Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[N:9]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:32][C:7]1[C:6](=[O:11])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:4]([S:3][CH2:1][CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: BrBr
Reactant: CCSc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCSc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4′-{[2-(ethylthio)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (3.83 g) and sodium acetate (0.87 g) in acetic acid (40 mL) was added bromine (0.54 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (4.66 g, 99%) as a colorless solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:26]1[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=1>>[N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([NH:22][C:26]4[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cc(N2CCN(C(=O)CN3CCOCC3)CC2)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(C(=O)CN4CCOCC4)CC3)ncn2)s1

Procedure:
42-3 (0.36 g, 1.18 mmol), sodium hydride (0.094 g, 2.35 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.17 g, 1.18 mmol) were treated as in Scheme 4 above. The reaction was cooled, quenched with methanol and water, evaporated to dryness and partitioned between methylene chloride, methanol and water. The organic layers were evaporated to dryness and purified on a C18 preparative hplc column and isolated via lyophilization to afford 42-4. Hi-Res MS: calc: 415.1659 found: 415.1638. 1H-NMR (CD3OD): 8.44(s, 1H); 8.01(s, 1H); 6.20(s, 1H); 4.36(s, 2H); 4.05(br s, 2H); 3.88(br s, 2H); 3.82(m, 2H); 3.76(m, 2H); 3.71(m, 2H); 3.56(m, 4H); 3.25(br s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[N:18]=[C:19]=[S:20]>CC(=O)OCC>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:19]([NH:18][C:12]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=1[Cl:10])=[S:20]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1ccc(F)cc1N
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1NC(=S)Nc1c(Cl)cccc1Cl
Yield: 77.9 %

Procedure:
A mixture of 4.37 g (0.0346 mol) of 4-fluoro-1,2-diaminobenzene and 7.07 g (0.0346 mol) of 2,6-dichlorophenyl isothiocyanate in 150 ml of EA was boiled under reflux for 3 hours. After distilling off the solvent, the residue was dissolved in methanol, treated with activated carbon, ⅔ of the solvent volume was distilled off, and the thiourea was allowed to crystallize in an ice bath for a number of hours. 8.9 g of the desired product was obtained. Colorless crystals, 1st m.p.: 175-178° C.; 2nd m.p.: 294-296° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 4-fluoro-phenyl isocyanate (0.065 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 54 as a colorless solid (0.055 g, 33%). LCMS m/z (%)=405 M+H+ (37Cl, 20), 404 M+H+ (35Cl, 50), 1H NMR (400 MHz, acetone-d6) δ: 8.62 (bs, 1H), 8.101 (s, 1H), 8.081 (d, J=2.3 Hz, 2H), 7.967 (t, 1H), 7.885 (d, J=2.21 Hz, 2H), 7.558 (d, J=8.91 Hz, 1H), 7.473 (t, 1H), 4.67 (m, 1H), 4.238 (s, 3H), 1.873 (d, J=6.61 Hz, 3H), 1.713 (d, J=6.61 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[O:7].[OH:12][C:13]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>CN(C=O)C>[OH:12][C:13]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:14]=1[NH:15][C:6]([NH:5][CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[Cl:1])=[O:7]
Reactant: O=C=NCc1ccccc1Cl
Reactant: N#Cc1ccc(N)c(O)c1
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)NCc2ccccc2Cl)c(O)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.4 %

Procedure:
To a solution of 2-chlorobenzylisocyanate (125.6 mg, 0.75 mmol) in DMF (1.0 ml), 2-hydroxy-4-cyanoaniline (100 mg, 0.75 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. Chromatography of the resulting liquid on silica gel (50% Ethyl acetate/Hexane) gave desired product (80 mg, 58.8%). EI-MS m/z 302.8 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+].[CH:15](OCC)=[O:16]>>[CH:15]([CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]#[N:11])=[O:16]
Reactant: COc1cccc(CC#N)c1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(C(C#N)C=O)c1

Procedure:
In the manner described in Example 46, the reaction of 3-methoxybenzeneacetonitrile with sodium methoxide and ethyl formate provides the product of the Example.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][N:8]=[C:7]([CH3:10])[C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O)=[N+]=[N-].CP(C)C>C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:6]3[C:7]([CH3:10])=[N:8][O:9][C:5]=3[CH2:4][N:1]=2)=[CH:20][CH:21]=1
Reactant: Cc1noc(CN=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: CP(C)C
Solvent: Cc1ccccc1
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a resealable vial was added crude (2-(5-(azidomethyl)-3-methylisoxazol-4-yl)phenyl) (4-chlorophenyl)methanone (27 mg, 0.077 mmol) and toluene. The vial was sealed and placed under N2 before addition of trimethylphosphine solution (92 μl, 1 M toluene, 0.092 mmol). The reaction was stirred at room temperature for 2 h before purifying via Biotage (10 g, EtOAc/hex) to afford 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine. 1H NMR (400 MHz, Acetone) δ 7.78-7.84 (m, 1H), 7.65-7.74 (m, 1H), 7.34-7.47 (m, 6H), 4.62 (br. s, 2H), 2.54 (s, 3H). LC/MS m/z 309 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:4]2[C:9]([C:10]=1[C:11](Cl)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:4]2[C:9]([C:10]=1[C:11]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1cccc(-n2c(Cl)c(C(=O)Cl)c3ccccc32)c1
Reactant: C1COCCN1
Product: COc1cccc(-n2c(Cl)c(C(=O)N3CCOCC3)c3ccccc32)c1

Procedure:
This compound was prepared from 2-chloro-1(3-methoxyphenyl)-indole-3-carboxylic acid chloride and morpholine to yield 2-chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acid morpholide which was reacted with N-methyl-piperazine according to Example 42. The yield of amorphous product was 85% of the theoretical yield; the amorpheus hydrochloride had a decomposition point above 160° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14](=[O:28])[N:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][OH:23].ClCCl>N1C=CC=CC=1>[Cl:12][C:13]1[C:14](=[O:28])[N:15]([C:24]([CH3:25])([CH3:27])[CH3:26])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][O:23][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)n1ncc(NCCCO)c(Cl)c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCNc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 0 °C

Procedure:
2.55 g of p-toluenesulfonyl chloride was added to a mixture comprising 3.16 g of 4-chloro-5-(3-hydroxypropylamino)-2-t-butyl-3(2H) pyridazinone prepared in Reference Example 4, 1.44 g of pyridine and 50 ml of dichloromethane under stirring and cooling with ice, and the mixture was stirred at the same temperature for 2 hours. Then, 2.0 g of pyridine and 2.5 g of p-toluenesulfonyl chloride were added to the reaction mixture in this order. The mixture was stirred for further 2 hours under cooling with ice, and left to stand overnight in an ice chamber. The solvent was distilled off, and the pale yellow oily substance thereby obtained was extracted with benzene. The extract was washed sequentially with dilute hydrochloric acid, water (twice) and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, solvent was distilled off to obtain a pale yellow oily substance. The oily substance was purified by silica gel column chromatography by using benzene-ethyl acetate (1:1, v/v) as the developer, to obtain 4.67 g of the above identified compound as a pale yellow viscous oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=3)[O:16][N:15]=2)[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[NH3:26]>CO>[NH2:26][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=3)[O:16][N:15]=2)=[CH:5][C:6]=1[CH3:13]
Reactant: N
Reactant: CCc1ccc(-c2nc(-c3cc(C)c(OCC4CO4)c(C)c3)no2)s1
Solvent: CO
Product: CCc1ccc(-c2nc(-c3cc(C)c(OCC(O)CN)c(C)c3)no2)s1

Procedure:
A solution of 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazole (123 mg, 0.345 mmol) in 7 N NH3 in methanol (10 mL) is stirred at 45° C. for 16 h. The solvent is evaporated and the residue is separated by chromatography on prep. TLC plates with DCM containing 6% of 7 N NH3 in methanol to give 1-amino-3-{4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (35 mg) as a white solid; LC-MS: tR=0.84 min, [M+1]+=374.14.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH2:13][OH:14]>C1COCC1.O=[Mn]=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[CH:13]=[O:14]
Reactant: Cn1c(CO)nnc1-c1ccccc1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: Cn1c(C=O)nnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of (4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)methanol, 35, (1.3 g, 6.9 mmol) in THF (20 mL) was added MnO2 (6.0 g, 68.7 mmol). The reaction stirred at room temperature for 2 h. The reaction mixture was then filtered through a plug of Celite® and concentrated in vacuo. The crude material was purified via silica gel chromatography (0-5% methanol/dichloromethane) yielding 820 mg (64%) of 36: 1H NMR (400 MHz, CDCl3) δ 10.14, (s, 1H), 7.68-7.60 (m, 2H), 7.59-7.45, (m, 3H), 3.98 (s, 3H); ESI+ MS: m/z (rel intensity) 188 (100, M+H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10](=[O:32])[N:11]1[CH2:20][C:19]2[N:15]([CH:16]=[N:17][C:18]=2[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[C:14]2[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=2[CH2:12]1)(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[NH2:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:11]1[CH2:20][C:19]2[N:15]([CH:16]=[N:17][C:18]=2[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[C:14]2[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=2[CH2:12]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To solution of (R)-[3-oxo-3-[3-(pyrrolidine-1-carbonyl)-4H,6H-2,5,10b-triaza-benzo-[e]azulen-5-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (45 mg, 0.08 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.24 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction, as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford a gummy solid which was crystallized from hexane to afford trifluoroacetic acid salt of (R)-3-amino-1-[3-(pyrrolidine-1-carbonyl)-4H,6H-2,5,10b-triaza-benzo[e]azulen-5-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one (40 mg, 86%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[C:21]1([CH3:36])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1C1C=CC=CC=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:14]=[C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:36])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)c(N)s1
Reactant: Cc1ccccc1-c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(S(=O)(=O)c2cccc(-c3ccccc3C)c2)c(N)s1

Procedure:
5-Amino-4-(2′-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester was prepared following the procedure as in Example 1: step c using 5-amino-4-(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (598.9 mg, 1.6 mmol) (Example 20: steps a–c), o-tolyl-phenyl boronic acid (435.6 mg, 3.2 mmol), Pd(PPh3)4 (366.6 mg, 0.32 mmol), aqueous Na2CO3 (2M, 6.4 mL, 12.8 mmol), ethanol (6.4 mL) and toluene (12.8 mL). Purification by flash column chromatography (Biotage Flash™ System—40 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the adduct (137 mg, 23%) as a light brown solid. ESI-MS (m/z): Calcd. for C19H17NO4S2: 387.02; found: 388.3. 5-Amino-4-(2′-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester (61 mg, 16 mmol) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (6 mg, 10%) as a light brown solid. 1H-NMR (CD3OD): δ: 7.96–7.99 (m, 1H), 7.95 (s, 1H), 7.93–7.94 (m, 1H), 7.63–7.69(m, 3H), 7.18–7.32 (m, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C18H17N3O2S2: 372.0 (M+H); found: 372.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[O:20])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:5]2=[CH:4][CH:3]=1.[NH:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: O=C(OCc1cccc(F)c1)c1cc2nc(Cl)ccc2n1Cc1cccc(F)c1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OCc3cccc(F)c3)n2Cc2cccc(F)c2)n1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
3-Fluorobenzyl 5-chloro-1-(3-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (0.40 g, 0.97 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (0.25 g, 1.1 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.076 g, 0.097 mmol, Aldrich), and Cs2CO3 (0.32 g, 0.97 mmol, Aldrich) were combined in toluene (8.6 mL) and the mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was stirred at 110° C. for 6 hours. The reaction mixture was partitioned between water and ethyl acetate, the aqueous was extracted three times, and the combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes, was used to purify the product. Yield: (0.33 g, 56%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1>C(N)(C)C.O>[CH:6]([NH:7][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1)([CH3:8])[CH3:5]
Reactant: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1
Solvent: O
Solvent: CC(C)N
Product: CC(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-(4-fluoro-phenylethynyl)-pyrimidine (1 equiv.) in iso-propylamine (0.2 M) is heated at 35° C. for 24 h. The mixture is cooled to rt, diluted with water, and extracted with EtOAc. The organic layer is concentrated and the residue purified by column chromatography to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([C:10](OC)=[O:11])[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.Cl.C(=O)([O-])O.[Na+]>ClCCl.C1(C)C=CC=CC=1>[C:1]([C:5]1[N:9]=[C:8]([CH2:10][OH:11])[S:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(C(C)(C)C)ns1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nsc(CO)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
0.96 g of methyl 3-t-butyl-1,2,4-thiadiazole-5-carboxylate was dissolved in 48 ml of dichloromethane and then cooled to −78° C. under a nitrogen atmosphere. To the solution, 11 ml of a solution (1 mol/L) of diisobutylaluminum hydride in toluene was added and the mixture was stirred at 0° C. for 3 hours. After 10 ml of 1 mol/L hydrochloric acid was added, the reaction mixture was stirred for 10 minutes and 50 ml of aqueous saturated sodium hydrogen carbonate was then added. The reaction mixture was extracted with chloroform, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.56 g of (3-t-butyl-1,2,4-thiadiazol-5-yl)methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].Cl[CH2:10][CH2:11]Cl>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: Cc1ccccc1C
Product: Cc1cccc(CCc2cccc(C)c2C)c1C

Procedure:
o-Xylene and 1,2-dichloroethane were reacted in the presence of anhydrous AlC13 catalyst to obtain 1,2-di(dimethylphenyl)ethane (bromine number: 0.1) of 136 to 148° C. in distillation temperature at 3 to 5 mmHg. This was cracked in the like manner as in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([O:18][CH3:19])[C:12]([O:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([N:31]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:26]3[C:22]=2[CH2:23][CH2:24][CH2:25]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][Li].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])([CH3:46])[CH3:16])=[C:13]([O:18][CH3:19])[C:12]([O:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([N:31]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:26]3[C:22]=2[CH2:23][CH2:24][CH2:25]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(Oc2c(C)cc(N(Cc3ccccc3)Cc3ccccc3)c3c2CCC3)ccc(OCc2ccccc2)c1C(C)=O
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(Oc2c(C)cc(N(Cc3ccccc3)Cc3ccccc3)c3c2CCC3)ccc(OCc2ccccc2)c1C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[6-benzyloxy-3-(7-dibenzylamino-5-methylindan-4-yloxy)-2-methoxyphenyl]ethanone (13.3 g) in tetrahydrofuran (100 mL) was added dropwise a 1.14 mol/L solution of methyllithium in diethyl ether (30 mL) under an argon atmosphere at −78° C. The mixture was stirred for 30 min, and then warmed up to room temperature gradually. To the dark-red reaction mixture was added a saturated aqueous solution of ammonium chloride (40 mL). The reaction mixture was stirred for 10 min. The organic solvent was evaporated under reduced pressure to dryness. The residue was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to dryness to give 2-[6-benzyloxy-3-(7-dibenzylamino-5-methylindan-4-yloxy)-2-met hoxyphenyl]-propane-2-ol (13.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17])[CH:13]=1)[C:8](O)=[O:9])=[O:4].NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O.C(I)CC.B.C1COCC1>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([N:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:15][CH2:16][CH3:17])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: CCCN(c1cc(C(=O)O)cc(C(=O)OC)c1)S(C)(=O)=O
Agent: B
Agent: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCN(c1cc(CO)cc(C(=O)OC)c1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of: 3-(methoxycarbonyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (12.0 g, 38.1 mmol, prepared from dimethyl 5-aminoisophthalate and propyl iodide using a similar procedure as described for the preparation of intermediate A) in THF (250 mL) cooled to 0° C. was added BH3-THF (190.3 mL, 190.3 mmol, 1 M in THF). After 10 min, the reaction mixture was allowed to warm to rt and stirred for 15 h. The reaction mixture was cooled back down to 0° C. and carefully quenched with MeOH. The mixture was concentrated to half its original volume and diluted with EtOAc and water. Following dilution, the organic layer was extracted, washed with sat. aq. NaHCO3 and brine, dried over sodium sulfate and concentrated in vacuo to provide methyl 3-(hydroxymethyl)-5-[(methylsulfonyl)(propyl)amino]benzoate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 4.79 (d, J=5.7 Hz, 2H), 3.94 (s, 3H), 3.67 (t, J=7.2 Hz, 2H), 2.90 (s, 3H), 1.87 (br t, J=5.7 Hz, 1H), 1.55-1.45 (m, 2H), 0.92 (t, J=7.4 Hz, 3H).