Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH2:24]O)[N:9]=2)[CH:7]=1.COCCN(S(F)(F)[F:37])CCOC>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH2:24][F:37])[N:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CO)n1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CF)n1
Reaction time: 0.25 h
Yield: 141.5 %

Procedure:
To a slurry of N-(7-(5-fluoro-2-methylphenyl)-5-(hydroxymethyl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg, 0.1 mmol), in dichloromethane (0.7 mL) cooled at −15° C. was added bis(2-methoxyethyl)aminosulfur trifluoride (0.045 mL, 0.2 mmol). After 15 minutes at this temperature, the reaction mixture was diluted with dichlormethane (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (50 mg, 50%). 1H NMR (400 MHz, DMSO) δ 11.23 (s, 1H), 9.38 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 7.47-7.33 (m, 2H), 7.21 (m, 1H), 5.99 (s, 1H), 5.88 (s, 1H), 2.37 (s, 3H), 2.11 (m, 1H), 0.89 (m, 4H). LCMS (Method G): RT=14.65 min, M+H+=354.4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]([CH3:40])([CH3:39])[CH2:35][C:36](O)=[O:37].O.ON1C2C=CC=CC=2N=N1.N=C=N>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][C:34]([CH3:40])([CH3:39])[CH3:33])[CH2:31][CH2:32]3)=[CH:23][CH:22]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)cc2)cc1
Reactant: CC(C)(C)CC(=O)O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)CC(C)(C)C)CC3)cc2)cc1

Procedure:
The title compound is prepared by reaction of 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-yl-phenyl)-urea (0.20 g, 0.46 mmol) with 0.51 mmol of 3,3-Dimethyl-butyric acid, (0.06 g, 0.46 mmol) of 1-Hydroxybenzotriazole hydrate and (0.8 g, 0.46 mmol) of polymer supported carbodiimide, dissolved in 16 mL of CH2Cl2. Mixture is stirred at r.t.o.n. It is filtered and the resin is washed with CH2Cl2 Solvent is evaporated and the residue is purified with an SCX cartridge eluting with NH4OH/CH3OH 2 N. ES+(m/z) 531 [M+H].
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:24]=[N:25][C:26]([CH3:32])=[C:27]([OH:31])[C:28]=3[CH2:29][OH:30])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][CH2:22][C:23]3[CH:24]=[N:25][C:26]([CH3:32])=[C:27]([O:31][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=4)[C:28]=3[CH2:29][OH:30])=[CH:19][CH:20]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CO)c1O
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CO)c1OCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A mixture of 4′-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (2) (190 mg, 0.42 mmol), α-bromo-m-tolunitrile (90 mg, 0.46 mmol) and potassium carbonate (177 mg, 1.28 mmol) in DMF (10 mL) were stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was evaporated to dryness, and the crude product was purified by column chromatography on silica gel using a gradient of dichloromethane:methyl alcohol (1:0 to 9:1) as eluant to give 4′-{[5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-biphenyl-2-sulfonic acid tert-butylamide (13) (149 mg, 62% yield) as a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1.Cl.[OH:21][C:22]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([CH3:32])[C:22]=4[OH:21])[CH2:27]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccncn2)nc2ccccc12
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccncn3)nc3ccccc13)C2
Yield: 15 %

Procedure:
Reaction of 2-(4-pyrimidinyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 73 (15% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.25-2.28 (m, 3H), 2.78 and 3.05 (2t, 2H), 3.56 and 4.21 (2t, 2H), 4.46 and 5.09 (2s, 2H), 6.30-7.07 (m, 2H), 7.74-7.82 (m, 1H), 8.04-8.12 (m, 2H), 8.35-8.42 (m, 1H), 8.65-8.75 (m, 1H), 9.02-9.10 (m, 1H), 9.55-9.60 (m, 1H); MS (ESI) m/z 398 ([M+H]+).
Reaction SMILES: [C:1](O)(=O)C.[CH3:5][NH:6][CH3:7].C=O.[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>C(O)C>[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]2[C:7](=[CH:19][CH:20]=1)[NH:6][CH:5]=[C:15]2[CH2:16][N:17]([CH3:1])[CH3:18]
Reactant: COc1ccc2[nH]ccc2c1C
Reactant: CC(=O)O
Reactant: CNC
Agent: C=O
Solvent: CCO
Product: COc1ccc2[nH]cc(CN(C)C)c2c1C
Temperature: 25 °C

Procedure:
Acetic acid (0.39 mL) and dimethylamine (0.85 mL of a 40% aqueous solution) were added to a suspension of paraformaldehyde (0.21 g) in 25 mL ethanol. The mixture was heated to reflux until it was clear. The solution was cooled to rt and a solution of 5-methoxy-4-methyl-indole (1.0 g) in 25 mL of ethanol was added. The reaction was heated to reflux for 3 h. The volatiles were removed in vacuo to yield (5-methoxy-4-methyl-1H-indol-3-ylmethyl)-dimethylamine (1.0 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:17])[CH2:13][O:14][CH2:15][CH3:16])[CH3:10].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CCCCCCC.O1CCCC1>[CH2:9]([O:11][C:12](=[O:17])[CH:13]([O:14][CH2:15][CH3:16])[CH:30]([C:29]1[CH:32]=[CH:33][C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:27][C:28]=1[CH3:34])[OH:31])[CH3:10]
Reactant: CCOCC(=O)OCC
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
To a −78° C. cold 2 M solution of lithium diisopropylamide (305 mmol) in THF/n-heptane (152.4 ml) was added a solution of ethoxy-acetic acid ethyl ester (45.2 ml, 331 mmol) in tetrahydrofuran (240 ml) within 1.5 h under an argon atmosphere. The mixture was stirred for 30 min. A solution of 4-benzyloxy-2-methyl-benzaldehyde (30 g, 132.6 mmol) in tetrahydrofuran (420 ml) was added dropwise over a period of 50 min. The reaction mixture was stirred 2 h at −78° C., poured onto ice water/aqueous ammonium chloride solution 1/1 and extracted two times with ethyl acetate. The combined extracts were washed three times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/AcOEt) to give 48.8 g (136.2 mmol) of the title compound as a mixture of stereoisomers as yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:28]([CH3:27])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:23])=[CH:25][CH:26]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)CCNC
Reactant: O=C(O)c1ccc(NC(c2cc3ccccc3s2)C2CCCCC2)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cc3ccccc3s2)C2CCCCC2)cc1

Procedure:
Using 4-{[1-benzothiophen-2-yl(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized above and ethyl 3-(methylamino)propanoate (108 mg) and in the same manner as in Example A1(4), the title object compound (277 mg, 90%) was obtained as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7](OC2CCC(=O)C=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[NH2:23][C:24]1[CH2:28][O:27][C:26](=[O:29])[CH:25]=1.[H-].[Na+]>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([NH:23][C:24]2[CH2:28][O:27][C:26](=[O:29])[CH:25]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Reactant: NC1=CC(=O)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)OC2)[C@@H]1O

Procedure:
34,5 mg of the epoxide of example 1 and 17 mg of 4-Amino-2-(5H)-furanone (CAS 92089-08-2) are reacted analogously to example 5 with sodium hydride in dimethylsulfoxide. The usual working up yields yellowish crystalls of the title compound having a m.p. of 182° C. (from ethanol/dichloromethane, decomposition).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](Cl)=[O:11].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:11]
Reactant: NCCCCO
Reactant: O=C(Cl)c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(NCCCCO)c1nc2ccccc2s1

Procedure:
1 g (5 mmol) benzothiazol-2-carbonyl chloride, 542 mg (6 mmol) 4-aminobutan-1-ol and 1.4 g (10 mmol) K2CO3 in acetonitrile is stirred for three days at room temperature. The solvent is evaporated and the product is dissolved in ethyl acetate and washed with 2N HCl and water. After evaporation of the solvent the yellow semisolid is crystallized from ethyl acetate.
Reaction SMILES: [H-].[Na+].C(S)CC.C1([O:12][C:13]2[CH:14]=[C:15]([C@@H:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])CCCC1>CN(C=O)C>[OH:12][C:13]1[CH:14]=[C:15]([C@@H:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:22][C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccccc2)cc1OC1CCCC1
Agent: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccccc2)cc1O
Reaction time: 0.5 h
Yield: 406.8 %

Procedure:
To a stirred solution of NaH (60% dispersion in mineral oil) (0.483 g, 12.075 mmol) in DMF under nitrogen at RT was added propanethiol (1.09 ml, 12.07 mmol) and the mixture stirred for 30 min. A solution of (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (made as described in WO 94/14742) (1.8 g, 4.83 mmol) in DMF was added, the mixture heated to reflux for 5 h, allowed to cool (the reaction was followed by tic) and concentrated in vacuo. The residue was taken up in CH2Cl2 and washed with aqueous NaHCO3 solution. The aqueous phase was extracted with CH2Cl2, the combined organic phase dried (MgSO4), filtered and concentrated in vacuo. The residue was subjected to chromatography (SiO2 ; Et2O) then recrystallised (i-propylether) to give the title compound (6.00 g) as a white solid. m.p. 158°-159° C. (Found C, 79.37; H, 6.96; N, 3.66. C24H25O2N requires C, 80.19; H, 7.01; N, 3.90%). δH (CDCl3) 1.5-1.9 (8H, m, (CH2)4), 3.39 (2H, dd, J 8, 1 Hz, CH2 pyridine), 4.12 (1H, t, J 8 Hz, CHCH2), 4.62 (1H, m, OCH), 5.52 (1H, br s, OH), 6.57 (1H, m, C6H3), 6.6-6.7 (1H, m, C6H3), 6.75-6.8 (1H, m, C6H3), 6.91 (2H, d, J 6. Hz, H3, H5 pyridine), 7.1-7.3 (5H, m, C6H5), and 8.38 (2H, d, J 6 Hz, H2, H6 pyridine).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[C:3]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: Cc1cccc([N+](=O)[O-])c1S(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(N)c1S(C)(=O)=O
Temperature: 45 °C
Reaction time: 48 h
Yield: 97.8 %

Procedure:
A solution of 158 g (0.74 mol) of 3-methyl-2-methylsulfonylnitrobenzene in 1.5 l of ethyl acetate and 5 g of a catalyst comprising 10% by weight of palladium on carbon were introduced into a hydrogenation apparatus fitted with gas inlet tube. The hydrogenation apparatus was flushed twice with nitrogen. Hydrogen was then introduced, and the mixture was stirred at 45° C. for 48 hours. The reaction mixture was filtered off with suction through kieselguhr and the filtrate was concentrated under reduced pressure, giving 134 g (98% of theory) of 3-methyl-2-methylsulfonylaniline as an orange-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(CCl)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCc2ccc(OC)cc2)cc1

Procedure:
A mixture of 33 g. of ethyl p-aminobenzoate, 100 ml. of hexamethylphosphoramide and 15.7 g. of p-(chloromethyl)anisole are heated at 100°-110° C. for 22 hours. The solution is chilled, diluted with 60 ml. of water, chilled, filtered and the solid washed with ethanol and with water to give yellow crystals. Recrystallization from ethanol gives pale yellow crystals, m.p. 128°-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=O)[C:14]#[C:15][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH:19][NH2:20]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([CH3:16])[N:19]([CH3:18])[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNN
Reactant: CC#CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: CO
Product: Cc1cc(C2CCN(C(=O)OC(C)(C)C)C2)nn1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 88.7 %

Procedure:
To a stirred solution of 3-(1-oxo-but-2-ynyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.8 g, 3.4 mmol) in MeOH (20 mL) was added methyl-hydrazine (5 g, 44 mmol). The mixture was stirred at room temperature for 10 hours. The reaction mixture was quenched with water (50 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (PE/EA=1:1) to afford 3-(1,5-dimethyl-1H-pyrazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (800 mg, 88%) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:29]([Cl:39])[CH:28]=1)=[N:7]2>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:29]([Cl:39])[CH:28]=1)=[N:7]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c3cnc(Nc4ccc(N5CCOCC5)c(Cl)c4)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc(Nc2ncc3c(Br)ccc(OC4CCNCC4)c3n2)ccc1N1CCOCC1
Yield: 50 %

Procedure:
A solution of tert-butyl 4-(5-bromo-2-(3-chloro-4-morpholinophenylamino) quinazolin-8-yloxy)piperidine-1-carboxylate in 30% TFA/DCM was stirred at room temperature for 30 min. The solvent was evaporated and crude was purified by semi-prep HPLC to provide 5-bromo-N-(3-chloro-4-morpholinophenyl)-8-(piperidine-4-yloxy) quinazolin-2-amine in 50% yield. ES/MS m/z 518.0 (MH+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)=[O:8].Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:21][CH:22]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: CNC1CCN(C(=O)c2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cc2)CC1
Reactant: Fc1ccc(CBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCC(NCCc4ccc(F)c(F)c4)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,4-dichloro-N-{6-[4-(4-methylamino-piperidine-1-carbonyl)phenoxy]pyridin-3-yl}benzamide dihydrochloride (114 mg, 0.2 mmol) was dissolved in DMF (3 mL). To the resulting solution were added 4-bromomethyl-1,2-difluorobenzene (31 μl, 0.24 mmol) and potassium carbonate (111 mg, 0.8 mmol), and this solution was stirred for 4 hours at room temperature. The resulting reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. This residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby yield 60 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH2:9][C:10]#[CH:11]>>[C:17]1([C:14]2[CH:13]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:16][N:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Ic1ccccn1
Reactant: C#CCCc1cc(-c2ccccc2)no1
Product: C(#Cc1ccccn1)CCc1cc(-c2ccccc2)no1
Yield: 76.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodo-pyridine (70 mg, 0.34 mmol) and 5-but-3-ynyl-3-phenyl-isoxazole (67 mg, 0.34 mmol). Reaction time: 24 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 70 mg (0.26 mmol, 75%) of 2-(4-(3-phenylisoxazol-5-yl)but-1-ynyl)pyridine as a brown solid.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].COC[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16](O)=O.N1C=CC=C[CH:20]=1>C1(C)C=CC=CC=1>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:20][O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: COCCOCCOCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Product: COCCOCCCOCC(=O)Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Oxalyl chloride (100 g, 0.78 mol) was added dropwise over 1 h to a solution of 2-[2-(2-methoxy-ethoxy)ethoxy]-acetic acid (90 mL, 0.59 mol) and pyridine (0.1 mL, 1 mmol) in anhydrous toluene (250 mL) and the resulting solution was stirred at ambient temperature for 48 h. The reaction solution was concentrated in vacuo to afford CH3(OCH2CH2)2CH2OCH2COCl as a slightly yellow oil (120 g, 96%). This compound was used without any further purification.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)(=[O:5])=[O:4])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>>[CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Nc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Product: CCS(=O)(=O)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Yield: 59.2 %

Procedure:
Beginning with 1.45 gm (6.5 mMol) 5-ethanesulfonylamino-1H-indole and 1.03 mL (8.4 mMol) 1-methyl-4-piperidone, 1.23 gm (59.7%) of the title compound were recovered as pale orange crystals.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26]C)=[O:24])[C:17]([O:19][CH2:20]C)=[O:18])=[CH:13][C:12]([Cl:28])=[C:11]2[C:7]=1[C:8]([Cl:29])=[N:9][NH:10]2)(=O)C.C[O-].[Mg+2].C[O-]>CO>[Cl:29][C:8]1[C:7]2[C:11](=[C:12]([Cl:28])[CH:13]=[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:17]([O:19][CH3:20])=[O:18])[C:6]=2[CH2:5][OH:4])[NH:10][N:9]=1
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]nc(Cl)c2c1COC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]nc(Cl)c2c1CO)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-3,7-dichloro-1H-indazol-5-yl)methyl)succinate (1.30 g, 2.92 mmol) was dissolved in methanol (45 mL). 6-10% Magnesium methoxide in methanol (8.4 mL, 6.35 mmol) was added to the mixture. Reaction stirred at room temperature for 16 hours. Reaction was quenched with 14 mL 1N hydrochloric acid. Methanol was removed from the mixture by roto-vap. Residue was treated with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. The combined organic phases were washed with water and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as dark amber oil in 91% yield. MS (M−H)−=373.0, 375.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.O>[N:23]([C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[N+:24]=[N-:25]
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (659 mg) in dimethyl sulfoxide (10 ml) was added sodium azide (487 mg), and the mixture was stirred at 90° C. for 8 hours. The mixture was diluted with water (20 ml), and the precipitate was filtered and washed with water to give 4-azido-8-(2,6-dichlorobenzoylamino)quinoline (560 mg) as white solid.