Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=S)=[CH:5][CH:4]=1.O.[NH2:22][NH2:23]>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7](=[N:22][NH2:23])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=S)Nc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=NN)Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 10 g of 4-methoxy-4'-nitrothiobenzanilide [prepared by process of Ann. Chem., Vol. 716 (1968), p. 209-211], 100 ml of ethanol and 15 ml of hydrazine hydrate was heated to reflux and then was allowed to return to room temperature and was filtered. The product was washed with ethanol and dried at 80° C. under reduced pressure to obtain 7.9 g of 4-methoxy-N-(4-nitrophenyl)-benzene-carbohydrazonamide melting at 104° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].C(OCC)C.O.Br[CH2:13][C:14]([CH3:28])=[CH:15][C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17]>>[C:1]([O:4][CH2:13][C:14]([CH3:28])=[CH:15][C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=CC(=O)OCCOc1ccccc1)CBr
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)OCC(C)=CC(=O)OCCOc1ccccc1

Procedure:
β-phenoxyethyl 4-bromo-3-methyl-2-butenoate (15g) obtained in Example 7 was refluxed with anhydrous sodium acetate (5.32g) in glacial acetic acid (15g) for 8 hours. Ethylether (300ml) and water (20ml) were added to the reaction mixture and the ether layer was washed with water, dried, and concentrated, giving a crude product (11.7g). The crude product on fractionation gave a fractionation gave a fraction (6.1g), b.p. 165°-168° C./0.6mmHg. Structural assignment for this compound was made from its infrared absorption spectrum; 1738, 1710, 1658, 1600, 1590, 1500, 1240, 1215, 1145, 1055, 1040, 755, and 690cm-1.
Reaction SMILES: C1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)C=CC=1C(O)=O.[C:17](O)(=O)C1C=CC(C(O)=O)=CC=1.[N+]([O-])(O)=O>C1(C)C(C)=CC=CC=1>[CH3:17][C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][C:7]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Solvent: O=[N+]([O-])O
Solvent: Cc1ccccc1C
Product: Cc1ccccc1C(=O)O

Procedure:
Organic acids, such as naphthalene-2,6-dicarboxylic acid or terephthalic acid, are highly useful in the manufacture of polyester-type and polyamide-type resins, including polyethyleneterephthalate. Such organic acids customarily have been prepared by a liquid phase oxidation of an alkyl-substituted aromatic precursor in the presence of an aqueous acidic reaction medium, and usually in the presence of a metal catalyst. For example, U.S. Pat. No. 2,766,281 discloses the preparation of phthalic acids, including terephthalic acid, by a step-wise oxidation of a corresponding xylene with concentrated nitric acid at atmospheric pressure and in the presence of an inert organic reaction medium that is liquid at the reaction temperatures. In the first step, the xylene starting material is reacted with the nitric acid at a temperature of from about 120 ° C. up to the boiling point of the xylene starting material, while removing water by distillation, to form a toluic acid. In the second step, nitric acid is slowly added to the toluic acid at a temperature in excess of about 140 ° C., while removing water by distillation, to form the product phthalic acid.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-:36])=[O:35])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1OCCCCCN1CCC(O)CC1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[5-(2-nitrophenoxy)pentyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[5-(2-nitrophenoxy)pentyl]piperidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43]2[N:47]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[C:46]3[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=3[N:44]=2)[CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[C:3]([C:8]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([NH:42][C:43]3[N:47]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=4)[C:46]4[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=4[N:44]=3)[CH2:38][CH2:37]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Nc1nccnc1C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: Nc1nccnc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a stirred mixture of 2.1 parts of 3-amino-2-pyrazinecarboxylic acid, 2.8 parts of N,N-dibutylbutanamine and 195 parts of dichloromethane were added 3.83 parts of 2-chloro-1-methlypridinium iodide. After stirring for 15 minutes at room temperature, 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine were added and stirring was continued for one hour. The reaction mixture was washed with water, dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The latter was decanted and the residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 2.8 parts (38%) of 3-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-pyrazinecarboxamide; mp. 156.9° C. (compound 113).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([O:17]C(=O)C)[C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:17])[C:12]([CH3:15])([CH3:16])[C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H](CCOCc1ccccc1)C(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C#N)[C@@H](O)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.8 g (17.5 mmol) of 5-benzyloxy-2,2-dimethyl-3(S)-acetoxy-pentane-nitrile from the second fraction is dissolved in 50 ml of methanol and mixed with 1.4 g (35 mmol) of NaOH. It is stirred for 3 hours at 25° C., added to 200 ml of water, extracted with 2×200 ml of MTB ether, dried on sodium sulfate and concentrated by evaporation.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]=1.[N:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.CCOCC>C(#N)C>[Br-:1].[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][CH2:2][N+:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:6]1
Reactant: BrCCCC1=CCc2ccccc21
Reactant: Cc1ccncc1
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc[n+](CCCC2=CCc3ccccc32)cc1
Product: [Br-]
Yield: 82.2 %

Procedure:
A solution of 121 g (0.51 mole) of 3-(3-bromopropyl)indene (prepared as in Example 7) and 68 g (0.74 mole) of γ-picoline in 150 ml of acetonitrile is heated at reflux temperature overnight. A small amount of ether is added and the mixture let stand at room temperature for 3 hours, and then filtered. The solid collected is washed with ether and dried in vacuo to give 138 g (0.419 mole) of tan solid, mp 93°-123°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH2:26]([O:28][CH:29]([O:32][CH2:33][CH3:34])[CH2:30][NH2:31])[CH3:27].CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>C1COCC1.O>[N+:1]([C:4]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH:31][CH2:30][CH:29]([O:32][CH2:33][CH3:34])[O:28][CH2:26][CH3:27])=[O:8])([O-:3])=[O:2]
Reactant: CCOC(CN)OCC
Reactant: CC(C)(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CNC(=O)c1ccc(C(C)(C)C)cc1[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
2-nitro-4-tert-butylbenzoic acid (1.5 g, 7 mmol, prepared according to J. Am. Chem. Soc, 1955, 77, 5441) was stirred in THF at room temperature, 1.7 mL diisopropylethyl amine (13 mmol, 2 eq) was added, followed by 984 mg (7.7 mmol, 1.1 eq) 2-amino acetaldehyde diethylacetal. (3-Dimethylamino-propyl)-ethyl-carbodiimide (1.55 g, 8 mmol, 1.2 eq) was added, followed by a catalytic amount (ca. 50 mgs) hydroxybenzotriazole hydrate. The mixture was stirred at room temperature for 16 hours, diluted with water, extracted with diethyl ether 3×, the ether layers were washed with water, brine, and dried over MgSO4. Removal of solvent under vacuum, followed by chromatography on silica gel, eluting with 25% ethyl acetate in hexanes, gave the title compound 0.950 g, (M+H)+=224.
Reaction SMILES: [Na].[N+:2]([CH:5]=[C:6](SC)[S:7]([CH3:9])=O)([O-:4])=[O:3].Br.[Br:13][CH2:14][CH2:15][CH2:16][NH2:17]>CO>[N+:2]([CH:5]=[C:6]([S:7][CH3:9])[NH:17][CH2:16][CH2:15][CH2:14][Br:13])([O-:4])=[O:3]
Reactant: NCCCBr
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Agent: Br
Agent: [Na]
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCCCBr
Reaction time: 5 h
Yield: 39.2 %

Procedure:
A solution of sodium (0.09 g, 0.004 mol) in methanol (10 ml) was added dropwise to a stirred solution of 1-nitro-2-methylthio-2-methylsulphinyl-ethylene (0.5 g, 0.003 mol) and 3-bromopropylamine hydrobromide (0.9 g, 0.004 mol) in methanol (30 ml). The mixture was stirred for 5 hours, and then the solvent was removed in vacuo. The residue was dissolved in water (20 ml) and extracted with chloroform (2×30 ml). The extracts were combined, dried, and concentrated in vacuo. The solid residue was recrystallised from propan-2-ol to give 1-nitro-2-methylthio-2-(3-bromopropylamino)ethylene (0.3 g, 43%) m.p. 92°-92.5°. Found: C, 28.2; H, 4.3; N, 10.9; S, 12.5; Br, 31.3; C6H11BrN2O2S requires: C, 28.2; H, 4.35; N, 11.0; S, 12.6; Br, 31.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13]C(=O)OC(C)(C)C)[CH2:8]1.[NH2:22][C:23]1[C:24]([C:30]([OH:32])=O)=[N:25][C:26](Br)=[CH:27][CH:28]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[NH2:22][C:23]1[C:24]([C:30]([NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:21])[C:6]=2[N:7]2[CH2:11][CH2:10][C@H:9]([CH2:12][NH2:13])[CH2:8]2)=[O:32])=[N:25][C:26]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])=[CH:27][CH:28]=1
Reactant: Cn1ncc(N)c1N1CC[C@H](CNC(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: OB(O)c1ccccc1F
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)ccc2N)c1N1CC[C@H](CN)C1
Yield: 37 %

Procedure:
Following the procedures for Example 141, (R)-tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate and 3-amino-6-bromopicolinic acid were coupled and the intermediate amide was reacted with 2-fluorophenylboronic acid under palladium catalyzed Suzuki conditions to give 136 as a white solid (51 mg, 37%) over three steps. 1H NMR (400 MHz, DMSO) δ 9.75 (s, 1H), 8.04 (dd, J=11.3, 4.6, 1H), 7.73 (dd, J=8.7, 2.0, 1H), 7.57 (s, 1H), 7.51-7.23 (m, 4H), 7.07 (s, 2H), 3.65 (s, 3H), 3.30-3.20 (m, 3H), 3.00 (dd, J=8.8, 6.3, 2H), 2.35-2.12 (m, 2H), 1.97 (td, J=12.4, 7.2, 1H), 1.56 (tt, J=40.8, 20.4, 1H). ESIMS m/z=410.1 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([CH3:18])[N:11]=1.[Se](=O)=[O:20]>COCCOCCOC.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([CH:18]=[O:20])[N:11]=1
Reactant: Cc1nc(Nc2ccc(F)cc2F)ccc1C#N
Reactant: O=[Se]=O
Solvent: CC(=O)O
Solvent: COCCOCCOC
Product: N#Cc1ccc(Nc2ccc(F)cc2F)nc1C=O
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,4-difluorophenylamino)-2-methylnicotinonitrile (350 mg, 1.4 mmol) and selenium dioxide (238 mg, 2.14 mmol) in 1-methoxy-2-(2-methoxyethoxy)ethane (7.00 mL) and 0.2 mL of glacial acetic acid was heated in an oil bath at 120° C. for 10 min. The temperature of the oil bath was slowly warmed to 155° C. in 30 min and stirred at this temperature for 3 h. The reaction mixture was cooled to RT, filtered through a pad of Celite washing with EtOAc, and concentrated. The remaining brown solution was purified on an ISCO 12 g column and the product eluted with 50-80% EtOAc in hexanes to afford 6-(2,4-difluorophenylamino)-2-formylnicotinonitrile in residual amount of 1-methoxy-2-(2-methoxyethoxy)ethane. MS (ESI, pos.ion) m/z: M+1=260.0
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C@@H:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].[CH2:21]([N:28]([CH3:37])[CH:29]1[CH:34]2[CH2:35][CH2:36][CH:30]1[CH2:31][NH:32][CH2:33]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(O)C>[CH2:21]([N:28]([CH3:37])[CH:29]1[CH:34]2[CH2:35][CH2:36][CH:30]1[CH2:31][N:32]([CH2:11][C@H:9]([NH:10][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=1)[CH2:33]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]1COc1ccc(C#N)cc1
Reactant: CN(Cc1ccccc1)C1C2CCC1CNC2
Solvent: CC(C)O
Product: CN(Cc1ccccc1)C1C2CCC1CN(C[C@@H](COc1ccc(C#N)cc1)NC(=O)OC(C)(C)C)C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (2S)-2-[(4-cyanophenoxy)methyl]-1-aziridinecarboxylate (see step (iii) above; 1.26 g, 4.6 mmol) and N-benzyl-N-methyl-3-azabicyclo[3.2.1]octan-8-amine (see step (vii) above; 1.05 g, 4.6 mmol) in IPA (15 mL) was stirred at 60° C. overnight. The solvent was evaporated and the residue purified by chromatography on silica gel, eluting with DCM:MeOH (20:1). This gave 1.8 g (78%) of the subtitle compound
Reaction SMILES: CO.[C:3]([OH:11])(=[O:10])[C:4]([CH2:6][C:7]([OH:9])=[O:8])=[CH2:5].C(N(CC)CC)C.Cl([O-])(=O)(=O)=O>[H][H].C1CCCCC=CC=1.[Rh]>[CH3:5][CH:4]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Rh]
Agent: C1=CCCCCC=C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(CC(=O)O)C(=O)O
Yield: 91.9 %

Procedure:
To 10 ml of methanol were added 1.301 g (10 m-mol) of itaconic acid, 1.4 ml (10 m-mol) of triethylamine and 8.8 mg (0.01 m-mol) of rhodium cyclooctadiene BCPM complex perchlorate ([Rh(COD)BCPM]+ClO4-). The mixture was stirred in hydrogen atmosphere at 1 atm. for 20 hours at 20° C. and the reaction mixture was concentrated under reduced pressure. To the residue was added 20 ml of an aqueous solution of 1N-NaOH and the mixture was filtered to remove insoluble matter. The filtrate was made acidic with 6N-HCl and extracted with ether. From the ethereal extract, 2-methylsuccinic acid was obtained quantitatively by distilling off the solvent. It was confirmed that the itaconic acid had been converted by 100% in view of a result of 1H-NMR. [α]D22 =-15.51° (c=2.00, EtOH)(optical yield: 91.9%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][NH2:8])=[O:6].[CH3:13]OC(C1C=C(C2C=CC(NC(=O)C3C(F)=CC=CC=3F)=CC=2)C(C)=CC=1)=O>>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:13]=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(C(=O)NN)cc1I
Reactant: COC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c1
Product: Cc1ccc(-c2nnco2)cc1I

Procedure:
3-Iodo-4-methyl benzoic acid methyl ester was treated with hydrazine to form 3-Iodo-4-methyl benzoic acid hydrazide. 2-(3-Iodo-4-methyl-phenyl)-[1,3,4]oxadiazole was prepared from 3-iodo-4-methyl benzoic acid hydrazide according to a method analogous to that described in J. of Medicinal Chemistry (2001), 44(8):1268-85, the entire teachings of which are incorporated herein by reference. Compounds 46, 68, 69, 70, and 71 were prepared via an amide coupling reaction analogous to that described in step A of the synthesis of Compound 1, followed by a Suzuki coupling reaction analogous to that described in step B of the synthesis of Compound 1. The amide coupling reaction and Suzuki coupling reaction are shown for Compound 69 in Scheme XX below:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:18]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)c(Cl)cc2c1N
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)c(Cl)cc2c1NCC(=O)c1ccccc1

Procedure:
Dissolve 3-amino-2-carbethoxy-5,6-dichloroindole (2.2 g, 8 mmol) in methylene chloride (70 mL) and add triethylamine (1.16 mL, 8 mmol) followed by benzoyl chloride (0.93 mL, 8 mmol). Stir the reaction 48 hours at room temperature. Dilute the reaction with ethyl acetate (300 mL), wash with water (100 mL), dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue from ethyl acetate/hexane to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O-]S([O-])(=O)=O.[Mg+2].[CH3:15][C:16]([CH3:20])(O)[C:17]#[N:18]>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([CH3:20])([CH3:15])[C:17]#[N:18])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(O)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(C)(C#N)Nc1ccc(O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A mixture of 4-aminophenol (1.09 g, 10 mmol), acetone cyanohydrin (10 ml) and MgSO4 (2 g) was heated to 80° C. and stirred for 4 h. After concentration of the medium under vacuum, compound 3a was crystallized from water (20 ml). The solid was filtered and dried to yield 2-(4-hydroxyphenylamino)-2-methylpropanenitrile, 3a (1.69 g, 9.6 mmol, 96%).
Reaction SMILES: OC[C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:16])[N:7]2[C:12]=1[C:11]1[S:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8]2.[C:23]([O:26][C:27](=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:26][CH2:27][SH:13]1[C:11]2[C:12]3[N:7]([CH2:8][CH2:9][C:10]=2[CH:15]=[CH:14]1)[C:6](=[O:16])[C:5]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:4][CH:3]=3)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccsc1-2
Solvent: c1ccncc1
Product: CC(=O)OC[SH]1C=CC2=C1c1ccc(-c3ccccc3)c(=O)n1CC2

Procedure:
A suspension of 1.55 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one in 6.7 ml of pyridine was treated with 3.35 ml of acetic anhydride while stirring, whereby a clear solution was obtained after about 15 minutes. After stirring overnight, the precipitated yellow crystals were removed by filtration under suction and washed with ether. The filtrate was evaporated in vacuo and the residue together with the above yellow crystals were recrystallized from methanol. There was obtained pure (4,5-dihydro-7-oxo-8-phenyl-thieno[2,3-a]-quinolizin-1-yl)methyl acetate of m.p. 145°-146°.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH3:27][CH:28]([S:30]([Cl:33])(=[O:32])=[O:31])[CH3:29].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[ClH:33].[NH2:16][C@H:15]([C:24](=[O:26])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:14][CH2:13][CH2:12][NH:11][S:30]([CH:28]([CH3:29])[CH3:27])(=[O:32])=[O:31]
Reactant: C1CCNC1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)S(=O)(=O)NCCC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, 2-propanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:48]=[CH:49][C:50]=1[O:51][CH3:52])[CH2:32][O:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44](O)=[O:45])[C:39](=[O:47])[N:38]=1)=[O:35]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:44](=[O:45])[CH2:43][N:40]2[CH:41]=[CH:42][C:37]([NH:36][C:34]([O:33][CH2:32][C:31]3[CH:48]=[CH:49][C:50]([O:51][CH3:52])=[C:29]([O:28][CH3:27])[CH:30]=3)=[O:35])=[N:38][C:39]2=[O:47])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2ccn(CC(=O)N3CCN(S(=O)(=O)c4nc5ccccc5s4)C(=O)C3)c(=O)n2)cc1OC

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(3,4-dimethoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.73 (brs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.71 (m, 2H), 7.03 (s, 1H), 7.02 (t, 1H), 6.94 (s, 2H), 5.09 (s, 2H), 4.82 (s, 1.2H), 4.72 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.21 (t, 1.2H), 4.06 (t, 0.8H), 3.99 (t, 1.2H), 3.85 (t, 0.8H), 3.75(s, 3H), 3.74 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[C:18](=[O:20])[CH3:19]>CN(C=O)C>[CH2:7]([O:17][C:15]1[CH:14]=[CH:13][C:12]([C:18](=[O:20])[CH3:19])=[C:11]([OH:10])[CH:16]=1)[CH3:8]
Reactant: CCI
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)=O)c(O)c1
Reaction time: 4 h
Yield: 69.4 %

Procedure:
Potassium carbonate (13.6 g, 99 mmol) followed by ethyl iodide (2.4 mL, 29.6 mmol) were added to a solution of 2′,4′-dihydroxyacetophenone (5 g, 33 mmol) in DMF (50 mL). The mixture was stirred for 4 hours and then partitioned between H2O and EtOAc. The organic layer was washed with satd NaHCO3, brine, dried over Na2SO4 and concentrated to a clear oil. Purification by column chromatography gave the product as a white solid (3.7 g, 63%). 1H NMR (400 MHz, CDCl3): δ 1.43 (t, J=6.8 Hz, 3H), 2.55 (s, 3H), 4.07 (d, J=7.1 Hz, 2H), 6.40 (s, 1H), 6.43 (d, J=8.8 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 12.74 (s, 1H).