Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.S(Cl)(Cl)=O.[NH2:22][C:23]1[S:24][C:25]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=2[N:27]=1.N1C=CC=CC=1>CO.BrC1C=C(F)C(N2CC=C(C(Cl)=O)CC2)=NC=1.O1CCCC1.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([NH:22][C:23]3[S:24][C:25]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=4[N:27]=3)=[O:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(O)C1=CCN(c2ncc(Br)cc2F)CC1
Reactant: Nc1nc2ccc(F)cc2s1
Agent: O=C(Cl)C1=CCN(c2ncc(Br)cc2F)CC1
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(F)cc2s1)C1=CCN(c2ncc(Br)cc2F)CC1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
In a 50 mL vial with a screw-top septum, 1.03 grams 1-(5-bromo-3-fluoropyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid 23 (3.32 mMol) were cooled to 0° C. Ten milliliters thionyl chloride were poured directly onto the solid and stirred until the vial reached room temperature. The vial was heated to 45° C. for one hour. The reaction was confirmed complete by LC/MS using the methyl ester of the acid in methanol. Volatiles were removed under vacuum until the yellow solid was dry. All material was used as is in the next reaction without further characterization. In a 50 mL vial with a screw-top septum, 1-(5-bromo-3-fluoropyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carbonyl chloride (28) was dissolved in 10 mL tetrahydrofuran (THF), stirred with a magnetic stir bar, and cooled to 0° C. 1.1 eq. 2-amino-6-fluorobenzothiazole (3.65 mMol) were dissolved in 2 mL dimethylformamide (DMF) and the solution slowly added to the vial. After the reaction stirred for 10 minutes, 3 eq. pyridine (9.96 mMol) were added to the mixture dropwise and the reaction progressed for 18 hours. The precipitate was collected by vacuum filtration and washed with 2×15 mL EtOAc. (30% white solid): m/z 451, 1H NMR (DMSO) δ 12.43 (s, 1H), 8.17-8.10 (m, 1H), 7.96-7.95 (m, 1H), 7.86-7.78 (m, 1H), 7.71-7.64 (m, 1H), 7.28-7.19 (m, 1H), 7.09-7.04 (m, 1H), 4.19-4.12 (m, 2H), 3.64-3.51 (m, 2H), 2.59-2.53 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([NH:17][CH:18]([CH2:22][CH2:23][CH3:24])[C:19]([OH:21])=O)=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[O:27][C:28]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])=[CH:29][N:30]=1.Cl.CN(C)C>C(Cl)Cl.C(Cl)CCl>[C:31]([C:28]1[O:27][C:26]([NH:25][C:19](=[O:21])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:22][CH2:23][CH3:24])=[N:30][CH:29]=1)(=[O:32])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCCC(NC(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)O
Reactant: Nc1ncc(C(=O)c2ccccc2)o1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)Nc1ncc(C(=O)c2ccccc2)o1

Procedure:
A mixture of 2-[2-(3-phenoxy-phenyl)-acetylamino]-pentanoic acid (65 mg, 0.2 mmol), (2-Amino-oxazol-5-yl)-phenyl-methanone (38 mg, 0.2 mmol.), HBOT (32 mg, 0.24 mmol), EDC. HCl (58 mg, 0.3 mmol) and a trimethylamine (0.11 ml, 0.8 mmol) in methylene chloride was stirred at room temperature until disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound, LC-MS M+1=498.5.
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[Cl:13])(=O)C.N(OCCC(C)C)=O.[Cl:23][Si](C)(C)C>[Cl-].C([N+](CC)(CC)CC)C>[Cl:23][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([Cl:13])[N:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)n1cnc2c(Cl)nc(N)nc21
Agent: CC(C)CCON=O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Product: Clc1nc(Cl)c2[nH]cnc2n1
Temperature: 55 °C
Reaction time: 10 h
Yield: 78.5 %

Procedure:
9-Acetyl-2-amino-6-chloropurine (0.50 g, 2.36 mmol), tetraethylammonium chloride (0.025 g, 0.15 mmol) and isoamyl nitrite (0.42 g, 3.54 mmol) were added to chlorotrimethylsilane (4.0 g, 36.8 mmol), and the mixture was heated to 50-60° C. and stirred for 10 hr. After the completion of the reaction, the mixture was filtrated. The obtained crystals were diluted with water (4.0 ml), and the mixture was adjusted to pH 4-5 with a 2M aqueous sodium hydroxide solution. After aging under ice-cooling for 1 hr, the mixture was filtrated, and the obtained crystals were dried under reduced pressure at 80° C. to give 2,6-dichloropurine as a white powder (0.35 g, yield 78.3%). The properties of the obtained compound were the same as in Example 1(2).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[O:23])[C:20]([CH2:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:19][N:18]=2)[N:9]=1)[CH3:1]
Reactant: CSc1ncc(CCc2cccnc2)c(=O)[nH]1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: c1ccncc1
Product: CN(C)Cc1nc(CSCCNc2ncc(CCc3cccnc3)c(=O)[nH]2)cs1

Procedure:
Following the procedure of Example 12, a mixture of 1.29 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.37 g. of 2-methylthio-5-[2-(3-pyridyl)ethyl]-4-pyrimidone in 25 ml. of anhydrous pyridine was heated to refluxing temperature for about 4 days. The solvent was removed in vacuo. The residue was dissolved in ethanol and the ethanol evaporated. The residue was purified by high pressure liquid chromatography over silica using a gradient elution technique with an ethyl acetate/ethanol/ammonium hydroxide solvent system as the eluant. Fractions shown by tlc to contain the desired product were combined and the combined fractions rechromatographed on a silica preparative plate using 3% ammoniated ethanol as the solvent. 2-[2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-[2-(3-pyridyl)ethyl]-4-pyrimidone free base thus prepared was converted by standard procedures to the trihydrochloride salt which melted at 226°-228° C. after recrystallization from an ethanol/ethyl acetate/ether solvent mixture. Yield=1.0 g.
Reaction SMILES: [CH:1](=[CH:10][C:11]([OH:13])=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH:1](=[CH:10][C:11]([Cl:16])=[O:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=CC=Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)C=CC=Cc1ccccc1
Yield: 94 %

Procedure:
8.7 g of cinnamylideneacetic acid was added to 100 ml of benzene and then an excessive amount of thionyl chloride (1.2 molar equivalent to cinnamylideneacetic acid) was added dropwise to the mixture while heating to 70°-90° C and stirring the mixture to form a cinnamylideneacetic acid chloride. By distilling off the solvent from the reaction product, yellow crystals having a melting point of about 60° C were obtained. The crystals were dissolved in 20 ml of methyl ethyl ketone and then 8 g of hydroxyethyl methacrylate was added slowly to the solution with stirring under ice-cooling. After further stirring under ice-cooling for about 20 minutes, 50 ml of pyridine was added slowly to the mixture as a hydrogen chloride accepting agent to conduct esterification. When the reaction product was treated with diluted (5%) hydrochloride acid, crystals were formed, which were recovered and recrystallized from hexane to provide crystals of a monomer having a melting point of 51°-52.5° C with a yield of 94%.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[CH:12]=[C:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[CH2:17][CH2:16][C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]1=2>>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]2[C:13](=[CH:12][C:3]3[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=3)[C:14]3[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=3[CH2:16][CH2:17][C:18]=2[CH:23]=1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)c1

Procedure:
Following procedures essentially as described in Example 219, below, and using m-tolylboronic acid (61 mg, 0.45 mmol) and 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (119 mg, 0.37 mmol) provides the title compound. GC/MS data: retention times in minutes (MS data for M+.ion): 19.60 (330), 19.95(330) Mass Spec (EI+) 330.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C1C(=O)N([Cl:18])C(=O)C1>>[Cl:18][C:9]1[CH:8]=[CH:7][C:6]([NH2:10])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)c1cccc(N)c1
Product: CC(C)c1cc(N)ccc1Cl

Procedure:
Prepared from 7.84 g of 3-iso-propyl-phenylamine and 7.75 g NCS. Yield: 4.6 g. LC-MSD, m/z for C9H12ClN [M+H]+=170.2, 172.0;
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:17])=O.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 80 °C

Procedure:
2-Hydroxy-3-nitro-5-trifluoromethylpyridine (8.8 g, 42.3 mmol) was added to a mixture of phosphorous oxychloride (4.2 mL, 45.9 mmol) and phosphorous pentachloride (9.6 g, 46.1 mmol) at 60° C. The reaction mixture was then heated under nitrogen at 80° C. overnight. The resulting dark product mixture was allowed to cool to room temperature and was poured into ice/water. The mixture was extracted with ether and the ether extract was washed with water and brine. After drying over magnesium sulfate, the solvent was removed to leave a dark oil which was subjected to flash chromatography on silica gel eluting with chloroform. Fractions containing only the desired product were combined and concentrated to leave a brown oil (5.0 g, 52%). 1H NMR (DMSO-d6): δ9.20 (s, 1H), 9.07 (s, 1H).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.Cl.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)=[O:15])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)[C@@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1.0 g (3.22 mmol) Boc-D-Phe(4-NO2)—OH (Iris Biotech) and 0.84 g (3.22 mmol) H-Phe(4-NO2)—OMe.HCl (Aldrich) were suspended in 25 ml of DMF and stirred on the ice bath. After addition of 1.66 g (3.22 mmol) of PyBOP and 1.67 ml (9.66 mmol) of DIPEA (pH 7-8), the mixture was stirred at 0° C. for 2.5 h. The solvent was removed in vacuo and the yellow oil was taken up in 5% KHSO4 soln./EtOAc. The organic phase was washed 3× with 5% KHSO4 soln., 1× with sat. NaCl soln., 3× with sat. NaHCO3 soln. and 3× with sat. NaCl soln. The organic phase was dried with MgSO4, filtered, and the solvent was removed in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[N:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[N:24]=[CH:25][C:20]([Cl:19])=[CH:21][N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncc(Cl)cn1
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-pyrimidine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=400.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:35][C:36]#[N:37]>CC(C)=O>[CH2:1]([O:8][C:9](=[O:27])[C@@H:10]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:35][C:36]#[N:37])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCC#N)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 109.6 %

Procedure:
N-Boc-L-tyrosine benzyl ester (0.371 g, 1 mmol) was dissolved in acetone (5 mL) and cesium carbonate (0.650 g, 2 mmol) was added followed by chloroacetonitrile (0.150 g, 2 mmol). The mixture was then reflux for 2 h. The reaction was cooled to room temperature and insoluble salts removed by filtration using acetone for washings. Volatiles were removed under reduced pressure and the residue dissolved in DCM. The solution was washed with brine, dried (MgSO4) and concentrated to give the desired product as an oil (450 mg).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[C:8]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:7]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:6]2[CH:29]=1)#[N:2].[N-:30]=[N+:31]=[N-:32].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:7]1[N:6]2[CH:29]=[C:3]([C:1]3[NH:32][N:31]=[N:30][N:2]=3)[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[C:8]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1nc2nc(C#N)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2nc(-c3nnn[nH]3)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 70.1 %

Procedure:
To a stirred solution of tert-butyl (2-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (intermediate for Example 152, 27 mg, 0.06 mmol) in DMF (2 mL) was added NaN3 (6 mg, 0.09 mmol) and NH4Cl (5 mg, 0.09 mmol). After heating to 100° C. for 24 h, the reaction was diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded crude tert-butyl (5-(2,4-dichlorophenyl)-7-methyl-2-(1H-tetrazol-5-yl)imidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (20 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C=O)C>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[CH:6][CH:7]=1)#[N:10]
Reactant: N#Cc1ccc(OCCBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 95 °C

Procedure:
4-(2-Bromoethoxy)benzonitrile (7.3 g) was reacted with potassium phthalimide (5.98 g) in DMF (35 ml) by heating at 95° C. for 3 hours. The N-[2-(4-cyanophenoxy) ethyl]phthalimide obtained after extractive workup (7.30 g) was suspended in IMS (350 ml) and treated with hydrazine hydrate (6.25 g). The mixture was stirred for 22 hours and filtered. The solid obtained was washed with IMS and the combined filtrate and washings were evaporated to dryness. Water was added to this residue and the mixture basified with 10M sodium hydroxide solution. The mixture was extracted with dichloromethane to give 4-(2-aminoethoxy)benzonitrile as an oil.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[C@@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26]([C@@H:27]([NH:32][C:33](=[O:34])[O:35][CH3:36])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:37])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
A solution of the product of Example 1G (1.55 g, 2.45 mmol) in dichloromethane (12.5 mL) was treated with trifluoroacetic acid (12.5 mL), stirred at 25° C. for 1 hour and concentrated. The concentrate was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase extract was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (1.4 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]([CH:4](O)[C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH2:3].[ClH:12]>>[Cl:12][CH2:3][C:2]([F:1])=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: Cl
Reactant: C=C(F)C(O)C#CC(C)(C)C
Product: CC(C)(C)C#CC=C(F)CCl
Reaction time: 5 h

Procedure:
Ten grams (0.064 mole) of 2-fluoro-3-hydroxy-6,6-dimethylhept-1-ene-4-yne was added 200 ml of concentrated hydrochloric acid, and the mixture was aged for 5 hours at room temperature with stirring. The reaction mixture was extracted with three 100 ml portions of diethylether. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 5 g of 1-chloro-2-fluoro-6,6-dimethylhept-2-ene-4-yne.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.B(Br)(Br)Br.CCOC(C)=O.O>ClCCCl.C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: COc1ccc(-c2nc(C#N)c(N)nc2-c2ccccc2)cn1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCCl
Product: N#Cc1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Temperature: 80 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile (370 mg) was dissolved in 1,2-dichloroethane (37 ml). To the solution was added 1M boron tribromide solution in CH2Cl2 (12.2 ml) The mixture was stirred at 80° C. for 24 hours. The mixture was cooled to 20-25° C., and portioned to EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, and dried over MgSO4. Evaporation of solvent in vacuo gave reddish solid residue. The residue was pulverized with water, to give 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile as powder (254 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:24][CH:25]([C:27]1[S:28][CH:29]=[C:30]([CH2:32][NH2:33])[N:31]=1)[CH3:26]>>[CH:25]([C:27]1[S:28][CH:29]=[C:30]([CH2:32][NH:33][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[N:31]=1)([CH3:26])[CH3:24]
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: CC(C)c1nc(CN)cs1
Agent: Cl
Product: CC(C)c1nc(CNC(=O)c2ccc(OCC3CC3)c(-c3ccc(Cl)cc3)n2)cs1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 2-(1-methylethyl)-4-thiazole-methanamine dihydrochloride (CAN 1171981-10-4) as starting materials, LC-MS (peak area/EIC) 97.9%, 442.0 (M+H)+.
Reaction SMILES: C([C:8](=[N:17]O)[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>C(O)C>[CH2:8]([NH:17][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1)[C:9]1[CH:16]=[CH:15][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(C(Cc2ccccc2)=NO)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.44 g (15 mmol) of 4-(benzyloximinomethyl)benzonitrile in 120 ml of ethanol are cooled to -15° C. 4.46 g (48 mmol, 4.85 ml) of borane-pyridine complex are then added dropwise in the course of 10 minutes and then 26 ml of ethanolic HCl solution in the course of 20 minutes. After stirring at room temperature for 24 h, the resulting solid is filtered off, dissolved in dichloromethane and the solution is washed with water and sodium hydrogen carbonate solution. The organic phase is dried and concentrated in vacuo.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[C:19]#[N:20])#[CH:13]>>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:13]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=2)[C:19]#[N:20])=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#Cc1ccc(OC)c(C#N)c1
Product: COc1ccc(C#Cc2ccc(OC(F)F)cc2)cc1C#N

Procedure:
The title compound was prepared in substantially the same manner as described in Example 12, step 3 starting from 1-Difluoromethoxy-4-iodo-benzene (0.17 g, 0.64 mmol), and 5-Ethynyl-2-methoxy-benzonitrile (0.10 g, 0.64 mmol), and was obtained as a light brown solid, (0.170 g, 89%), identified by NMR and mass spectral analyses. MS (APPI+): 299 (M+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[Na+].[NH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN>[Cu](I)I.CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:11]
Reactant: Nc1ccc(I)cn1
Reactant: Cc1cc(S(=O)[O-])ccc1Br
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cc(S(=O)(=O)c2ccc(N)nc2)ccc1Br
Temperature: 100 °C
Yield: 20.3 %

Procedure:
Sodium 4-bromo-3-methylbenzenesulfinate (2.92 mg, 11.36 mmol), 2-amino-5-iodopyridine (1.25 g, 5.68 mmol, Alfa Aesar, Ward Hill, Mass.), copper iodide (216 mg, 1.14 mmol, Strem Chemical Inc, Newburyport, Mass.), potassium carbonate (785 mg, 5.68 mmol), N,N-dimethylethylenediamine (0.25 mL, 2.27 mmol, Alfa Aesar, Ward Hill, Mass.), and DMSO (15 mL) were added to a reaction vial. The vial was closed, purged with nitrogen for several minutes, and heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic extracts were dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 20% to 50% EtOAc in hexane, to provide 5-((4-bromo-3-methylphenyl)sulfonyl)-2-pyridinamine (377 mg) as a white solid.