Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CN(C=O)C.[Pd].[Cu]I>[Br:8][C:6]1[N:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Br)nc1Br
Agent: [Cu]I
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of 3,5-Dibromo-pyrazin-2-ylamine (3.00 g, 11.86 mmol) in DMF (35 ml) was added triethylamine (16 ml), then tetrakistriphenylphine palladium (0) (685 mg, 0.59 mmol) and copper(I) iodide (271 mg, 1.42 mmol) were added sequentially. Finally trimethylsilylacetylene (2.0 ml, 14.3 mmol) was added dropwise. The reaction mixture was stirred at 120° C. for 30 minutes and then directly adsorbed onto silica gel. Purification by flash chromatography on silica gel with a gradient of ethyl acetate/hexane afforded the title compound (2.30 g, 71% yield) as yellow oil. MS: m/z 270.0/272.0 [MH+].
Reaction SMILES: C([O:5][P:6]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])CCC.Cl[C:18]([O:20][CH3:21])=[O:19]>>[CH3:21][O:20][C:18]([P:6](=[O:5])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19]
Reactant: CCCCOP(OCCCC)OCCCC
Reactant: COC(=O)Cl
Product: CCCCOP(=O)(OCCCC)C(=O)OC

Procedure:
From 26.6 g (0.10 mole) of tri-n-butylphosphite and 18.9 g (0.20 mole) of methyl chloroformate (80° C., 6 hours).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][N:34]2[CH:35]=[C:31]([C:9]3[C:8]4[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][C:7]=4[NH:11][N:10]=3)[CH:32]=[N:33]2)[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1nccc2[nH]nc(-c3cnn(CC4CC4)c3)c12
Yield: 45 %

Procedure:
Prepared according to the general procedure described in Example 86, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with cyclopropylmethyl bromide to give the title compound (21.3 mg, 45% over two steps). LC-MS (Method G): m/z=270.0 [M+H]+; 3.41 min. 1H-NMR (400 MHz, DMSO): δ 13.25 (s, 1H), 8.33 (s, 1H), 7.99 (s, 1H), 7.85 (d, J=5.7, 1H), 7.08 (d, J=5.9, 1H), 4.09-4.03 (m, 5H), 1.37-1.24 (m, 1H), 0.63-0.54 (m, 2H), 0.46-0.39 (m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[N:16][CH:17]=1.O>C1COCC1>[Br:11][C:12]1[CH:13]=[N:14][C:15]([O:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[N:16][CH:17]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cnc(OCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg (1.15 mmol, 60%) NaH are added to a solution of 0.17 mL (1.38 mmol) N-(2-hydroxyethyl)pyrrolidine in 10 mL THF at RT. The reaction solution is stirred for 15 min at RT and then 200 mg (1.03 mmol) 5-bromo-2-chloropyrimidine are added. The solution is stirred for 16 h at RT. 10 mL water are added and the aqueous phase is extracted with 20 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 9:1:0.1).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].[N:13]#[C:14]Br>>[O:6]([CH2:5][C@@H:2]1[CH2:3][O:4][C:14]([NH2:13])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CBr
Reactant: N[C@@H](CO)COc1ccccc1
Product: NC1=N[C@H](COc2ccccc2)CO1

Procedure:
In analogy to example 1b (S)-2-amino-3-phenoxy-propan-1-ol was reacted with cyanogen bromide to give (R)-4-phenoxymethyl-4,5-dihydro-oxazol-2-ylamine. Colourless gum. MS (ISP): 193.1 ([M+H]+))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:30][CH2:31]CS([O-])(=O)=O)[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[C:38]1([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:30][CH2:31][N:47]3[CH2:46][CH2:45][C:44]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:15][CH2:14][N:13]([C:16](=[O:29])[C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1ccc(C2(CCCS(=O)(=O)[O-])CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Agent: Cl
Product: COc1ccc(C2(CCN3CCC(C(N)=O)(c4ccccc4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC

Procedure:
Prepared by the method of example 3.3 using 2-[3-(3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.55 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (175 mg, 0.73 mmol). Chromatography on silica gel (30 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and 10% methanol in dichloromethane gave the title compound:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11]O)(=[O:4])=[O:3].P(Br)(Br)[Br:14]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:14][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1CBr
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of (2-methanesulfonyl-phenyl)methanol (735 mg, 3.99 mmol) in dry DCM (2 mL) at 0° C., add a solution of 1M phosphorous tribromide in DCM (6.0 mL, 6.0 mmol) and continue stirring for 1 h. Dilute with saturated aqueous NaHCO3, extract three times with ethyl ether, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (12:1) to provide the title compound as a white solid (950 mg, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:9])=[C:4]([Cl:8])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cncc(Cl)n1
Solvent: ClC(Cl)Cl
Product: Nc1cnc(Br)c(Cl)n1
Yield: 18.6 %

Procedure:
A solution of 2-amino-6-chloropyrazine (5.0 g) and N-bromosuccinimide (13.9 g) in chloroform (200 ml) was heated under reflux for 2 hours. Insoluble material was removed by filtration and the filtrate was concentrated by evaporation. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane, to give 2-amino-5-bromo-6-chloropyrazine (1.5 g); m.p. 120-122° C.; mass spectrum (+ve CI): 208 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][CH:29]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:3]=12.[CH3:38][Zn]C>C1COCC1>[CH:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]3[N:4]4[CH2:27][CH2:28][CH:29]([CH2:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C:3]4=[C:2]([CH3:38])[C:10]=3[CH:9]=2)=[CH:14][C:15]=1[C:23]([F:26])([F:24])[F:25])([CH3:21])[CH3:22]
Reactant: C[Zn]C
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(I)c2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: C1CCOC1
Product: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C(F)(F)F)c4)cc13)CCC2CC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of tert-butyl 2-(9-iodo-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.778 g, 1.236 mmol) in THF (12.3 mL) under nitrogen was added 2 M solution of dimethylzinc (1.854 mL, 3.71 mmol), followed by bis(tri-t-butylphosphine)Pd(0) (0.057 g, 0.111 mmol). The reaction was stirred overnight, slowly quenched with saturated NaHCO3, diluted with EtOAc, and filtered through Celite®. The organics were washed with water (twice), brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give the title compound as a solid (0.366 g). LCMS m/z=518.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.94 Hz, 6H), 1.38 (s, 9H), 2.15 (s, 3H), 2.19-2.30 (m, 1H), 2.43-2.48 (m, 1H), 2.69-2.81 (m, 2H), 3.54-3.64 (m, 1H), 3.86-3.96 (m, 1H), 3.98-4.07 (m, 1H), 4.73-4.84 (m, 1H), 5.07 (s, 2H), 6.74 (dd, J=8.65, 2.34 Hz, 1H), 7.00 (d, J=2.27 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.29 (d, J=9.35 Hz, 1H), 7.64-7.71 (m, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([NH:36][S:37]([C:40]2[C:41]3[N:42]=[CH:43][CH:44]=[N:45][C:46]=3[CH:47]=[CH:48][CH:49]=2)(=[O:39])=[O:38])[CH:27]=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:35][C:34]1[C:26]([Cl:25])=[CH:27][C:28]([NH:36][S:37]([C:40]2[C:41]3[N:42]=[CH:43][CH:44]=[N:45][C:46]=3[CH:47]=[CH:48][CH:49]=2)(=[O:38])=[O:39])=[C:29]([C:30]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:32])[CH:33]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCOCC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid (EXAMPLE 5, Step D) and morpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C19H16Cl2N4O4S, 466.0; m/z found, 465/467 [M−H]−. HPLC (reverse phase): RT=8.84 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 9.06 (d, J=1.8 Hz, 1H), 9.03 (d, J=1.8 Hz, 1H), 8.51 (dd, J=7.0, 1.5 Hz, 1H), 8.38 (dd, J=8.4, 1.4 Hz, 1H), 8.08 (d, J=1.5 Hz, 1H), 7.91 (dd, J=8.4, 7.4 Hz, 1H), 7.70 (s, 1H), 7.14 (s, 1H), 4.35-4.10 (br m, 4H), 3.65-3.48 (br m, 4H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([NH2:10])=[O:9])[N:5]=[CH:4]1.Br[CH:12]([CH2:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].O>CN(C=O)C>[C:8]([C:6]1[N:5]=[CH:4][N:3]([CH:12]([CH2:18][CH2:19][CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1c[nH]cn1
Reactant: CCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C(=O)OCC)n1cnc(C(N)=O)c1
Temperature: 55 °C
Reaction time: 1.5 h

Procedure:
NaH (60% in mineral oil, 60 mg) was added to a stirred solution of 4-imidazolecarboxamide (obtained in Preparation 1) (167 mg) in DMF (3.5 ml), and the reaction mixture was stirred for 1.5 hours at 55° C. Ethyl 2-bromovalerate (0.153 ml) was added to this mixture, and the reaction mixture was stirred for 3 hours at 55-60° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel (12 g) chromatography eluting with chloroform/methanol (25:1) to give ethyl 2-(4-carbamoyl-1-imidazolyl)valerate (150 mg).
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33].O>CN(C)C=O>[F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:18]=2)=[CH:11][C:5]2[N:6]([CH2:33][C:32]#[CH:31])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-c3ncc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
Then, 1.22 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-49) was dissolved in 15 ml of N,N-dimethylformamide, to which 0.59 g of potassium carbonate and 0.47 g of propargyl bromide were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.60 g (total yield in two steps (4) and (5), 25%) of 3-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-61; m.p., 141.4° C.).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1F
Yield: 57 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 2-fluoro-phenylhydrazine according to the method described for Example 1 in 57% yield.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.[Cl:10][CH2:11][C:12](O)=O>O.O.N>[Cl:10][CH2:11][C:12]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1N
Agent: Cl
Agent: N
Solvent: O
Product: ClCc1nc2ccccc2[nH]1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To 108 g of o-phenylenediamine, 1 l of 4N hydrochloric acid and 142 g of chloroacetic acid were added and refluxed for 1.5 hours. After allowing to stand overnight, the solution was diluted with 2 l of water and neutralized with dilute ammonia water. The formed crystals were filtered off to obtain 113 g of 2-chlorom ethylbenzimidazole.
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16](OC)=[O:17])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[O:25][CH:26]=[C:27]([CH3:29])[N:28]=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[O:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[O:17])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Reactant: Cc1coc(N)n1
Solvent: Cc1ccccc1C
Product: Cc1coc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)n1
Yield: 19.8 %

Procedure:
3.0 gm (9.1 millimols) of methyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino-[5,6-b]indole-3-carboxylate-1,1-dioxide and 0.98 gm (10 millimols) of 2-amino-4-methyloxazole were refluxed for 4 hours in 250 ml of xylene. Upon cooling, the raw product crystallized out. Recrystallization from ethanol yielded 0.7 gm (20% of theory) of 2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(4-methyl-2-oxazolyl)-1,2-thiazino[5,6-b]-indole-3-carboxamide-1,1-dioxide; M.p.: 128° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:16]2([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:15][CH:14]=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:28][CH2:27]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: c1cc(C2(CN3CCNCC3)CCCCC2)ccc1OCCCN1CCCC1
Product: CC(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCCCC2)CC1
Yield: 73 %

Procedure:
The title compound (73 mg, 73%) was prepared using 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl) piperazine and acetic anhydride similarly to the procedure used for example 166. 1H NMR (400 MHz, CDCl3) δ 1.31-1.34 (m, 3H), 1.48-1.53 (m, 5H), 1.82-1.85 (m, 4H), 1.99 (s, 3H), 2.02-2.07 (m, 4H), 2.13-2.17 (m, 4H), 2.28 (s, 2H), 2.58-2.64 (m, 4H), 2.70 (t, 2H), 3.20 (t, 2H), 3.41-3.43 (m, 2H), 4.01 (t, 2H), 6.83 (d, 2H), 7.25 (d, 2H). HRMS ESI+ m/z 428.3264 [MH]+.
Reaction SMILES: [O:1]=[C:2]1C2C=CC=CC=2C2N=C(O)C=[C:5]3[CH:17]=[CH:18][CH:19]=[C:3]1[C:4]=23.C1(C[C:27]([N:29]2[C:33](=[O:34])[C:32]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]3[C:30]2=O)=[O:28])C=CC=CC=1>>[OH:28][C:27]1[N:29]=[C:33]([O:34][C:2](=[O:1])[C:3]2[CH:4]=[CH:5][CH:17]=[CH:18][CH:19]=2)[C:32]2[C:31]([CH:30]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2
Reactant: O=C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2-c2nc(O)cc3cccc1c23
Product: O=C(Oc1nc(O)cc2ccccc12)c1ccccc1

Procedure:
7-OXO-7H-dibenzo-[d e,h]-quinolin-2-ol which is useful as an intermediate in the preparation of dyestuffs is prepared by cycloisomerizing the novel compound, N-phenylacetyl phthalimide in an inert solvent and in the presence of a Friedel-Crafts catalyst to form the novel compound O-(3-hydroxy-1-isoquinolinyl)-benzoic acid which is then cyclized by dehydrating condensation to form the 7-oxo-7H-dibenzo-[d e,h]-quinolin-2-ol.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1([CH3:13])[C:9]([O:11][CH3:12])=[O:10].CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:6]2[CH2:7][CH2:8][CH:3]([OH:2])[C:4]([CH3:13])([C:9]([O:11][CH3:12])=[O:10])[CH2:5]2)=[N:28][CH:29]=1
Reactant: COC(=O)C1(C)CNCCC1O
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)C1(C)CN(c2ncc(Br)cn2)CCC1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
To a solution of methyl 4-hydroxy-3-methyl-piperidine-3-carboxylate hydrochloride (0.4 g, 1.91 mmol) in EtOH (10 mL) was added DIPEA (1.7 mL, 9.55 mmol) at rt. The resulted mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.37 g, 1.91 mmol). The reaction mixture was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue was purified over 100-200 M silica-gel by using 25% EtOAc: hexane to obtain the product as an off white solid (0.345 g, 55%). MS: 330.12 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[Br:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([F:9])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Oc1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(Br)cc(F)c1OCc1ccccc1
Reaction time: 12 h
Yield: 87.8 %

Procedure:
To a solution of 5.0 g (24.0 mmol) of 2,6 difluoro-4-bromophenol in 20 ml of DMF at rt was added 5 g (36.0 mmol) of K2CO3 followed by 4.5 g (26.3 mmol) of benzyl bromide. The mixture was stirred for 12 h, diluted with H2O, the organic phase washed with sat'd NaCl, and the aqueous phase was then extracted 3× with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography with a gradient of 0-15% ethyl acetate/hexanes (v/v) afforded 6.3 g (88%) of the title compound: 1H NMR (500 MHz) δ 5.17 (s, 21), 7.06-7.11 (2H). 7.34-7.45 (5H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][CH3:24])[CH:17]=1)=[CH:12][C:11]([S:25]([CH2:28][CH2:29][C:30]([OH:32])=O)(=[O:27])=[O:26])=[CH:10][C:9]=2[CH3:33])=[O:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[ClH:1].[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:13]3[C:8](=[C:9]([CH3:33])[CH:10]=[C:11]([S:25]([CH2:28][CH2:29][C:30]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:32])(=[O:26])=[O:27])[CH:12]=3)[N:7]=[CH:6][C:5]=2[C:3]([NH2:2])=[O:4])=[CH:17][C:18]=1[O:23][CH3:24]
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCC(=O)O)cc23)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCC(=O)N4CCOCC4)cc23)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Example 481 (0.035 g) in N,N-dimethylformamide (2 ml) was added O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.029 g). After 5 min, morpholine (0.007 ml, available from Aldrich) and N,N-diisopropylethylamine (0.026 ml) were added. The resulting solution was stirred at room temperature overnight, and applied directly to an SCX cartridge (IST Isolute™, 5 g). Elution with methanol and 2M ammonia/methanol gave an orange residue, which was further purified by mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.006 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH2:12]([Sn](CCCC)(CCCC)CC=C)[CH2:13][CH2:14]C.CN(C)C=O.[F-].[K+]>C(N(CC)CC)C>[CH2:14]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCc2c(Br)cccc21
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCc1cccc2c1CCC2=O
Temperature: 20 °C

Procedure:
15 g of 4-bromo-1-indanone, 24 ml of tributyl allyl stannane, 150 ml of dimethylformamide, 0.82 g of tetrakis triphenyl phosphine palladium and 7.89 g of triethylamine are taken to 120° C. for one hour. After cooling to 20° C., the reaction mixture is poured over 300 ml of an aqueous solution of potassium fluoride, agitated, and filtered on celite; the filtrate is extracted with isopropyl ether. The insoluble part is taken up with ethyl acetate and filtered on celite. The reunited organic phases are washed with water saturated with sodium chloride, dried and brought to dryness under reduced pressure. The residue is chromatographed on silica with hexane-ethyl acetate (9-1) and 11.84 g of expected product is recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5](=[CH:11][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:13][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1ccc(Cl)cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1ccc(Cl)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
Ethyl 4-chlorosalicylate (174 mg), 4-chloro-6,7-dimethoxyquinoline (195 mg), and 4-dimethylaminopyridine (320 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed therefrom by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (26 mg, yield 8%).