Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][C@:5]([NH2:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:6][CH3:7].[CH3:19][NH:20][C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=S>>[C:26]([O:25][C:24](=[O:30])[NH:23][C:21]1[N:20]([CH3:19])[C:3](=[O:18])[CH2:4][C@@:5]([CH2:6][CH3:7])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:17]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC[C@](N)(CC(=O)OC)c1cccc([N+](=O)[O-])c1
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CC[C@@]1(c2cccc([N+](=O)[O-])c2)CC(=O)N(C)C(NC(=O)OC(C)(C)C)=N1

Procedure:
Starting from (S)-3-amino-3-(3-nitro-phenyl)-pentanoic acid methyl ester (1.2 mmole) and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-ethyl-1-methyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (372 mg) was obtained as white solid. MS (ESI): m/z=375.4 [ M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH:13]1([C:16]2[CH:17]=[C:18]([CH3:28])[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[C:18]([CH3:28])=[CH:17][C:16]([CH:13]4[CH2:14][CH2:15]4)=[CH:21][N:20]=3)[CH2:23][CH2:24]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Yield: 82.2 %

Procedure:
Using 4-bromo-2-cyanobenzoic acid (2.14 g) described in Preparation Example 76 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (2.16 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.31 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:25])O)=[C:10]([N+:26]([O-:28])=[O:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1COCC1>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:25])=[C:10]([N+:26]([O-:28])=[O:27])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(Cl)c1C(O)Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COc1cccc(Cl)c1/C=C/c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 55.9 %

Procedure:
To a solution of {4-[2-(2-chloro-6-methoxy-phenyl)-2-hydroxy-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (0.45 g, 1.06 mmol)in THF (10 mL) was added 2,2,2-trifluoroacetic anhydride (671 mg, 3.18 mmol) at 25° C. resulting in a color change to dark blue. The reaction was allowed to stir at 25° C. for 30 min after which 8-diazabicyclo[5.4.0]undec-7-ene (0.76 g, 5.00 mmol) was added. The reaction was heated to 70° C. for 3 h and then cooled to 25° C. and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (90/10 hexanes/ethyl acetate) afforded {4-[(E)-2-(2-chloro-6-methoxy-phenyl)-vinyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (240 mg, 60%) as an oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(O)=O>C1(C)C=CC=CC=1>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][OH:2])=[CH:15][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: OCCCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Yield: 64.8 %

Procedure:
To a solution of 4-[(S)-2-(4-benzyl-phenoxymethyl)-pyrrolidin-1-yl]-butyric acid methyl ester (0.37 g, 1 mmol) in toluene (2 mL) was added 1.5M diisobutylaluminum hydride in toluene (2 mL, 3 mmol) at −60° C. and then stirred the reaction at −30 to −20° C. for 2 h, followed by addition of 15% AcOH dropwise. The reaction was stirred at room temperature for 30 minutes and formed white solid was filtered and washed with acetone. The filtrate was concentrated in vacuo to yield the title compound as a white solid (0.22 g, 79%); MS; m/z 340.8 (M+H). 1H NMR (400 HMz, CDCl3) δ 1.61-2.26 (m, 8H), 2.79 (m, 1H), 2.85 (m, 1H), 3.25 (m, 2H), 3.42 (m, 2H), 3.54 (m, 1H). 3.68 (m, 1H), 3.75 (m, 1H), 3.92 (s, 2H), 6.82 (d, J=8.8 Hz, 2H), 7.09-7.21 (m, 5H), 7.28 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[C:12](=[O:21])[C:13]([C:16]([O:18]CC)=O)=[CH:14][N:15]=[C:4]12)[CH3:2].[CH3:22][NH2:23]>>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[C:12](=[O:21])[C:13]([C:16]([NH:23][CH3:22])=[O:18])=[CH:14][N:15]=[C:4]12)[CH3:2]
Reactant: CN
Reactant: CCOC(=O)c1cnc2n(CC)c3ccccc3n2c1=O
Product: CCn1c2ccccc2n2c(=O)c(C(=O)NC)cnc12
Yield: 63 %

Procedure:
10 g. of 90% pure 10-ethyl-4,10-dihydro-4-oxo-pyrimido[1,2-a]-benzimidazole-3-carboxylic acid, ethyl ester produced in Example 1b are dissolved in 50 ml. of alcohol. After addition of 10 ml. of methylamine, the solution is heated in an autoclave at 100° for 12 hours. After this time, the solvent is distilled off and the crystalline residue is heated with hot acetone. The small amount of isomeric 1-ethyl-1,4-dihydro-N-methyl-4-oxo-pyrimido[1,2-a]benzimidazole-3-carboxamide is insoluble and is filtered off. After addition of water to the mother liquor, the 10-ethyl-4,10-dihydro-N-methyl-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxamide crystallizes, yield 63%; m.p. 178°-180° (acetone).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH2:27][CH:28]([OH:39])[CH2:29][NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][C:21]([Br:26])=[CH:20][CH:19]=3.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Br:26][C:21]1[CH:20]=[CH:19][C:18]2[N:17]([CH2:27][CH:28]([OH:39])[CH2:29][N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[C:8](=[O:10])[CH3:9])[C:16]3[C:24]([C:23]=2[CH:22]=1)=[CH:25][C:13]([Br:12])=[CH:14][CH:15]=3
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Reactant: CC(=O)Cl
Agent: CCCC[Sn](=O)CCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)C(C)=O)c1
Temperature: 150 °C

Procedure:
Following a literature procedure (Morcuende, A; Ors, M; Valverde, S; Herradón, B. J. Org. Chem. 1996, 5264-5270) triethylamine (14 μl, 0.10 mmol) and acetyl chloride (8 μl, 0.11 mmol) were added to a heterogeneous mixture of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (53 mg, 0.11 mmol) and dibutyltin oxide (5.5 mg, 0.022 mmol) in anhydrous toluene (1.5 ml). The reaction vessel was purged with nitrogen, sealed and heated under microwave radiation to 150° C. for 9 minutes. The reaction was monitored by lc/ms and all SM had been consumed. The heterogeneous solution was filtered under vacuum to yield a white solid. The crude product was used without purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[C:14](=O)[C:13]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:12]=1[O:11]2>CO.[OH-].[OH-].[Pd+2]>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:14][C:13]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:12]=1[O:11]2
Reactant: COC(=O)c1ccc2c(c1)C(=O)C1(O2)C(=O)Nc2ncccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CC1(O2)C(=O)Nc2ncccc21
Reaction time: 18 h

Procedure:
A mixture of methyl 2′,3-dioxo-1′,2′-dihydro-3H-spiro[benzofuran-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate (200 mg, 0.64 mmol) and 20 wt. % palladium hydroxide on carbon (40 mg) in MeOH (5 mL) is stirred under an atmosphere of hydrogen (50 psi) for 18 h. The reaction mixture is then filtered through a pad of Celite° and the filtrate is concentrated in vacuo. The residue is partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The layers are separated and the aqueous layer is further extracted with CH2Cl2 (2×). The combined organic extracts are dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][N:28]([C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=2)[CH2:29][CH2:30]1)=[O:6]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1Br
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3Br)CC2)c(C)c1
Yield: 84.6 %

Procedure:
Using methyl 2-bromo-4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoate (312 mg) described in Preparation Example 177 and 1-(3,5-dimethylpyridin-2-yl)piperazine (171 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (384 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][C:20]([CH3:29])([CH3:28])[CH2:19]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[C:20]([CH3:29])([CH3:28])[CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1OC)CC(C)(C)NC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1cc2c(cc1OC)CC(C)(C)N(C(=O)c1cc3ncc(Br)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[F:19][C:20]([F:31])([F:30])[C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:19][C:20]([F:30])([F:31])[C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][O:7][C:8]2[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:28])[CH2:25][CH2:26]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifluoroactetic acid) salt (EXAMPLE 34 Step 1) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[N:10]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:9]1=[O:27])(C)(C)C>C(OCC)(=O)C>[NH2:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[N:10]([CH2:21][CH2:22][C:23]([F:24])([F:25])[F:26])[C:9]1=[O:27]
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CCC(F)(F)F
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(3,3,3-trifluoropropyl)piperidin-3-yl]carbamate (152 mg, 0.380 mmol) in ethyl acetate (10 mL), pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The ice-bath was removed and the acidic solution was allowed to warm to 23° C. as stirring was continued for 2 h. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. MS: m/z=301.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.[C:40]([Cu])#[N:41].N1C=CC=CC=1>CC(N(C)C)=O>[C:40]([C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]1)#[N:41]
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)CCCC1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(C#N)c2)CCCC1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
To a 5 mL microwave vial were added methyl 1-{[1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]methyl}cyclopentanecarboxylate (94 mg, 0.16 mmol), CuCN (31 mg, 0.34 mmol), pyridine (0.5 mL) and DMA (1.5 mL). The vial was flushed with N2, then capped and irradiated in the microwave at 200° C. for 4 h. The resulting mixture was cooled to RT, poured into water (10 mL) and extracted with EtOAc. The organics were concentrated to dryness and the resulting residue was purified by FCC to provide 40 mg of the title compound. MS (ESI): mass calcd. for C33H30N4O3, 530.63; m/z found, 531.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cccc(NC(C)=O)c1
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
m-Anisidine (50 g, 0.406 mol) was added to acetic acid (25 mL)and cooled in an ice bath. Acetic anhydride (45.6 g, 0.447 mol) was added dropwise with stirring over 10 min. The resulting mixture was stirred and allowed to come to room temperature. After 1.5 hr the mixture was concentrated under reduced pressure until crystallization commenced. The crystals were collected and allowed to air dry in the hood overnight and finally in a desiccator to afford 66.5 g (99%) of N-(3-methoxyphenyl)acetamide.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7](=[S:23])[NH:8][NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1(C)C=CC=CC=1>[CH2:11]([C:10]1[S:23][C:7]([NH2:6])=[N:8][N:9]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCC(=O)NNC(N)=S
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCc1nnc(N)s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonic acid (6.26 g, 0.065 mol) was added in one portion to a slurry of the compound prepared in Step 1 above (11.9 g, 0.044 mol) in toluene (300 mL) at 0° C. After 5 minutes, the mixture was heated to reflux for 18 hours, allowed to cool to 0° C., filtered, and the residue washed with cold toluene (50 mL at 5° C). The solid was dried in vacuo, suspended in water (200 mL), and made basic with ammonium hydroxide (0.1M) while stirring vigorously. The resulting solid was filtered, washed with water, dried in vacuo to give 7.2 g of a white solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]([F:16])([F:15])[CH2:6][O:7][CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>O>[OH:14][C:11]1([C:1]#[N:2])[CH2:10][CH2:9][CH:8]([O:7][CH2:6][C:5]([F:15])([F:16])[F:4])[CH2:13][CH2:12]1
Reactant: O=C1CCC(OCC(F)(F)F)CC1
Reactant: [C-]#N
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: O
Product: N#CC1(O)CCC(OCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
13.74 g of sodium cyanide are dissolved in 200 ml of water. Over a period of 30 min, 50 g of 4-trifluoroethoxycyclohexanone are then added dropwise at 20-28° C. with slight cooling. The mixture is stirred at 25° C. for 5 minutes, and 31.48 g of sodium disulfite, dissolved in 100 ml of water, are then added dropwise with cooling at 25-30° C. over a period of 30 min. With monitoring by thin-layer chromatography, the mixture is stirred at room temperature. The aqueous phase is extracted 3× with in each case 90 ml of toluene. The organic phases are combined and concentrated under reduced pressure.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:35].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]([NH2:31])=[O:35])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(C)(C)C#N)CC3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(C)(C)C(N)=O)CC3)ccc1-2
Reaction time: 5.5 h
Yield: 19 %

Procedure:
2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (346 mg, ˜50% pure, ˜0.40 mmol) was treated with concentrated sulphuric acid (5 mL) and the mixture was stirred for 5.5 hours then diluted with ice chips (˜50 mL) and made basic with solid sodium carbonate. The mixture was extracted with 10% MeOH in DCM (×4) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in DCM first time then 0-100% EtOAc in DCM) to give 483 as a white solid (36 mg, 19%). LCMS: RT=3.28 min, [M+H]+=481. 1H NMR δ (ppm) (DMSO-d6): 9.54 (1 H, s), 8.27 (1 H, d, J=8.13 Hz), 8.05 (1 H, s), 7.98 (1 H, s), 7.86 (1 H, s), 7.05 (1 H, d, J=8.29 Hz), 6.90 (1 H, s), 5.81-5.73 (1 H, m), 4.32 (2 H, s), 3.41-3.30 (4 H, m), 3.12 (1 H, m), 2.83 (1 H, m), 2.13 (2 H, d, J=13.80 Hz), 1.99 (1 H, d, J=13.56 Hz), 1.72 (1 H, s), 1.50 (12 H, d, J=6.50 Hz). 1 Proton obscured by water peak
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([OH:29])=O)[N:25]=2)=[N:10]1.C[CH2:31][N:32]=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:32][CH3:31])=[O:29])[N:25]=2)=[N:10]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)O)cs2)=NC1c1ccc(F)cc1Br
Agent: CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
A solution of 2-(2-(4-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-6-methyl-1,4-dihydropyrimidin-2-yl)thiazol-4-yl)acetic acid (3 g, 6.2 mmol), EDC.HCl (1.55 g, 8.06 mmol), HOAt (0.84 g, 6.2 mmol) and DIPEA (1.6 g, 12.4 mmol) in DMF (60 mL) was cooled to 10° C. and then stirred at −10° C. for 30 minutes. Then methanamine hydrochloride (0.63 g, 9.3 mmol) was added and the mixture was stirred for another 1 hour. The mixture was warmed to 50° C. and stirred for 4 hours. The reaction solution was diluted with EtOAc (150 mL), and washed with brine (100 mL×6). The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a yellow solid (1.2 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1.C1COCC1.[OH-].[Na+].Cl>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=1
Reactant: COC(=O)Cc1ccc2nc(-c3cccnc3)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc2nc(-c3cccnc3)oc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.5 %

Procedure:
To methyl (2-(3-pyridyl)-6-benzoxazolyl)acetate (360 mg, 1.34 mmol) were added THF (8 ml) and 0.5N NaOH (8.0 ml, 4.00 mmol). The resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture were added water and 1N HCl (5.0 ml, 5 mmol) to acidify the mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give (2-(3-pyridyl)-6-benzoxazolyl)acetic acid (179 mg, 52%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[S:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22]1>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:26]([C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)=[O:27])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)c1ccsc1
Product: O=C(CNC(=O)c1ccsc1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and thiophene-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A mixture of 3-(4-fluorophenyl)-propylamine (306 mg, 2 mmol), 2-bromomethyl-benzoic acid methyl ester (458 mg, 2 mmol), and K2CO3 (200 mg, 1.45 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(4-fluorophenyl)-propyl]-2,3-dihydroisoindol-1-one (432 mg, 80%). GC/MS gave: m/z (rel.int.) 269 (M+, 32), 147 (100), 146 (76), 119 (43), 109 (30) and 91 (39).