=1.7 and 4.7 Hz), 8.36 (d, 1H, J=2.0 Hz), 8.21 (s, 1H), 8.00 (dd, 1H, J=1.7 and 7.7 Hz), 7.59 (dd, 1H, J=4.7 and 7.7 Hz).LCMS: rt5.20 min (A), purity 94%, MS (m/e) 231 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:18])[C:6]([NH:9][C:10](=[O:17])[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:7][CH:8]=1)#[CH:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29](I)=[N:30][CH:31]=2)=[CH:22][CH:21]=1.N1CCCCC1>C1COCC1.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.[Cu]I>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:2]#[C:1][C:3]3[CH:4]=[C:5]([CH3:18])[C:6]([NH:9][C:10](=[O:17])[CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:7][CH:8]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1cnc(NC(=O)CN2CCCC2)c(C)c1
Reactant: Clc1ccc(-c2ccc(I)nc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cnc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere 4 mg (0.01 mmol) Pd(PPh3)2Cl2 and 1 mg (0.01 mmol) CuI are added to a solution of 73 mg (0.3 mmol) N-(5-ethynyl-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide and 95 mg (0.3 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine in 59 μL (0.6 mmol) piperidine and 10 mL THF and the reaction mixture is stirred for 30 min at RT. It is evaporated down i.vac., the residue is taken up in EtOAc, the organic phase is washed with water and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified first by chromatography (silica gel, EtOAc/MeOH/NH3 95:5:0.5) and then by HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][S:11](Cl)=[O:12]>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][S:11]([CH3:10])=[O:12])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CS(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)NCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfinyl chloride was obtained as described in the literature. A solution of C-(6-chloro-pyridin-3-yl)-methylamine (2.1) (25 g, 178 mmol) in tetrahydrofuran (200 ml) was cooled to 0° C. and methanesulfinyl chloride (7 g, 71 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for 16 hours. The precipitate was removed by filtration, the filtrate was diluted with EtOAc and washed with H2O. The organic phase was dried over Na2SO4 and evaporated under reduced pressure.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](OC)=[O:31]>CCCCCC.C1COCC1>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[CH:30]=[O:31]
Reactant: COC(=O)c1cccc(Cc2cccc(OCc3ccc4ccccc4n3)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Cc2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 0 °C

Procedure:
A solution of diisobutyl aluminum hydride (0.01 mol) in hexane is added dropwise to a solution of methyl 3-(3-(2-quinolinylmethyloxy)benzyl)benzoate (0.01 mol) in 100 ml of THF at0° C. The reaction mixture is stirred at 0° C. for 30 minutesand then quenched with methanol and Rochelle salt. Extraction with ethyl acetate and purified by column chromatography gives 3-(3-(2-quinolinylmethyloxy)benzyl)benzaldehyde.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:44]2[CH:43]([CH2:45][CH2:46][OH:47])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]>C1COCC1.O>[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([O:47][CH2:46][CH2:45][CH:43]2[C:44]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]3[C:42]2=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:62][CH:63]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCC1c2ccccc2-c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCC2c3ccccc3-c3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0° C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 2-(9H-fluoren-9-yl)-ethanol (0.208 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature and stirring continued for 20 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (4×50 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to a colourless gum. This was then purified by column chromatography on SiO2 (15% Et2O in petroleum eluent) to give the title compound as a colourless gum; 0.20 g (47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[ClH:32]>ClCCl.C(OCC)C>[ClH:32].[ClH:32].[Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Br)c3)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1NCc1cccc(Br)c1
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of t-butyl 4-(3-(3-bromobenzylamino)-4-nitrophenyl)piperazine-1-carboxylate (104 mg, 0.23 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The solvent was evaporated and the precipitate was recrystallized from methanol (0.3 mL), dichloromethane (0.5 mL) and diethyl ether (5 mL). The product was collected by filtration and dried in vacuo to afford the title compound (35.0 mg, 39% yield after recrystallization). 1H NMR (400 MHz, CD3OD): δ 8.07 (d, 1H), 7.42 (s, 1H), 7.33 (m, 2H), 7.28 (m, 1H), 6.40 (d, 1H), 6.03 (s, 1H), 4.61 (s, 1H), 3.56 (m, 4H), 3.27 (m, 4H); MS (ESI) m/z: Calculated for C17H20ClN4O2: 347.13; Observed: 347.5 (M++1).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([C:11](=[O:15])[CH:12]([OH:14])[CH3:13])[CH:7]=[CH:8][C:9]=1[F:10].[C:16](O)(=[O:18])C.[C:20](O)(=O)C.IC1C=CC=CC=1>CO>[CH3:20][O:15][C:11]([O:18][CH3:16])([C:6]1[CH:7]=[CH:8][C:9]([F:10])=[C:4]([F:3])[CH:5]=1)[CH:12]([OH:14])[CH3:13]
Reactant: CC(O)C(=O)c1ccc(F)c(F)c1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Ic1ccccc1
Product: COC(OC)(c1ccc(F)c(F)c1)C(C)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a round bottom flask containing 200 mL of MeOH was added pellets of potassium hydroxide (23.0 g, 410.0 mmol). The solution was cooled to 0° C. and 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one (7.0 g, 41.2 mmol) in 10 mL MeOH was added dropwise. The solution was stirred for 10 min and then iodobenzene diacetate (22.5 g, 70 mmol) was added in two portions. The solution first became orange and then turned yellow. It was stirred overnight at room temperature and then solvent was removed in vacuo. The residue was dissolved in water and was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine and then dried over Na2SO4. After filteration, the solvent was removed in vacuo to get 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one dimethyl acetal as a yellow viscous oil (crude wt.=9.2 g). It was dissolved in 150 mL of acetone and 10 drops of concentrated sulfuric acid were added. After stirring for 3 h, TLC analysis indicated that the reaction was complete. Acetone was removed in vacuo and after basification with saturated NaHCO3, the residue was extracted in EtOAc and was washed with brine. The organic layer was separated, dried over Na2SO4 and then filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (Rf=0.4, 3:2 hexane/EtOAc) to obtain 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one as a pale yellow oil (3.3 g, 51% yield over two steps).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[C:6]([C:22]2[S:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:30]([C:31](O)=[O:32])[C:24]=3[CH:23]=2)=[N:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:9][CH:10]=1.[C:34]([O:38][C:39](=[O:42])[NH:40][NH2:41])([CH3:37])([CH3:36])[CH3:35].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[Li+]>CN(C=O)C>[C:34]([O:38][C:39]([NH:40][NH:41][C:31]([C:30]1[C:24]2[CH:23]=[C:22]([C:6]3[C:5]([Cl:4])=[CH:10][N:9]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[N:7]=3)[S:26][C:25]=2[CH:27]=[CH:28][CH:29]=1)=[O:32])=[O:42])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)O)cccc4s3)n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NNC(=O)OC(C)(C)C)cccc4s3)n2)CC1
Temperature: 50 °C
Yield: 82 %

Procedure:
A mixture of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid tri-hydrochloride (425 mg, 0.960 mmol), tert-butylcarbazate (398 mg, 3.01 mmol), diisopropylethylamine (0.500 mL, 2.87 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (510 mg, 1.15 mmol), and lithium chloride (498 mg, 11.7 mmol) in DMF (6 mL) is heated at 50° C. for 20 hours. After cooling to room temperature, the solvent is removed and the residue is subjected to chromatography on silica gel, eluting with 2.0 M NH3/MeOH) in dichloromethane 0-10%, to give N′-(2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (441 mg, 82% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:18][CH2:17][CH2:16][C@@H:10]([C:11]([O:13]CC)=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-].Cl>CO.O>[C:1]([N:8]1[CH2:18][CH2:17][CH2:16][C@@H:10]([C:11]([OH:13])=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Temperature: 4 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethyl N-Boc-(R)-nipecotate (7.61 g, 29.6 mmol) in 25 mL of methanol was added LiOH (2.48 g, 2 eq.) in 25 mL of H2O dropwise at 4° C. The reaction mixture was stirred overnight at 4° C. The pH of the mixture was adjusted to ca. 1 by adding aqueous HCl (10% w/w). The aqueous layer was extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with aqueous NH4Cl (sat., 2×50 mL), brine (50 mL), and dried over anhydrous Na2SO4, filtered and evaporated to give N-Boc-(R)-nipecotic acid 25 as a white solid 6.25 g (92%).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12](O)[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1.P(Br)(Br)[Br:27]>O1CCOCC1>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([Br:27])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(O)c1cccc(OCc2c(C)cccc2C)c1
Reactant: BrP(Br)Br
Solvent: C1COCCO1
Product: CCOC(=O)CCC(Br)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-hydroxy-butyrate (Step D) in dioxane, add phosphorous tribromide in dioxane dropwise. After stirring at room temperature for 16 hours, quench with water and chloroform. After few minutes, the reaction mixture can be neutralized by mild aqueous base, dry organic layer over Na2SO4, filter, concentrate and purify by flash chromatography on silica gel column (EtOAc:hex).