Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](OCCN1C=CC(N)=N1)(C(C)(C)C)(C)C.[N+:17]([C:20]1[N:25]=[CH:24][C:23]([N:26]2[CH2:29][CH:28]([OH:30])[CH2:27]2)=[CH:22][CH:21]=1)([O-])=O>>[NH2:17][C:20]1[N:25]=[CH:24][C:23]([N:26]2[CH2:27][CH:28]([OH:30])[CH2:29]2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Agent: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: Nc1ccc(N2CC(O)C2)cn1
Yield: 95.1 %

Procedure:
Using the same general procedure for the preparation of 119b, reduction of 120a (1.43 g, 7.32 mmol) gave a 95% yield (1.15 g) of 120b as a yellow semi-solid: 1H NMR (500 MHz, DMSO-d6) δ 7.22 (d, 1H, J=2.5 Hz), 6.69 (m, 1H), 6.35 (d, 1H, J=8.0 Hz), 5.16 (s, 1H), 4.48 (m, 1H), 3.96 (m, 2H), 3.34 (m, 2H); MS (ESI+) m/z 166.2 (M+H).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1>ClCCl>[CH3:1][NH:2][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN
Solvent: ClCCl
Product: CNc1ccc([N+](=O)[O-])cn1
Yield: 80 %

Procedure:
Methylamine gas was bubbled through a stirred solution of 2-chloro-5-nitropyridine (4 g, 25.2 mmol) in dichloromethane (60 mL), at room temperature, until saturation had occurred. The resulting yellow precipitate was then filtered off, washed with dichloromethane and dried under vacuum to afford the title compound as a yellow solid in 80% yield, 3.07 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=S)[CH:5]=[C:6]([F:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH2:16][CH3:17])([CH3:14])[CH3:15])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC(C)(C)NC(=S)Nc1cc(F)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)N=C=Nc1cc(F)cc(Cl)c1

Procedure:
To a solution of 3.5 g of N-(3-chloro-5-fluorophenyl)-N'-t-pentylthiourea produced in Example A-12 in 20 ml of dichloromethane were added 7.4 g of triphenylphosphine, 4.9 g of carbon tetrachloride and 2.85 g of triethylamine. The mixture was refluxed for 2 hours and evaporated in vacuo. The residue was extracted with petroleum ether and the extract was evaporated in vacuo to give N-(3-chloro-5-fluorophenyl)-N'-t-pentylcarbodiimide as an oil. To a solution of this oil in 20 ml of DMF were added 1.31 g of cyanamide and 2 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 15 hours, cooled to room temperature, poured into ice-water and extracted with ethyl acetate. The extract was evaporated in vacuo. The residue was chromatographed on a silica gel column using chloroform as a solvent and recrystallized from isopropyl alcohol to give 1.0 g of the title compound as colorless needles melting at 130°-131.0° C.
Reaction SMILES: ClN1CCCCCC1=O.Cl[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH3:15].[C:17](OC)(=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C1C=CC=CC=1>[CH3:15][C:14]1[C:17]([OH:23])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:12][C:13]=1[OH:16]
Reactant: CCC(=O)CCCl
Reactant: COC(=O)CC(=O)OC
Agent: O=C1CCCCCN1Cl
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)c(C)c1O
Temperature: 30 °C
Yield: 85 %

Procedure:
In a 1-L three-necked flask fitted with a mechanical stirrer and a reflux condenser protected by a calcium chloride drying tube, are placed a solution of 60.5 g of N-chlorocaprolactam in 400 ml of benzene and 75.5 g of methyl 3-methyl-dihydroresorcylate, prepared from 5-chloropentan-3-one (R. B. Woodward et al., J.Am.Chem.Soc. 74, 4223 (1952)) and dimethyl malonate; m.p. 126.5° - 127.9° C. The reaction mixture is stirred at reflux temperature for 8 hours, then cooled to 30° C, transferred to a separatory funnel and washed successively with water, 0.2 molar sodium carbonate solution and again with water. The organic layer is then cooled to 5° C and extracted with cold 0.4N sodium hydroxide solution. The aqueous solution is acidified with a slight excess of 15% hydrochloric acid. The temperature is maintained at 0° C throughout the acidification. The solid product is filtered off, washed thoroughly with water and dried, yielding 63.5 g (85%) of methyl 3-methyl-resorcylate (identified by NMR, IR and mass spectral analysis). M.p. 130.5° - 131.6° C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][OH:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.C(OCC)(=O)C.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH:10]=[O:11]
Reactant: COc1cc(C)cc(CO)c1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C)cc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of (3-methoxy-5-methylphenyl)methanol (2.20 g) in DMSO (15 mL) was added 2-iodoxybenzoic acid (4.00 g), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate (50 ml) and water (10 mL) were added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.00 g) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([NH2:17])[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].Cl.[CH:19]#[C:20][CH2:21]CCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1.[C:52]([OH:61])(=[O:60])[C@@H:53]([C@H:55]([C:57]([OH:59])=[O:58])[OH:56])[OH:54]>CO.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.CCOCC.C1COCC1>[OH:56][C@H:55]([C@@H:53]([OH:54])[C:52]([OH:61])=[O:60])[C:57]([OH:59])=[O:58].[CH3:1][O:2][C:3]([C@@:5]1([NH2:17])[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:19]#[C:20][CH3:21])=[CH:12][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: C#CCCCCCC
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(Br)cc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC#Cc1ccc([C@@H]2CC[C@](N)(C(=O)OC)C2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a three-neck round bottom flask was added (1R,3R)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid methyl ester; hydrochloride (4.00 g, 12.0 mmol), 1-octyne (3.54 mL, 24.0 mmol), triphenylphosphine (314 mg, 1.20 mmol), piperidine (7.13 ml, 72.0 mmol), and THF (100 mL). The mixture was degassed, and Pd(PPh3)2Cl2 (421 mg, 0.60 mmol) was added and the mixture was stirred for a few minutes under an atmosphere of nitrogen before addition of the copper(I) iodide (114 mg, 0.60 mmol). The reaction was stirred under an atmosphere of nitrogen at 60° C. for 4 hours. More 1-octyne (5.31 mL, 36.0 mmol) was added in two portions and the reaction mixture was heated at 60° C. for a total of about 30 hours. The solvent was then removed and crude material was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was back-extracted once with EtOAc. Organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using 1 L of EA followed by 1 L of 2% MeOH in EtOAc to give 3.52 g (90%) crude product as a yellow oil. A portion of the crude product (60.0 mg, 0.126 mmol) was dissolved in minimum amount of MeOH, to which L-tartaric acid (1.69 g) in MeOH was added. Ether was then added dropwise until solution just turned turbid. The mixture was left to crystallize. The solid was collected by filtration, washed with ether to give 45.0 mg (60%) (1R,3R)-1-amino-3-(4-prop-1-ynyl-phenyl)-cyclopentanecarboxylic acid methyl ester; compound with (2R,3R)-2,3-dihydroxy-succinic acid.
Reaction SMILES: [NH4+].[SH:2][C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([NH-:14])=[O:13])=[C:7]2[N:6]=[C:5]([CH3:15])[CH:4]=1.CC(O[CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O.B(F)(F)F.[OH-].[Na+]>C(#N)C.O>[NH2:28][C@@H:25]1[C:26](=[O:27])[N:23]2[C@@H:24]1[S:29][CH2:30][C:21]([CH2:20][S:2][C:3]1[N:8]3[N:9]=[CH:10][C:11]([C:12](=[O:13])[NH2:14])=[C:7]3[N:6]=[C:5]([CH3:15])[CH:4]=1)=[C:22]2[C:31]([OH:33])=[O:32]
Reactant: Cc1cc(S)n2ncc(C([NH-])=O)c2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2ncc(C(N)=O)c2n1
Reaction time: 0.67 h

Procedure:
A mixture of 2.80 g of 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide ammonium salt and 3.38 g of (7R)-7-aminocephalosporanic acid was treated with 25 ml of a 20 percent solution of boron trifluoride in acetonitrile and stirred at 20° for 40 minutes. The reaction mixture was treated with 30 ml of water and the pH was adjusted to 3.5 by means 28 percent aqueous sodium hydroxide solution. The precipitate thus formed was filtered off under suction and was chromatographed on OPTI-UP (C12) (ANTEC AG, CH-Bennwil) using water as the eluent. There was obtained (6R,7R)-7-amino-3-[[(3-carbamoyl-5-methylpyrazolo[1,5-a]-pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:27]([Cl:28])=[CH:26][N:25]([CH2:29][CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:27]([Cl:28])=[CH:26][N:25]([CH2:29][CH3:30])[N:24]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A small screw cap test tube was charged with 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 85 mg, 0.1946 mmol) and THF (2.0 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (37.3 mg, 0.195 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (˜5 mL) and Hexane (˜50 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with acetone (10 mL) to afford the title compound in 43% yield (0.051 g, 0.084 mmol).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=O)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:19])=O>>[CH2:1]([C:5]1[N:6]=[C:7]([Cl:19])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1[nH]c(=O)ccc1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nc(Cl)ccc1C(=O)OCC
Temperature: 120 °C
Yield: 80.9 %

Procedure:
Ethyl 2-butyl-6-oxo-1,6-dihydropyridine-3-carboxylate (450 mg, 2.02 mmol) was stirred in phosphorous oxychloride (10 ml, 30.5 mmol) and heated to 120° C. for 2 hours giving a clear brown solution. The reaction was evaporated and the residue was taken up in EtOAc (25 ml), washed with water (25 ml), saturated brine (25 ml) then dried over MgSO4 filtered and evaporated. Chromatography of the residue (SiO2) eluting with ethyl acetate/isohexane 10-30% gave ethyl 2-butyl-6-chloronicotinate (395 mg, 81%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH3:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50]Br.[I-].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH3:38])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: COCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCOCCOCCOCCOC)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 73.7 %

Procedure:
A mixture of 2.0 g (3.83 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 4.15 g (15.3 mmol) of 2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl bromide, 1.2 g (7.66 mmol) ofsodium iodide and 1.6 g (11.5 mmol) of potassium carbonate in 60 ml of acetone and 30 ml of DMF was stirred at reflux for 48 hours. The solvents were removed at reduced pressure and the residual oil was purified by HPLCusing 60% ethyl acetate-hexane to give 2.01 g (73% yield) of N-[3-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1.[H-].[Na+].[CH3:25][S:26][CH2:27]Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([O:21][CH2:25][S:26][CH3:27])=[CH:19][CH:20]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1
Reactant: CSCCl
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(O)cc4)c3c2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCOc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenol (1.17 g, 4.00 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.320 g, 8.00 mmol) at room temperature, and the resulting mixture was stirred for 15 min. (Chloromethyl) methyl sulfide (90%, 0.744 mL, 8.00 mmol) was added to the reaction mixture, and the resulting mixture was further stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1) and recrystallized from methanol to give the title compound (1.22 g, yield 87%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.C([O:40]C(NOC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]([OH:40])[C:20]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCN(O)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (Example 96, 100 mg, 0.3 mmol), N,O-Bis-tert-butoxycarbonylhydroxylamine (Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 20, 3471., 140 mg, 0.6 mmol) and triphenylphosphine (158 mg, 0.6 mmol) in THF (10 mL) was added diethyl azodicarboxylate (DEAD) (0.1 mL, 0.6 mmol). The mixture was stirred under nitrogen atmosphere at room temperature for 2.5 h. The solvent was removed and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 174 mg (quant.) of the title compound as yellow amorphous: 1H-NMR (CDCl3) δ 7.84 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.16 (1H, s), 3.92 (2H, t, J=6.7 Hz), 3.05 (2H, t, J=6.7 Hz), 2.76 (2H, q, J=7.6 Hz), 1.56 (9H, s), 1.46 (9H, s), 1.33 (3H, t, J=7.6 Hz).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]([CH:34]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:35]OS(C)(=O)=O)=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)=[N:26]2)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([S:1][CH2:35][CH:34]([C:33]2[N:25]([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[N:26]=[C:27]3[C:32]=2[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Temperature: 100 °C

Procedure:
To a solution of methyl 4-mercaptobenzoate (54.0 mg, 0.306 mmol; CAS Reg. No. 6302-65-4) in dry DMF (3 ml) was added K2CO3 (43.0 mg, 0.306 mmol) at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. [rac]-Methanesulfonic acid 2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethyl ester (135.0 mg, 0.306 mmol) dissolved in dry DMF (1 ml) was then added at 0° C. The reaction mixture was then heated at 100° C. in a sealed tube for 12 hours. LC-MS shows the formation of the desired compound with some starting material. 10 ml of 10% citric acid solution was then added to the reaction mixture and extracted with EtOAc (3×8 ml). Combined organic layers were washed with brine (10 ml) and finally dried over Na2SO4. Organic layer was distilled under reduced pressure to get light yellow oil (234 mg), which was purified by column chromatography [SiO2 (230-400 mesh), EtOAc:Hexane 8/92] to give the title compound (57 mg, 36.2%) as a off white sticky solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=2[OH:25])[CH:14]([OH:21])[CH2:15][NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:9])=[CH:6][CH:5]=1.C(O)(=O)C.ClCl.ClCl>C(O)(=O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:22]=[C:23]([Cl:1])[C:24]=2[OH:25])[CH:14]([OH:21])[CH2:15][NH:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:9])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)Nc2cc(C(O)CNC(C)(C)C)ccc2O)cc1
Agent: Cl
Agent: ClCl
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2cc(C(O)CNC(C)(C)C)cc(Cl)c2O)cc1
Reaction time: 0.17 h

Procedure:
To a slurry of 3-(4-methoxybenzamido)-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrochloride (0.5 g, 0.0013 mole) in glacial acetic acid (5 ml) a glacial acetic acid/chlorine solution (11.86 ml) containing 0.0898 g (0.0013 mole) of chlorine was added at room temperature with stirring during 10 minutes. The mixture was kept with continued stirring for 24 hours at room temperature, whereafter insoluble substance was filtered off, washed with ether, and air-dried (160 mg) (32%), melting point 196° - 199° C. 80 mg of the crude product was recrystallized from methanol (2 ml) (insoluble substance was filtered off). The yield of the analytically pure 3-(4-methoxybenzamido)-4-hydroxy-5-chloro-α-(tert.butylaminomethyl)benzylalcohol hydrochloride was 50 mg (20%), m.p. 205° - 206° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9](S)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=2[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Fc1cccc2oc(S)nc12
Solvent: CN(C)C=O
Product: Fc1cccc2oc(Cl)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.4 %

Procedure:
To a solution of 560 mg (3.31 mmol) 4-fluoro-benzooxazole-2-thiol in 3.6 mL (49.65 mmol) thionyl chloride was added dropwise 60.3 □L N,N-dimethylformamide dry at room temperature. The mixture was stirred at room temperature for 2.5 h. The solvent was removed in vacuo. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 434 mg (76.4%) of the title compound as a white solid. MS(m/e): 171 (M+H+).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]1([C@@H:23]2[CH2:25][C@H:24]2[NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:17]1([C@@H:23]2[CH2:25][C@H:24]2[NH:26][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CCN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1 g, 4.40 mmol) in methanol (15 mL) were added (trans)-2-phenylcyclopropanamine (0.762 g, 5.72 mmol) and acetic acid (0.252 mL, 4.40 mmol), and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (0.415 g, 6.60 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (10 mL) and the mixture was concentrated to remove methanol. The resulting aqueous layer was extracted with DCM (3×). The DCM extract was washed with 10% HOAc aqueous solution, dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 720 mg of product as pale yellow oil. MS: (M+H)+=345.4. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94-1.75 (m, 18H), 1.86-1.95 (m, 1H), 2.35 (dt, J=7.01, 3.69 Hz, 1H), 2.60-2.86 (m, 4H), 4.08 (br. s., 2H), 6.91-7.38 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1Br.[F:28][CH:29]([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3=[C:23]([CH3:26])[CH:24]=[CH:25][N:12]3[N:11]=2)[C:3]=1[C:32]1[CH:33]=[N:34][CH:35]=[C:30]([CH:29]([F:39])[F:28])[CH:31]=1
Reactant: Cc1ccn2nc(CNc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cncc(C(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc(CNc3ncnc(N)c3-c3cncc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of 2-(((6-amino-5-bromopyrimidin-4-yl)amino)methyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.12 mmol) were added (5-(difluoromethyl)pyridin-3-yl)boronic acid (31 mg, 0.18 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 0.01 mmol) and 117 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 33 mg (59% yield) as a white solid. Purity 100%.