Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:18][C:19]1[C:20]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][N:33]=[C:32](Cl)[N:31]=2)=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([NH:24][CH3:25])=[O:23]>>[Cl:18][C:19]1[C:20]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][N:33]=[C:32]([NH:1][C:2]3[CH:17]=[CH:16][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[NH:14][CH3:15])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:31]=2)=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([NH:24][CH3:25])=[O:23]
Reactant: CNC(=O)CN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)CN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(Cl)cccc4C(=O)NC)n3)cc2CC1

Procedure:
3-Chloro-2-[5-chloro-2-(3-methylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and 3-chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (53 mg, 23%). LCMS (m/e) 528 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H, J=8.0 Hz), 7.50 (d, 1H, J=7.7 Hz), 7.34-7.26 (m, 1H), 7.16 (s, 1H), 7.06 (d, 1H, J=7.3 Hz), 6.90 (d, 1H, J=8.0 Hz), 6.85 (s, 1H), 6.13-6.06 (m, 1H), 3.12 (s, 2H), 2.88 (d, 3H, J=5.0 Hz), 2.87-2.82 (m, 2H), 2.80 (d, 3H, J=4.9 Hz), 2.77-2.72 (m, 2H), 2.71-2.62 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.F[P-](F)(F)(F)(F)F.[N:21]1([O:30][C:31](N(C)C)=[N+](C)C)[C:25]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:21]([O:30][CH3:31])[CH3:25])=[O:13])[NH:6]2
Reactant: O=C(O)c1cc2c(Cl)cccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2c(Cl)cccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.8 %

Procedure:
A mixture of 4-chloro-1H-indole-2-carboxylic acid (from Ryan Scientific, 1.0 g, 5.1 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.9 g, 7.7 mmol) and triethylamine (3.6 mL, 26 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (0.75 g, 7.7 mmol) was added and the resulting suspension was stirred at room temperature overnight. The mixture was quenched with water and then extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-35% EtOAc in hexane) to give the desired product (0.35 g, 29%). LCMS calculated for C11H12ClN2O2(M+H)+: m/z=239.1. Found: 239.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1>>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([OH:17])=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)=[CH:25][C:26]=1[C:32]([F:33])([F:35])[F:34]
Reactant: COc1ccc(CCl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Product: COc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F

Procedure:
From tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and 4-(chloromethyl)-1-methoxy-2-(trifluoromethyl)benzene, the title compound was prepared using a similar method to the one described in Example 1.48, Step B. LCMS m/z=420.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.31-2.39 (m, 1H), 2.50 (dd, J=16.3, 9.9 Hz, 1H), 2.75 (dd, J=16.3, 4.4 Hz, 1H), 2.83-2.93 (m, 1H), 3.59-3.67 (m, 1H), 3.85 (s, 3H), 3.95-4.05 (m, 2H), 4.06-4.14 (m, 2H), 5.30 (s, 1H), 6.67-6.74 (m, 2H), 6.86 (d, J=8.6 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C@@H:13]([CH3:14])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: C[C@H](Nc1ccccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCO
Product: C[C@H](Nc1ccccc1N)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.5 h

Procedure:
A flask containing a solution of (2S,3S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenylamino)-butyric acid (5.8 g, 17.1 mmol) in ethanol (60 ml) was purged with nitrogen followed by the addition of 10% palladium on carbon (600 mg). The atmosphere above the ethanol solution was exchanged for hydrogen and the reaction mixture stirred vigorously for 30 minutes at atmospheric pressure. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give (2S,3S)-3-(2-amino-phenylamino)-2-tert-butoxycarbonylamino-butyric acid which was used in the subsequent step without further purification (5.29 g, 100%).
Reaction SMILES: [CH3:1]SC1N=C(NC(C)C)N=C(NC)N=1.[CH3:15][CH2:16][NH:17][C:18]1[N:19]=[C:20]([NH:26][CH:27]([CH3:29])[CH3:28])[N:21]=[C:22]([S:24][CH3:25])[N:23]=1>>[CH3:25][S:24][C:22]1[N:21]=[C:20]([NH:26][CH:27]([CH3:28])[CH3:29])[N:19]=[C:18]([NH:17][CH:16]([CH3:1])[CH3:15])[N:23]=1
Reactant: CCNc1nc(NC(C)C)nc(SC)n1
Reactant: CNc1nc(NC(C)C)nc(SC)n1
Product: CSc1nc(NC(C)C)nc(NC(C)C)n1

Procedure:
2-Methylthio-4-isopropylamino-6-methylamino-1,3,5-triazine (ametryne
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][C:4](=O)[C:5](=[C:11]([CH3:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].O.[NH2:18][NH2:19]>C(O)(=O)C>[CH3:12][C:11]1([CH3:13])[NH:19][N:18]=[C:4]([CH2:3][C:2]([OH:1])([CH3:16])[CH3:15])[CH:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)CC(C)(C)O)=C(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CC(C)(C)O)=NNC1(C)C
Temperature: 180 °C
Yield: 98 %

Procedure:
500 mg of the product of Step B were added to 3 ml of acetic acid and 121 mg of hydrazine hydrate and the temperature rose spontaneously to 40° C. The acetic acid was distilled by heating the mixture up to 180° C. during which the majority of the acetic acid was removed. The mixture was cooled and water was added thereto. The mixture was extracted with chloroform and the organic phase was dried over magnesium sulfate and evaporated to dryness to obtain 520 mg of ethyl 4,5-dihydro-5,5-dimethyl-3-(2-hydroxy-2-methylpropyl)-[1H]-pyrazole-4-carboxylate in the form of a liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:18]([NH:20][C:21]3[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:24]=[CH:25][CH:26]=3)=[O:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=1.C[CH2:35][N:36]([CH2:39]C)[CH2:37]C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:43].Cl.CNC>C(Cl)Cl>[CH3:35][N:36]([CH3:39])[C:37]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:18]([NH:20][C:21]3[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:24]=[CH:25][CH:26]=3)=[O:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=1)=[O:43]
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)c2cc(-c3cccc(O)c3)cc3ccccc23)c1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cccc(NC(=O)c2cc(-c3cccc(OC(=O)N(C)C)c3)cc3ccccc23)c1
Yield: 36 %

Procedure:
To a flask containing 24a (0.9 mmol, 1.0 equivalent) in 10 mL of anhydrous CH2Cl2 was added NEt3 (4.57 mmol, 5.0 equivalents). 4-nitrophenyl chloroformate (1.37 mmol, 1.5 equivalents) was added slowly to the reaction flask at 0° C., and the solution was stirred until the reaction was complete (3 h) as determined by TLC. N,N-dimethylamine hydrochloride (2.74 mmol, 3 equivalents) was added and the reaction mixture was stirred at room temperature for 2 h. The solution was then diluted with DCM, and washed with water, aqueous K2CO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The resulting solid was purified using silica gel column chromatography using EtOAc/Pet Ether as eluent to afford 26 as a white solid.
Reaction SMILES: C[C:2]1(C)[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])(C)[NH:3]1.C([Li])CCC.[N:16]1[CH:21]=[CH:20]C=C[C:17]=1[C:22]([OH:24])=O.[O:25]=C1CCN(C(OC(C)(C)C)=O)C1>CCCCCC.C1COCC1>[NH:16]1[CH2:21][CH2:20][C:22]2([C:5]3[C:4](=[N:3][CH:2]=[CH:7][CH:6]=3)[CH2:9][O:24]2)[C:17]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: O=C(O)c1ccccn1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NCCC12OCc1ncccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (0.820 mL, 0.00486 mol) in tetrahydrofuran (5 mL, 0.06 mol) at −75 Celsius was added to 1.600 M of n-butyllithium in hexane (4.05 mL). After the mixture was stirred for 15 min, a solution of 2-pyridinecarboxylic acid (199 mg, 0.00162 mmol) was added. The resulting mixture was stirred at −75 Celsius for 10 minutes, then at −20 Celsius for 30 minutes. A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (250 mg, 0.0013 mol) in THF (2 mL) was then added to the above mixture. The reaction mixture continued to be stirred at −20 Celsius for 20 minutes, then was warmed up to r.t. and then stirred for additional 1 hour. The reaction mixture was quenched with water, then concentrated to remove THF, and then acidified to pH ˜1 using 6M aqueous HCl solution, and then stirred at r.t. overnight. The resulting mixture was extracted with methylene chloride. The aqueous layer was concentrated and the residue was directly purified by flash chromatography on silica gel column with 10% methanol in methylene chloride to give the desired compound. MS (ESI): 190.9 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C1(C)C=CC=CC=1>[Br-:1].[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[NH:4][CH2:3][CH2:2][N+:19]1[CH:20]=[CH:21][N:17]([CH3:16])[CH:18]=1
Reactant: COc1cc([N+](=O)[O-])ccc1NCCBr
Reactant: Cn1ccnc1
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1NCC[n+]1ccn(C)c1
Product: [Br-]

Procedure:
A mixture of 46.8 g (0.17 mol) of (2-bromoethyl)-(2-methoxy-4-nitrophenyl)amine and 20.5 g (0.25 mol) of 1-methyl-1H-imidazole in 170 ml of toluene was refluxed for 7 hours.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]=[N:13][N:12]([CH3:15])[C:11]=1[CH2:16][OH:17].Cl[C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][N:20]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]=[N:13][N:12]([CH3:15])[C:11]=1[CH2:16][O:17][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][N:20]=1
Reactant: Cn1nnc(-c2ccccc2F)c1CO
Reactant: Clc1ccc(I)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(I)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a suspension of NaH (0.73 g, 18.1 mmol, 60% in mineral oil) in DMF (10 ml) under N2 atmosphere at 0° C. was added [5-(2-Fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (2.5 g, 12.06 mmol) and stirred for 1 h. Then 2-chloro-5-iodopyridine (3.17 g, 13.27 mmol) was added and reaction mixture was slowly warmed to room temperature and stirred for 4 h. The reaction was monitored by TLC. The reaction mixture was quenched with ice-water, extracted with ethylacetate (50 ml), washed with brine (10 ml), dried over Na2SO4 and concentrated under reduced pressure to afford crude mass (4.4 g, 88.9% mass balance). It was triturated with hexane and the solid was filtered and dried under vacuum to furnish 2-[5-(2-Fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-5-iodo-pyridine (2.4 g, 48.48%) as yellow solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH:21]([CH2:23][C:24]([O:26]CC)=[O:25])[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=3[CH2:18][C:17]=2[CH:33]=1.[OH-].[Na+]>CCO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=3[CH2:18][C:17]=2[CH:33]=1
Reactant: CCOC(=O)CC1Cc2ccc(CCCc3nc4ccccc4[nH]3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1Cc2ccc(CCCc3nc4ccccc4[nH]3)cc2Cc2ccccc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-[3-(2-benzimidazolyl)-1-propyl]-5H-dibenzo[a,d]cycloheptene-10-acetate (236.3 mg, 0.54 mmole), 1.0 N NaOH (0.65 mL, 0.65 mmole), and absolute EtOH (4.8 mL) was warmed in an oil bath preset at 50° C. After 16 hr, the reaction was concentrated to dryness and the residue was purified by ODS chromatography (gradient: 35% MeOH/H2O, then 40% MeOH/H2O). Concentration followed by lyophilization gave the title compound (143 mg, 58%) as a colorless powder: HPLC (PRP-1®, 40% CH3CN/H2O containing 0.1% TFA) K'=1.5; 1H NMR (400 MHz, CD3OD) δ 7.41-7.49 (m, 2 H), 6.86-7.27 (m, 9 H), 4.24 (d, J=14.7 Hz, 1 H), 3.87 (d, J=14.7 Hz, 1 H), 3.73-3.85 (m, 1 H), 3.23-3.25 (m, 1 H, partially obscured by residual solvent signal), 2.80-2.93 (m, 3 H), 2.62 (t, J=7.5 Hz, 2 H), 2.56 (dd, J=14.4, 5.1 Hz, 1 H), 2.40 (dd, J=14.4, 9.7 Hz, 1 H), 2.05-2.17 (m, 2 H); MS (ES) m/e 411 (M+H)+. Anal. Calcd for C27H25N2O2Na. 1.5 H2O: C, 70.57; H, 6.14; N, 6.10. Found: C, 70.65; H, 5.95; N, 5.95.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH3:21])=[C:17](/[F:20])\[CH2:18][OH:19])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:3][C:4]1[C:5]([C:16]([CH3:21])=[C:17]([F:20])[CH:18]=[O:19])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1/C(C)=C(/F)CO)C=CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(C)=C(F)C=O)C=CCC2(C)C
Reaction time: 0.5 h

Procedure:
A solution of (2E)-3-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-en-1-ol (Compound A-49, 18 mg, 0.06 mmol), 4 Å molecular sieves (0.1 g) in dichloromethane (3 mL) was treated with tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4 methylmorpholine N-oxide (15 mg, 0.12 mmol). The solution was stirred under argon for 30 min and filtered through a silica gel plug (20% ethyl acetate in hexanes). The filtrate was concentrated under vacuum to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18](Cl)=[N:17][C:16]([Cl:20])=[CH:15][N:14]=1)(=[O:11])=[O:10].[CH2:21]([OH:24])[CH:22]=[CH2:23]>>[CH2:21]([O:24][C:18]1[C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:11])=[O:10])=[N:14][CH:15]=[C:16]([Cl:20])[N:17]=1)[CH:22]=[CH2:23]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: C=CCO
Product: C=CCOc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using allyl alcohol (10 mL) as solvent and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.35 g). Yield 0.32 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32])(=[O:35])[CH3:34]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Reactant: CC(=O)OC(C)=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(C)=O)c1=O

Procedure:
This compound was prepared from 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and acetic anhydride employing methods similar to those described in Step 2 of Example 373 and was obtained as a white solid: ES+ MS: 485 (M+H+).
Reaction SMILES: [CH3:1][CH2:2]OC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:36]([C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)#[N:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:1][CH2:2][N:28]2[CH:29]=[CH:30][N:31]=[C:26]([N:23]3[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]3)[C:27]2=[O:32])=[CH:40][CH:39]=1)#[N:37]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nccn(CCOc3ccc(C#N)cc3)c2=O)CC1
Reaction time: 8 h
Yield: 12.8 %

Procedure:
DEAD (0.520 ml, 3.3 mmol) was added to a slurry of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol), 4-cyanophenol (0.381 g, 3.20 mmol) and resin bound triphenylphosphine (1.1 g, 3.3 mmol) in dichloromethane (10 mL) and shaken overnight. The reaction mixture was filtered, concentrated and purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 0.168 g (13%) of the title compound. 1H NMR and MS analyses support the stated structure. HRMS m/z calcd for C22H27N5O4 (M)+ 425.2063, found 425.2075.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[CH2:6].[O:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1>Cl.C(OCC)C>[O:11]1[CH2:12][CH2:13][CH2:14][CH:15]1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:12]1[CH2:13][CH2:14][CH2:15][O:11]1)[CH:5]=[CH2:6]
Reactant: C1=COCC1
Reactant: C=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCOCC
Product: C=Cc1ccc(OC2CCCO2)c(OC2CCCO2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To 38.1 g (0.28 mol) of 3,4-dihydroxystyrene and 118 g (1.68 mol) of 2,3-dihydrofuran are added 5 drops of concentrated hydrochloric acid, whereupon an exothermic reaction ensues. The solution is stirred for 4 h at 50° C. and then poured on to a mixture of ice-water and diethyl ether. After two extractions with diethyl ether, the organic phase is washed three times at 0° C. with 1N NaOH and dried over Na2SO4. The solvent is removed by evaporation to leave a clear liquid which is purified by distillation in a bulb tube (155° C./0.02 torr) or by column chromatography (silica gel, hexane/ethyl acetate 4:1).
Reaction SMILES: [N:1]#[C:2]Br.[O-]Cl.[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[OH:17].[OH-].[Na+]>O1CCCC1.O>[NH2:1][C:2]1[O:17][C:9]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: N#CBr
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2ccc([N+](=O)[O-])cc2o1
Reaction time: 24 h
Yield: 71 %

Procedure:
A solution of cyanogen bromide (3.50 g, 33 mmol; caution: highly toxic! Waste disposal: addition of excess NaOCl to a basic aqueous solution of cyanogen bromide) in tetrahydrofuran (3 mL) was added to a solution of 2-amino-5-nitrophenol (4.62 g, 30 mmol) in tetrahydrofuran (20 mL). After stirring for 1 day at r.t, a precipitate had formed which was dissolved by addition of water (5 mL). After stirring further 3 days at r.t., water (10 mL) was added and NaOH was added until the mixture turned basic. The tetrahydrofuran was removed in vacuo and the precipitate formed in the remaining aqueous phase was separated by filtration, washed with water and recrystallized from methanol (100 mL). Upon additional fractional crystallisation of the mother liquor, a total of 3.80 g (21.2 mmol, 71%) of 2-amino-6-nitrobenzoxazole was obtained as a brown solid. LC/ESI-MS: m/z=180 [M+H]+; m/z=178 [M]−H−; R=2.52 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[F:13][CH:14]([F:29])[C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=2)[CH:18]=[CH:19][CH:20]=1.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:23]3[C:24](=[O:28])[CH2:25][CH2:26][CH2:27][C:22]=3[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]([F:13])[F:29])[CH:16]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Reactant: O=C1C=C(Nc2cccc(C(F)F)c2)CCC1
Solvent: O
Solvent: ClCCl
Product: O=C1CCCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (400 mg, 1.62 mmol) in dichloromethane (2.5 mL) is added to a solution of 3-(3-(difluoromethyl)phenylamino)-cyclohex-2-enone (intermediate 32, 385 mg, 1.62 mmol) in dichloromethane (2.5 mL). The mixture is heated at reflux for 2 h and cooled to room temperature. Water is added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 80:20 to ethyl acetate. Yield: 350 mg; ESI mass spectrum: [(79Br)-M+H]+=447, [(81Br)-M+H]+=449; Retention time HPLC: 0.61 min (X012_S01).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:19]=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:22]([C:23]([O:25]C)=[O:24])[C:5]=2[N:4]=1.[Li+].[OH-]>C1COCC1>[F:33][CH:2]([F:1])[C:3]1[N:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:19]=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:5]=2[N:4]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc2ccccc12
Yield: 66.4 %

Procedure:
A mixture methyl 2-(difluoromethyl)-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazole-4-carboxylate (700 mg, 1.55 mmol) and 2N LiOH (5 mL) in THF (10 mL) was stirred at 45° C. for 4 h. It was filtered, the filter cake was dissolved in water (10 mL) and formic acid was added to adjust pH to 3-4. Then a filtration was performed and the filter cake was collected, dried under vacuum to give the product (450 mg, 66%) as a white solid.