Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][NH2:28])=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([NH:27][NH:28][C:4]([C:3]2[C:2]([NH2:1])=[N:10][CH:9]=[C:8]([Br:11])[CH:7]=2)=[O:6])=[O:26])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)c2cc(Br)cnc2N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-amino-5-bromo-nicotinic acid (1.2 g, 5.53 mmol) in DMF (30 mL) were added 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 6.173 mmol), HATU (2.35 g, 6.184 mmol) and DIPEA (4 mL, 23.56 mmol) at RT. The reaction mixture was stirred for 18 h at RT. The reaction mixture was poured into ice-water (30 mL), extracted with ethyl acetate (3×50 mL), organic layer was washed with brine dried over anhydrous sodium sulphate concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 60% EtOAc in petroleum ether to afford the title compound as an off-white solid.
Reaction SMILES: [CH:1]([CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])=[O:2].S(=O)(O)[O-].[Na+].[C-:20]#[N:21].[Na+]>O.CCOCC>[C:20]([CH:1]([OH:2])[CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])#[N:21]
Reactant: [C-]#N
Reactant: CN1C(=O)C(CC=O)c2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CN1C(=O)C(CC(O)C#N)c2ccccc21
Temperature: 25 °C

Procedure:
89 Grams of 3-formylmethyl-1-methyloxindole and 54 g of sodium bisulfite was dissolved in a mixed solvent of 75 ml of water with 150 ml of ether, then to the resultant mixture was added dropwise a solution of 28 g of sodium cyanide with 60 ml of water, under stirring at a room temperature. The reaction mixture was stirred for 1 hour, then water was added to the reaction mixture until the crystals formed were dissolved, the whole reaction mixture was further stirred for 1 hour. The crystals formed were collected by filtration, washed with water, dried and recrystallized from benzene to obtain 30 g of 3-(2-cyano2-hydroxyethyl)-1-methyloxindole in the form of white powdery substance. Melting point: 136°-138°C.)
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(CCC[NH:22][C:23]([O:25][CH2:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1)=[O:24])(OC)=O.CN(C)[CH:38]=[O:39]>>[C:26]([CH2:27][CH2:32][CH2:31][CH:26]([O:25][C:23](=[O:24])[NH2:22])[C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:35])[NH:1][CH:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:3]2=[O:14])[CH:30]=[CH:31][CH:32]=1)([O:39][CH3:38])=[O:25]
Reactant: COC(=O)CCCNC(=O)OCc1cccc(N=C=O)c1
Reactant: CN(C)C=O
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Product: COC(=O)CCCC(OC(N)=O)c1cccc(NC(=O)NC2C(=O)Nc3ccccc3NC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 3-amino-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (1.91 g, 10.0 mmol) and 3-(3-(carbomethoxy)propylcarbamoyloxymethyl)phenylisocyanate (3.507 g, 12.0 mmol) in dimethylformamide (19 ml) is stirred for 1 hr at room temperature. To the residue obtained by concentrating the reaction mixture under reduced pressure is added methylene chloride (300 ml) and methanol (100 ml), and the mixture is stirred for 30 min at room temperature. The reaction mixture is filtered through a silica gel (50 g) layer to obtain Compound 6 (4.822 g, 100%) as colorless crude crystals. M.p. =151°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:15])[C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C.Cl>[NH2:8][C:6]1[CH:5]=[C:4]([N:11]([CH3:15])[C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: CC(=O)N(C)c1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(=O)N(C)c1cc(N)cc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
4.5 g (0.0165 mol) of N-(3-bromo-5-nitrophenyl)-N-methylacetamide were dissolved in 75 ml of ethanol, treated while cooling with a solution of 15.0 g (0.0665 mol) of SnCl2.2H2O in 30 ml of HCl (37%) and stirred at room temperature for 18 hrs. Then, the solvent was removed, the residue was adjusted to pH 8 with sat. NaHCO3 solution, extracted with ethyl acetate and sat. sodium chloride solution and the organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:2, 1:1 and finally 2:1. There were obtained 2.35 g (59%) of N-(3-amino-5-bromophenyl)-N-methylacetamide as light brown crystals. MS (EI): me/e=244,242 (C9H11BrN2O+).
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([CH2:30][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 25 mg of 2-bromoacetophenone was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 33 mg of white crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Cl[C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[C:14]=1[C:15]([OH:17])=[O:16].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:25][C:18]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=2)[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1
Reactant: CCCOc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCOc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A mixture of 24.5 g of 4-propoxyaniline, 19.8 g of 2,6-dichloro-3-nitrobenzoic acid, and 150 ml N,N-dimethylaniline was heated under nitrogen at 100° overnight. The cooled reaction mixture was treated with dilute base and chloroform. After the aqueous layer was washed several times with chloroform, it was treated with hydrochloric acid and the resulting orange needles were collected by filtration and washed with water to give 6-chloro-3-nitro-2-[(4-propoxyphenyl)amino]benzoic acid, mp 194°-196° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1oc2cccc(OC(C)=O)c2c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of ethyl-4-hydroxy-3-methylbenzofuran-2-carboxylate (2.2 g, 10 mmol) in dry THF (30 ml) was added triethylamine (2.07 ml, 15 mmol) followed by acetyl chloride (0.85 ml, 12 mmol). The mixture was stirred at 0° C. for 1 hour, and at room temperature for 2 hours, and was then poured into ice water (200 ml). The white precipitate was collected by filtration.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[CH3:17][CH:18]([NH2:20])[CH3:19]>ClCCl>[CH:18]([NH:20][CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1)([CH3:19])[CH3:17]
Reactant: CC(C)N
Reactant: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CCl
Solvent: ClCCl
Product: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CNC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A mixture of 151b (500 mg, 2.04 mmol), propan-2-amine (180 mg, 3.06 mmol), and dichloromethane (20 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to afford 151c (400 mg, 74%) as a yellow solid, which was used in the next step without further purification. MS-ESI: [M+H]+ 271.1
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([C:15]1[CH:20]=[C:19]([F:21])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[F:25])([CH2:11][CH:12]([CH3:14])[CH3:13])C(OCC)=O)C>CC(O)=O.O.CCO>[F:25][C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[C:19]([F:21])=[CH:20][C:15]=1[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)CC(C(=O)O)c1cc(F)c([N+](=O)[O-])cc1F
Yield: 64.7 %

Procedure:
The above 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester (57.0 g, 152.8 mmol) was dissolved in AcOH/H2O/EtOH (400 mL/120 mL/50 mL) and the reaction mixture was heated under reflux for 96 h. After cooling the solvent was evaporated under reduced pressure and water (200 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL), and the combined extracts were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave a yellow oil which crystallized on standing to yield 27 g of 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid. Chromatography of the residual oil (Heptane-EtOAc gradient) gave an additional 3 g of product (72% combined yield). 1H NMR (300 MHz, CDCl3/TMS): δ 9.63 (br s, 1H), 7.82 (dd, J=8.8, 6.0 Hz, 1H), 7.38 (dd, J=11.0, 5.8 Hz, 1H), 4.14-4.08 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 177.6, 158.2 (d, 1JCF=232.5 Hz), 150.9 (d, 1JCF=262.5 Hz), 136.0, 134.7, 119.0 (d, 2JCF=20.0, Hz), 113.1 (d, 2JCF=29.4 Hz), 41.7, 41.3, 26.0, 22.6, 21.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[Br:12]N1C(C)(C)C(=O)N(Br)C1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C(O)(=O)C>C1(Cl)C=CC=CC=1>[Br:12][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)cc1CBr
Yield: 27.3 %

Procedure:
5-Fluoro-2-nitrotoluene (9.3 g, 60 mmol), 1,3-dibromo-5,5-dimethylhydantoin (20 g, 70 mmol), and 1,1′-azobis(cyclohexanecarbonitrile) (VAZO 88, 600 mg, 2.5 mmol) were combined in C6H5Cl (600 ml) and stirred. Acetic acid (300 ul, 5.24 mmol) was added to the solution and the solution was stirred at 40° C. for 96 h. The crude reaction mixture was washed three times with hot NaHCO3 solution (200 ml, 80° C.), dried over magnesium sulfate, filtered and the solvent removed. The resulting crude red-orange solid was filtered through silica to yield a mixture that was about 1:1 brominated product and unbrominated starting material. The material was carried onto the next step without further purification. Pure material could be obtained from flash chromatography on silica (6:1 hexanes/EtOAc) to give a brown oil (3.84 g, 27%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1N.[OH-].[K+].[C:12](=[S:14])=S.C(O)(=[O:17])C>O.CO>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:12]([SH:14])=[N:1][C:2]=2[CH:3]=1
Reactant: S=C=S
Reactant: CC(=O)O
Reactant: Cc1ccc(N)c(N)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2oc(S)nc2c1
Temperature: 78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-diaminotoluene (20.0 g, 162.6 mmol) and potassium hydroxide (11.36 g, 203.0 mmol) in H2O (40 mL) and MeOH (150 mL) was added carbon disulfide (13.3 mL, 220.8 mmol) slowly via syringe, and the reaction was heated to 78° C. for 2.5 hours. The mixture was poured over a mixture of ice (200 mL) and acetic acid (30 mL), and thick yellow precipitate formed. The mixture was stirred at 45° C. for 30 minutes, and then filtered to collect the solid precipitate, which was washed twice with H2O (40 mL total). The filter cake was triturated in a minimum of EtOAc, and then filtered and dried to give the title compound.
Reaction SMILES: O[CH:2]1C(=C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:13]([O-:16])(=O)[CH3:14].[NH4+:17]>C(O)C>[NH2:17][CH:2]=[C:3]1[CH2:4][C:5]2[C:14](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:13]1=[O:16]
Reactant: [NH4+]
Reactant: C=C1c2ccccc2C(=O)C1O
Reactant: CC(=O)[O-]
Solvent: CCO
Product: NC=C1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-hydroxy-methylene-1-indanone (1.6 kg. as a 3.7 kg. wet cake) dissolved in ethanol (30 liters), and under a nitrogen atmosphere was added ammonium acetate (1.92 kg. 24.8 mole). After eight hours the reaction was complete and the ethanol was removed by vacuum distillation. The reaction mixture was cooled to room temperature and after filtration and air drying (1 hr.) yielded crude 2-aminomethylene-1-indanone (I) as orange crystals. The crystals were then dissolved in a minimum amount of hot ethanol and the solution was decolorized with activated charcoal. Crystals appeared in the filtrate and after cooling overnight at 5° C, the reaction mixture was filtered yielding 960 gm. of compound (I) as light orange crystals. The filtrate was again treated with activated charcoal and recrystallized providing an additional 200 gm. of compound (I). The combined sample (1160 gm.) was milled giving a fine yellowish powder which was dried at 50° C/25 mm/Hg for 48 hours. A sample (50 gm.) of this material was recrystallized three times from ethanol to give 2-aminomethylene-1-indanone (15 gm.), m.p. 166°-168° C.
Reaction SMILES: FC1C=CC(CN)=CC=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccn1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccccn1
Yield: 43 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 2-(aminomethyl)pyridine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 43% yield: mp 149-151° C.: 1H NMR (300 MHz, DMSO-d6) δ 8.52-8.46 (m, 2H), 7.72 (t, J=5.7 Hz, 1H), 7.39-7.19 (m, 7H), 4.49 (d, J=5.7 Hz, 2H), 4.40 (s, 2H), 3.97 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.46 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 162.4, 159.1, 157.9, 155.5, 151.5, 149.2, 137.1, 136.7, 129.1, 128.2, 127.9, 122.4, 121.2, 118.2, 47.3, 45.0, 42.4, 42.0, 17.6; MS (ES+) m/z 408.3 (M+1).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[C:5]([Cl:7])[CH:4]=[C:3]1C#N.[C:10]([O-])(=O)C.[CH:14]([NH2:16])=[NH2+:15]>CCO>[Cl:7][C:5]1[CH:4]=[C:3]2[N:2]([CH:6]=1)[N:1]=[CH:10][N:15]=[C:14]2[NH2:16]
Reactant: NC=[NH2+]
Reactant: N#Cc1cc(Cl)cn1N
Reactant: CC(=O)[O-]
Solvent: CCO
Product: Nc1ncnn2cc(Cl)cc12
Temperature: 80 °C
Yield: 54.5 %

Procedure:
To a stirred suspension of 1-amino-4-chloro-1H-pyrrole-2-carbonitrile (3.4 g, 24.02 mmol) in EtOH (160 mL) was added formamidinium acetate (25 g, 240.2 mmol). The mixture was heated to 80° C. over night. TLC analysis indicated that there was complete conversion of starting material. The reaction mixture was cooled to room temperature and then filtered. Ethanol was removed under reduced pressure and the remaining solids were purified by column chromatography (EtOAc) to afford 2.2 g of the above compound (13.1 mmol, yield 54%). 1H-NMR (MeOD-d4) δ 7.77 (s, 1H), 7.56 (d, J=1.6 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H); LCMS RT=1.30 min; MS {M+H]+=168.8
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
A solution of 3-chloro-2-(bromoacetamido)benzoic acid from Example 39 (7.5 g, 0.026 mol), aniline (5.8 mL, 250 mol %) and anhydrous DMF (60 mL) was heated at 95°-100° C. for 20h, cooled and stirred at rt for 4h. The reaction mixture was poured into ice-water (400 mL) and the precipitated product was solubilized by adding aqueous 5% KOH (60 mL). The resulting milky homogenous solution was extracted with CH2Cl2 (3×70 mL). The combined CH2Cl2 extracts were set aside and the aqueous layer was acidified to pH=3 with aqueous 5% HBr. The resulting oil was extracted into EtOAc (3×100 mL) and the combined extract was washed with brine, dried, filtered and concentrated. Recrystallization of the resulting solid from diethyl ether afforded 3 g (38%) of the title compound as a white crystals, mp 184°-185° C.; 1H NMR (CD3OD) δ 7.85 (dd, 1H, J=1.6, J=6), 7.66 (dd, 1H, J=1.6, J=6.4), 7.33 (t, 1H, J=8), 7.16 (t, 2H, J=7.2), 6.72 (dd, 3H, J=2, J=5.6), 3.91 (s, 2H); 13C NMR (CD3OD): 203.86, 196.95, 173.19, 173.17, 168.69, 149.44, 134.30, 130.41, 130.09, 128.42, 119.31, 114.44; MS (EI, m/z) 304 (M+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][CH2:11][O:5]1
Reactant: O=Cc1c(F)cccc1I
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(I)c1C1OCCCO1
Yield: 98.7 %

Procedure:
2-Fluoro-6-iodo-benzaldehyde (3.0 g, 12 mmol), 1,3-propanediol (1.3 ml, 18 mmol), and para-toluenesulfonic acid (342 mg, 1.8 mmol) is heated at reflux in toluene (60 ml) using a Dean-Stark apparatus for 2 hours. The organic layer is washed with brine and dried over MgSO4 and evaporated to afford the desired compound (3.65 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]([CH3:32])[NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([C:21]5[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=5)[CH:23]=4)[CH:28]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ncccc1-c1ccc2c(c1)CCNC2C
Product: COc1ncccc1-c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].C([O-])(=O)C.[Na+].CO>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7]
Reactant: COC(=O)CNC(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CNC(=O)c1ncc2ccccc2c1-c1ccccc1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of [(1-chloro-4-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (177 mg, 0.5 mmol, Example D-74 b), Pd/C (50 mg, 10 wt % Pd), sodium acetate (49 mg, 0.6 mmol), MeOH (10 ml) and EtOAc (5 ml) was stirred under a H2-atmosphere at ambient pressure and temperature for 2 h. Then the mixture was filtered through a pad of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo. To the residue was added concentrated aqueous NaHCO3 (10 ml) and the mixture was extracted with EtOAc (2×15 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless gum (154 mg); MS-(+)-ion: M+1=321.0.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([O:24][CH2:25][C:26]#[N:27])[C:14]([C:28]3[CH:32]=[CH:31][O:30][CH:29]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl.O>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:24][CH2:25][C:26]#[N:27])[C:14]([C:28]3[CH:32]=[CH:31][O:30][CH:29]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#CCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
t-Butyl 6-(benzenesulphonylmethyl)-2-(cyanomethoxy)-3-(furan-3-yl)benzoate (Intermediate 119, 0.043 g) was dissolved in DCM (2 ml) and water (1 drop) was added followed by trifluoroacetic acid (1 ml). The mixture was stirred at room temperature for 15 minutes then it was evaporated to dryness. The residue was redissolved in DCM and re-evaporated twice. The residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water containing 0.1% formic acid with a gradient of 40-55%. After evaporation, the residue was triturated with ether and the solid was collected by filtration to give 6-(benzenesulphonylmethyl)-2-(cyanomethoxy)-3-(furan-3-yl)benzoic acid (0.024 g) as a white solid.