Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:3].[CH3:46][O:47][CH2:48][CH2:49][NH:50][CH3:51]>C1(C)C=CC=CC=1>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH:9]2[O:8][CH2:7][C:6]2[CH:42]=[CH:43][C:44]([CH3:45])=[C:4]([C:2](=[O:3])[N:50]([CH2:49][CH2:48][O:47][CH3:46])[CH3:51])[CH:5]=2)=[CH:16][CH:17]=1
Reactant: CNCCOC
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)Cl)c2)cc1
Solvent: Cc1ccccc1
Product: COCCN(C)C(=O)c1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 0.222 g of tert-butyl 3-(3-chlorocarbonyl-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 6 ml of toluene is admixed at 0° C. with the solution of 0.129 g of 2-methoxy-N-methylethylamine in 6 ml of toluene. The reaction mixture is stirred at 0° C. over a further 1 hour and then concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.12 (1:2 EtOAc-heptane); Rt=5.72.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32](S(C3C=CC(C)=CC=3)(=O)=O)[CH:31]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:28][CH3:29])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C1COCC1>[Br:1][C:2]1[C:3]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH2:19][CH2:20]3)=[CH:11][C:10]=2[O:28][CH3:29])=[N:6][CH:7]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Br)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Br)c(-c2c[nH]c3ccccc23)n1
Yield: 108.2 %

Procedure:
5-Bromo-N-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(1-tosyl-1H-indol-3-yl)pyrimidin-2-amine (INTERMEDIATE 37, 150 mg, 0.21 mmol) and Cs2CO3 (134 mg, 0.41 mmol) in 1:1 MeOH/THF (2.0 mL) was stirred at reflux for 2 h. The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (MeOH/1% NH4OH in DCM) to give the title product (131 mg, 69.5%).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([C:30]#[N:31])[CH:37]=2)=[CH:7][CH:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(C#N)c3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Reaction time: 25 h
Yield: 95.2 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 350 mg) in acetonitrile (7 mL) under nitrogen was treated with 3-cyanophenylboronic acid (99 mg) followed by aqueous sodium carbonate (2M, 0.677 mL). Nitrogen was bubbled through and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg) was added. The mixture was stirred at 85° C. for 25 h. The solvent was partially evaporated and the solution was purified by chromatography on silica using 50% ethyl acetate in isohexane and then ethyl acetate as eluent to afford the sub-titled compound as a solid (316 mg).
Reaction SMILES: O[CH2:2][C:3]1[C:4](=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.Cl>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:11]3[C:10]4[C:5]([CH2:4][C:3]=3[CH:2]=[N:22]2)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:17][CH:16]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C1C(CO)=Cc2ccccc21
Agent: Cl
Solvent: CCO
Product: Clc1ccc(-n2ncc3c2-c2ccccc2C3)cc1

Procedure:
2-Hydroxymethyl inden-1-one (Example 1(ii)(a) (4.0 g; 25.00 mmol), p-chlorophenylhydrazine hydrochloride (Aldrich) (4.52 g; 25.25 mmol), 10M hydrochloric acid (1 cm3) and ethanol (30 cm3) were heated under reflux for 22 hours. After cooling, the solvent was evaporated and the residual dissolved in dichloromethane and washed with 2M sodium hydroxide. The organic extracts were then dried (Na2SO4), filtered and concentrated in vacuo. Purification was by column chromatography (Eluant: dichloromethane] and recrystallisation (ethanol) gave off-white needle shaped crystals, m.p. 128-129° C.; b.p. 185° C.; 0.05 mmHg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[SH:11])[C:6]#[N:7])#[N:2].[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@@H:17]1Br)(=[O:14])[CH3:13]>[O-2].[Zn+2]>[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@H:17]1[S:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:1]#[N:2])(=[O:14])[CH3:13]
Reactant: N#Cc1ccc(S)c(C#N)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2C#N)SC[C@H]1OC(C)=O
Yield: 47.9 %

Procedure:
If the procedure described in Preparation IV is followed starting from 1.6 g (9.73.10-3 mol) of 3-cyano-4-mercaptobenzonitrile, 4.07 g (11.45.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 0.84 g (10.10-3 mol) of zinc oxide (ZnO), 2.08 g (yield: 47%) of the expected product are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[C:44]([F:49])=[CH:45][CH:46]=[C:47]([F:48])[C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2cccc(C(C)=O)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2cccc(C(C)=O)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 178 (80 mg, 0.15 mmol) is treated with acid chloride 8 (57 mg, 0.21 mmol) using Method D to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].I[CH3:32].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:32])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (5.0 g) in DMF (50 mL) was added sodium hydride (60%, 576 mg) at 0° C., and the mixture was stirred at 0° C. for 30 min. Iodomethane (978 μL) was added, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.40 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][N:17]([CH2:25][CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(O)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CCN(S(F)(F)[F:42])CC>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[C:4]([C:9]([N:11]2[CH2:12][C:13]([CH2:16][N:17]([CH2:25][CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])([F:42])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(CC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1)C(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCN(CC1(F)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.1 %

Procedure:
To 1,1-dimethylethyl [{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}ethylcarbamate (27 mg, 0.044 mmol), prepared using procedures similar to those in Example 3 and followed by Boc-protection, in chloroform (2.5 mL) added DAST (11.8 μL, 0.089 mmol) and stirred for 3.5 hr at room temperature. Quenched with water (15 mL), partitioned phases and extracted aqueous phase with chloroform (2×15 mL). The combined chloroform extracts were dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified on a silica gel column to afford 1,1-dimethylethyl [{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-fluoroazetidin-3-yl]methyl}ethylcarbamate (19.0 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:24]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.2 %

Procedure:
A 15-mL, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid (0.075 g, 0.274 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (0.063 g, 0.411 mmol) 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (0.079 g, 0.411 mmol), 1-hydroxybenzotriazole (0.037 g, 0.274 mmol), diisopropylethylamine (0.141 g, 1.09 mmol), and DMF (1.0 mL). After stirring at ambient temperature for 18 h, the reaction was concentrated under reduced pressure and purified by preparative HPLC to afford 0.016 g (14% yield) of N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.95 (br s, 1H), 8.23 (d, J=6.9 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.65-7.57 (m, 3H), 4.58 (q, J=7.1 Hz, 1H), 3.18 (br s, 2H), 2.58 (m, 5H), 2.25-2.02 (m, 3H), 1.55 (s, 3H), 1.23 (m, 3H); MS (APCI) m/z 409 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:16]([CH3:17])=[N:15][N:14]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNc1ccc(-c2ccc(Cl)cc2)cn1
Product: Cc1nnc2ccc(-c3ccc(Cl)cc3)cn12

Procedure:
A mixture of 8.5 g. of 5-(4-chlorophenyl)-2-hydrazinopyridine and 80 ml. of ethyl orthoacetate is refluxed for 5 hours, the mixture is filtered and the solid is washed with hexane to afford 5.0 g. of the product of the Example as a tan solid, m.p. 192°-193.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[N:3]=1.[CH2:10]([O:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14])[CH3:11]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:13]([O:12][C:10]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[N:3]=1)=[CH2:11])[CH3:14]
Reactant: Cc1nc(Br)ccc1F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(F)c(C)n1
Temperature: 100 °C

Procedure:
A mixture of 2-bromo-5-fluoro-6-methylpyridine (25 g, 132 mmol), 1-ethoxyvinyltri-n-butyltin (48.9 ml, 145 mmol) and bis(triphenylphosphine)palladium (II) chloride (4.62 g, 6.58 mmol) in 1,4-dioxane (250 ml) was heated to 100° C. under nitrogen over night. The reaction was then cooled to room temperature and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (eluted with a gradient of ethyl acetate in hexanes) to give the product 2-(1-ethoxy-ethenyl)-5-fluoro-6-methyl-pyridine, together with an unidentified impurity. This product was used in the next step. 1H NMR (500 MHz, CDCl3): δ 7.51 (dd, 1H), 7.28 (t, 1H), 5.33 (d, 1H), 4.31 (d, 1H), 3.96 (q, 2H), 2.53 (d, 3H), 1.43 (t, 3H).
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16]N)=[O:15])=[CH:12][CH:11]=1>C(O)C>[NH:7]=[C:5]([NH:8][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][C:10]([Cl:9])=[CH:11][CH:12]=1)[CH3:6]
Reactant: CC(=N)N
Reactant: NNC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=N)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.09 g (20 mmol) sodium methoxide in 20 mL ethanol are added to a solution of 1.91 g (20 mmol) acetamidine hydrochloride in 30 mL ethanol. The mixture is stirred for 30 minutes at ambient temperature and then filtered. The filtrate is combined with 2.3 g (13.5 mmol) 4-chlorobenzoic acid hydrazide, stirred overnight at ambient temperature, cooled with an ice bath and then filtered. The precipitate is washed with cold ethanol and dried. Yellow solid. Yield: 1.45 g (51%); mass spectroscopy [M+H]+=212/214.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:34][C:35]([F:38])([F:37])[F:36])[CH:33]=1)[C:28](O)=[O:29])#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:34][C:35]([F:36])([F:38])[F:37])[CH:33]=1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:29])#[N:24]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: N#Cc1cc(OC(F)(F)F)cc(C(=O)O)c1
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(OC(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the procedure for Example 33, 50 mg (0.17 mmol) of the compound of Example 6A and 40 mg (0.18 mmol) of the compound of Example 41A were reacted with one another. After purification of the crude product by preparative HPLC, the product-containing fractions were concentrated to a small residual volume and made alkaline with a little saturated aqueous sodium bicarbonate solution. The precipitate formed was filtered off, washed with water and dried. This gave 56 mg (65% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].CCN(CC)CC.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>C1COCC1>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C=Nc1ccccc1F
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.09 g, 4.93 mmol) and Et3N (755 ml, 5.42 mmol) in THF (10 ml) was added 2-fluorophenyl isocyanate (610 μl, 5.44 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 4-[N′-(2-fluorophenyl)ureido]-3-methylphenylacetate (1.31 g, 74%) as a white crystalline powder. mp 89-91° C.; 1H-NMR (CDCl3) δ1.47 (s, 9 H), 2.06 (s, 3 H), 3.49 (s, 2 H), 6.62 (s, 1 H), 6.92-7.09 (m, 5 H), 7.21 (br s, 1 H), 7.49-7.51 (m, 1 H), 8.10-8.15 (m, 1 H); Anal. Calcd. for C20H23FN2O3; C, 67.02; H, 6.47; N, 7.82; F, 5.30. Found: C, 66.74; H, 6.35; N, 7.85; F, 5.69.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@@H:10]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH3:35])=[CH:29][CH:28]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[C:24](=[O:36])[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH3:35])=[CH:29][CH:28]=1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCc1ccc(CNC(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCN2C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1ccc(CNC(=O)[C@H]2CNCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To the compound (2.64 g) obtained in Step 2 in 1,4-dioxane (13 ml) was added, with stirring at room temperature, 4N hydrogen chloride/1,4-dioxane (13 ml). After stirring at room temperature for 3 hr, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (5%-10% methanol/chloroform) to give the title compound (1.59 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:22])[C@@H:13]([CH3:31])[CH2:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21](=[O:22])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH:13]([CH3:31])[CH2:12]2)[C:41](=[O:43])[CH3:42])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccc([N+](=O)[O-])cc3)C[C@@H]2C)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccc([N+](=O)[O-])cc3)CC2C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S,4R)-[4-(4-nitro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-methoxy-phenyl)-methanone (1.00 equiv.) in methylene chloride was added diisopropylethylamine (1.05 equiv) followed by acetyl chloride (1.00 equiv). The mixture was stirred at rt 48 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-(4-nitro-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide; which was reduced to N-(4-amino-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide using excess NH4CO2H, catalyic Pt(sulfided), in ethanol at reflux for 30 m., followed by filtration and concentration. The amine was used without further purification due to inherent chemical instability.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([CH:12]([S:15]([CH2:18][C:19]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:29])(=[O:17])=[O:16])[CH2:13][CH3:14])=[N:10][CH:9]=[CH:8][N:7]=1)=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:29][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([F:27])([F:26])[F:28])[C:19]=1[C:18]1[S:15](=[O:17])(=[O:16])[CH:12]([CH2:13][CH3:14])[C:11]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=2[C:4]=1[OH:3]
Reactant: CCOC(=O)c1nccnc1C(CC)S(=O)(=O)Cc1c(Cl)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1c2nccnc2C(O)=C(c2c(Cl)cccc2C(F)(F)F)S1(=O)=O
Temperature: 120 °C

Procedure:
A mixture of 3-[1-(2-chloro-6-trifluoromethyl-phenylmethanesulfonyl)-propyl]-pyrazine-2-carboxylic acid ethyl ester (0.106 g) and potassium carbonate (0.081 g) in N,N-dimethylformamide (2 ml) was heated to 120° C. for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with water and washed with diethyl ether. The aqueous layer was acidified with aqueous hydrochloric acid (2M) and extracted with ethyl acetate (2×20 ml). The organic layer was concentrated and the residue purified by reverse phase chromatography (eluent: 0-100% v/v acetonitrile in water with 0.05% trifluoroacetic acid) to give 7-(2-chloro-6-trifluoromethyl-phenyl)-5-ethyl-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-ol Compound No. E1 of Table E (0.042 g). MH+=405, RT=1.38 min.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[S:11][C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[S:11][C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:22][CH2:23][CH:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[O:14])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccc(F)cc4)s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1CCC(c2ccc(C(=O)Nc3nnc(Cc4ccc(F)cc4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
0.35 g of tert-butyl (4-{4-[5-(4-fluorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate (0.69 mmol, 1 eq.) is placed in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid (13.46 mmol, 19.6 eq.) is added and the reaction medium is stirred for 18 hours at room temperature. The solvent is evaporated off and the residue is taken up in ethyl acetate, ethanol and methanol to give 117 mg of (4-{4-[5-(4-fluorobenzyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetic acid.