Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:24]#[N:25])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C#N)cc1-2
Temperature: 175 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (120 mg, 0.31 mmol) was dissolved in DMF (1.6 mL) in a 10-mL microwave vial. Purged with N2 and added zinc cyanide (36 mg, 0.31 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol). Sealed the vial and evacuated and recycled twice with N2. The vessel was subjected to microwave irradiation with stirring for 10 min at 175° C. The vessel was then cooled to r.t. and the reaction mixture was diluted with dichloromethane and water. The phases were separated and the organic layer was washed once with water, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by ISCO chromatography (40 g column, 0-10% MeOH/DCM) to provide 76 mg (73% yield) of 136. LC/MS (ESI+): m/z 338 (M+H)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][N:33]2COCC[Si](C)(C)C)=[C:29]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][CH2:52]3)=[CH:47][CH:46]=2)[N:28]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][NH:33]2)=[C:29]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([N:51]3[CH2:52][CH2:53][N:54]([CH:57]4[CH2:58][O:59][CH2:60]4)[CH2:55][CH2:56]3)=[CH:49][CH:50]=2)[N:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3ncn(COCC[Si](C)(C)C)c3n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3nc[nH]c3n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
A mixture of 117g (550 mg, 0.660 mmol) and CF3COOH (6 mL) was stirred at room temperature for 2 h. It was then concentrated under reduced pressure to afford crude 117h as a yellow solid (140 mg, 30%), which was used in the next step without further purification. MS-ESI: [M+H]+ 706.4
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([C:26]([OH:28])=O)[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:28])[CH:18]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1cccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c1
Yield: 72.1 %

Procedure:
Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.0 mmol) benzene-1,3-dioic acid afforded, after flash chromatography (EtOAc), 4.68 g (72%) of the title compound as a yellow oil.
Reaction SMILES: N1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](O)(=O)[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O>N1C=CC=CC=1>[CH:2]1[C:6]2[C:6](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:5]=[CH:4][C:3]=1[CH:7]=[CH:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CC(=O)O
Reactant: C1CCNCC1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc2ccccc2c1

Procedure:
A solution of 2-naphthylaldehyde (3 g), piperidine (0.49 ml) and malonic acid (4.0 g) in pyridine (15 ml) was stirred for 2 hrs at 120° C. After cooling, the solution was acidified with conc. sulphuric acid. The solution was extracted with EtOAc. The oily layer was washed, dried, and evaporated to give the title compound (3.6 g) having the following physical data:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12](=O)[NH:13][N:14]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:12]1[N:13]=[N:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[CH:10][CH:11]=1
Reactant: Cc1ccc(-c2ccc(=O)[nH]n2)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccc(Cl)nn2)c(C)c1

Procedure:
6-(2,4-dimethylphenyl)pyridazin-3(2H)-one (example 13c) was heated with POCl3 (5.15 ml, 55 mmol) at 85° C. for 4 hours. Following cooling and treating with crushed ice a white solid obtained and was collected to give 1.36 g of the 3-chloro-6-(2,4-dimethylphenyl)pyridazine. 1H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.34 (s, 3H), 7.16-7.19 (m, 2H), 7.35-7.37 (d, 1H), 7.93-8.00 (dd, 2H); (M+H, 313).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:11][C:12]([C:14]#[C:15][C:16](OCCCC)=[O:17])=[O:13])[CH2:8][CH2:9][CH3:10]>C(O)C>[CH2:7]([O:11][C:12]([C:14]1[N:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:16](=[O:17])[CH:15]=1)=[O:13])[CH2:8][CH2:9][CH3:10]
Reactant: Nc1nccs1
Reactant: CCCCOC(=O)C#CC(=O)OCCCC
Solvent: CCO
Product: CCCCOC(=O)c1cc(=O)nc2sccn12

Procedure:
The procedure is as in Example 22, except that 5 g of 2-aminothiazole are reacted with 11.3 g of acetylene dicarboxylic acid di-n-butyl ester in presence of 50 ml of absolute ethanol. 7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid n-butyl ester melting at 142°-144° C. is thus obtained in a yield of 8.1 g (64.3% of the theoretical).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:30]3[NH:29][CH:33]=[CH:32][N:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ncc[nH]4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 1H-imidazole-2 carbaldehyde. MS (ESI) m/z 457.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].O[Li].O>C1COCC1.CO.O>[NH2:10][C:9]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(-c2ccccc2)sc1C(=O)O
Temperature: 85 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a suspension of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (5 g, 21.459 mmol) in a mixture of THF:MeOH:H2O (3:2:1, 75 mL), 1N aqueous solution of LiOH.H2O (64 mL, 64.378 mmol) was added. The reaction mixture was stirred at 85° C. (external temperature) for 4 h. Solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The water layer was separated and acidified with 1N HCl solution and then ethyl acetate was added to it. The organic phase was separated, dried (Na2SO4) and concentrated to obtain 3-Amino-5-phenyl-thiophene-2-carboxylic acid (4.15 g, 88%) as a yellowish solid. 1H NMR (DMSO-D6, 400 MHz): 7.59 (d, 2H), 7.40 (m, 3H), 6.92 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:39][CH2:38][C:11]2([CH2:14][N:13]([C:15](=[O:37])[CH2:16][N:17]3[CH2:21][CH2:20][C:19]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:18]3=[O:36])[CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:19]2([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:20][CH2:21][N:17]([CH2:16][C:15](=[O:37])[N:13]3[CH2:14][C:11]4([CH2:10][CH2:9][NH:8][CH2:39][CH2:38]4)[CH2:12]3)[C:18]2=[O:36])=[CH:30][CH:31]=1
Reactant: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccccc3)CC2)C1
Solvent: CCO
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCNCC2)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(2-(7-Benzyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethyl)-3,3-bis(4-fluorophenyl)pyrrolidin-2-one (Example 152, 0.185 g, 0.349 mmol) and ethanol (20 mL) were added to 20% Pd(OH)2—C, wet (0.037 g, 0.263 mmol) in a 50 mL pressure bottle and stirred for 1 hour at 30 psi and 50° C. The mixture was filtered through a nylon membrane and concentrated to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][SH:12])=[CH:2]1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:20][O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][S:12]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: SCCc1c[nH]c2ccccc12
Reactant: COC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)CC1(C)SCCc2c1[nH]c1ccccc21
Reaction time: 12 h

Procedure:
Indole-3-ethanethiol (1.5 g.) and methyl acetoacetate are mixed with 50 ml. of benzene and the solution heated for 30 min. (bath temperature 70°-80° C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester as a semi-solid, νmaxCHCl3 1715 cm-1.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[CH:32][CH:31]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN1CCN(c2ccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)cc2)CC1

Procedure:
(1-Methyl-cyclohexyl)-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperazine following general procedures as described in these Examples. MP 225-226° C., M+H=418.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[NH:13][CH:14]=[C:15]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:16](=[O:18])[N:17]=2)=[CH:6][C:3]=1[C:4]#[N:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]3[NH:13][CH:14]=[C:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[C:16](=[O:18])[N:17]=3)=[CH:6][C:3]=2[C:4]#[N:5])=[CH:29][C:28]=1[C:34]([F:35])([F:36])[F:37]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1cc(CCc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(CCc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 150 °C
Yield: 15.3 %

Procedure:
A mixture of 2-fluoro-5-(2-(4-oxo-5-(pyrimidin-5-ylmethyl)-1,4-dihydropyrimidin-2-yl)ethyl)benzonitrile (1.0 g, 2.68 mmol), 4-chloro-3-(trifluoromethyl)phenol (0.633 g, 3.22 mmol) and K2CO3 (0.556 g, 4.03 mmol) in NMP (5 mL) was heated with a microwave reactor at 150° C. for 1.5 h. Purification via MDAP then afforded the title compound as a white solid (210 mg, 15% yield). LCMS: rt=1.65 min, [M+H+]=512
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]1.C(N(CC)CC)C>O>[CH2:29]1[N:28]([CH2:31][CH2:32][O:33][C:10]([CH:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[O:11])[CH2:27][CH2:26][O:25][CH2:30]1
Reactant: OCCN1CCOCC1
Reactant: O=C(Cl)C1CC1(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCCN1CCOCC1)C1CC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.1 mol of 2,2-diphenyl-cyclopropane-carboxylic acid chloride in 30 ml. of anhydrous benzene is added dropwise to a mixture of 0.1 mol of β-morpholino-ethanol and 0.1 mol of triethylamine in 50 ml. of anhydrous benzene. The mixture is allowed to cool and then stirred for 2 hours at ambient temperature. 300 cc. of water are added, the mixture is extracted with diethyl ether, the extract dried over sodium sulphate, and the solvent removed in vacuo to yield the base.
Reaction SMILES: [S:1](=[N:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])=[O:2].[OH-].[Na+].[CH3:19]N=C=S.Cl>CN(C=O)C>[S:1](=[N:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:19])(=[O:2])=[O:3]
Reactant: CN=C=S
Reactant: COc1ccc(CC(=O)O)cc1N=S(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1ccc(CC(=O)O)cc1N=S(=O)=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5 g of 3-sulfonylamino-4-methoxyphenylacetic acid were dissolved in 3 ml of DMF and stirred at 40° C. for 30 minutes with 245 mg of sodium hydroxide. 328 mg of methyl isothiocyanate were added thereto and the mixture was stirred for a further 2 h at 70° C. 2N hydrochloric acid was added to the cooled solution and the product was filtered off with suction. M.p. 1740° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.C(N(CC)CC)C.CO>C(Cl)Cl>[CH2:1]([NH:8][C:14]1[CH:15]=[C:10]([Cl:9])[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Clc1cc(NCc2ccccc2)ncn1
Yield: 78.7 %

Procedure:
Benzyl amine (0.697 ml, 6.76 mmol) was added to 4,6-dichloropyrimidine (1.0 g, 6.76 mmol) neat causing a vigorous reaction and color change. The reaction was slowly diluted with methylene chloride resulting in a white precipitate. 1 ml of triethyl amine was added and TLC indicated conversion to product (5% MeOH:methylene chloride). The reaction was loaded directly onto a silica and purified (eluent:2% MeOH:methylene chloride) giving 1.17 g (5.32 mmol) of 12 as a yellow wax in 79% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5].[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH2:21].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH:21][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[CH3:1])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: Cc1ccccc1C(=O)C1CCCCC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: O
Solvent: COc1ccccc1
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1C
Temperature: 80 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To a mixture of 2-(2-methylbenzoyl)cyclohexanone (97.2 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-[(2-(2-methyl benzoyl)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (52.9 g, 34%).
Reaction SMILES: Cl.[NH:2]([C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17](Cl)([Cl:19])=[O:18]>C1(C)C=CC=CC=1>[CH3:15][C:13]1[CH:12]=[C:11]([CH3:16])[N:10]=[C:9]([N:2]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:17]([Cl:19])=[O:18])[N:14]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C)nc(Nc2ccccc2)n1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N(C(=O)Cl)c2ccccc2)n1
Reaction time: 8 h

Procedure:
2-Anilino-4,6-dimethylpyrimidine hydrochloride (100 g) was suspended in toluene (1200 ml). A slow stream of phosgene was passed through this over 5.5 hours at 108° (bath temperature of 120°) and then stirred for a further hour at the same temperature. After standing overnight, c. 300 ml of toluene was distilled at a bath temperature of 150°. It was then evaporated under reduced pressure. The oily residue was extracted twice with hexane (1000 ml) and the solution concentrated under reduced pressure. After a period of time crystals formed and these were separated to give N-(4,6-dimethylpyrimidin-2-yl)-N-phenylcarbamoyl chloride. This was shown by thin layer chromatography to be a uniform product, which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38]CC3C=CC=CC=3)=[C:22]([C:24]3[NH:25][C:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[C:27](Cl)[N:28]=3)[N:23]=[C:12]21)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:10][C:11]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([OH:38])=[C:22]([C:24]3[NH:28][CH:27]=[C:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[N:25]=3)[N:23]=[C:12]21
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(-c2nc(Cl)c(Cc3ccc(F)cc3)[nH]2)c(OCc2ccccc2)c1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of benzyl(3-(benzyloxy)-2-(4-chloro-5-(4-fluorobenzyl)-1H-imidazol-2-yl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 6 (60 mg, 0.092 mmol) in MeOH (3 mL) was added formic acid (0.100 mL, 2.65 mmol) followed by 10% Pd/C (98 mg, 0.092 mmol) and the mixture stirred at 40° C. for 3 h. After cooling to room temperature, the mixture was filtered through a pad of celite and concentrated. The mixture was then treated with sat. NaHCO3, extracted with dichloromethnae (×4), dried (Na2SO4), filtered and concentrated to afford the title compound (30 mg, 83% yield) as a light purple solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.53-1.60 (m, 2H), 1.73-1.81 (m, 6H), 2.37 (br. s., 1H), 2.51-2.54 (m, 2H), 3.93-3.99 (m, 2H), 4.01 (d, J=3.66 Hz, 2H), 7.10-7.17 (m, 3H), 7.30 (dd, J=8.24, 5.80 Hz, 2H). LCMS (M+H)=396.13.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6][Cl:7])=[O:2].C([O:15][C:16](=[O:18])[CH3:17])(=O)C>>[C:1]([O:2][CH:1]([O:15][C:16](=[O:18])[CH3:17])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:10](=[O:11])[CH3:9])[CH2:6][Cl:7])(=[O:2])[CH3:3]
Reactant: O=Cc1cc(CCl)ccc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(CCl)cc1C(OC(C)=O)OC(C)=O
Yield: 79 %

Procedure:
3-Formyl-4-hydroxy benzyl chloride (675 g., 3.96 moles) in 3.5 liters of acetic anhydride is refluxed for 24 hours. The reaction mixture is evaporated to dryness, triturated with a minimum amount of ether and filtered to yield 987 g (79%) of 3-(diacetoxymethyl)-4-acetoxybenzyl chloride, m.p. 93°-95°.
Reaction SMILES: [NH+]1C=CNC=1.N1([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:25])(=[O:24])[N:12]=2)C=CN=C1.[CH:26]([NH2:30])([CH2:28][CH3:29])[CH3:27]>>[CH:26]([NH:30][C:11]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=2[S:13](=[O:24])(=[O:25])[N:12]=1)([CH2:28][CH3:29])[CH3:27]
Reactant: CCC(C)N
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Agent: c1c[nH+]c[nH]1
Product: CCC(C)NC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide imidazolium salt was treated with sec-butylamine according to the general procedure Method A to give the title compound; m.p. 287-288° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18]>C(O)(=O)C>[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][N:20]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:18]
Reactant: NNC(=O)c1cccc(O)c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1cccc(O)c1
Temperature: 100 °C
Yield: 65 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 133 mg of the title compound (65%) as a yellow solid in 99.4% purity by HPLC (Rt: 4.83, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1>N1C=CC=CC=1>[CH3:23][C:22]1([CH3:24])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=2)[NH:14][CH:13]1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
In a round-bottomed flask, methanesulfonyl chloride (0.07 mL, 0.84 mmol) was added dropwise to a solution of 2-(3-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (0.1 g, 0.34 mmol) in dry pyridine (2 mL) was allowed to stir at room temperature for 1 h. The pyridine was removed under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:1) to afford 3,3-dimethyl-2-(3-(methylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid (27 mg, yield: 21.3%); MS (ES+APCI) M+1=375.1.