Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([F:11])=[C:9]([NH:12]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:8]=[C:7]([CH:32](OCC)[O:33]CC)[N:6]=2)[CH2:3][CH2:2]1.OS(O)(=O)=O.CC#N>O>[NH2:12][C:9]1[C:10]([F:11])=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:6]=[C:7]([CH:32]=[O:33])[CH:8]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(CC2CC2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: Nc1cc(C=O)nc(CC2CC2)c1F
Yield: 89.7 %

Procedure:
Using the procedure for Example 12, 2-(cyclopropylmethyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (4.34 g, 8.5 mmol), conc H2SO4 (1 mL), CH3CN (35 mL) and H2O (35 mL) gave 4-amino-6-(cyclopropylmethyl)-5-fluoropicolinaldehyde (1.48 g, 88%) as an off-white solid: mp 99-100° C.; 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.25 (d, J=6.7 Hz, 1H), 4.40 (br s, 2H), 2.76 (dd, J=7.0, 2.9 Hz, 2H), 1.17 (m, 1H), 0.50 (m, 2H), 0.29 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 193.10, 149.43 (d, J=15.4 Hz), 148.84 (d, J=253.6 Hz), 148.73 (d, J=5.4 Hz), 141.49 (d, J=12.6 Hz), 107.76 (d, J=3.8 Hz), 36.25 (d, J=1.8 Hz), 10.16 (d, J=1.5 Hz), 4.56; 19F NMR (376 MHz CDCl3) δ −144.19. HRMS-ESI (m/z) [M+H]+ calcd for C10H11FN2O, 194.0855. found, 194.0857.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:49][C:50]#[N:51]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:49][C:50]#[N:51])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#CCBr
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(CC#N)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 58 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with bromoacetonitrile was carried out as described in Example 3, Step A. After work-up, the residue was flash chromatographed over silica gel (30 mL for 0.162 mmole, gradient elution using 0.5-2.0% MeOH/CH2Cl2 to give the desired compound in 58% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) m/e 657 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:23]([O:22][CH:21]([O:25][CH2:26][CH3:27])[CH2:20][N:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[N:9]1)[CH3:24]
Reactant: CCOC(CBr)OCC
Reactant: Fc1ccc(-c2cc[nH]n2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(Cn1ccc(-c2ccc(F)cn2)n1)OCC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-fluoro-2-(1H-pyrazol-3-yl)pyridine obtained in Reference Example 10 (11.7 g, 58.6 mmol) in DMF (195 mL), Cs2CO3 (57.3 g, 0.18 mol) and 2-bromo-1,1-diethoxyethane (11.5 mL, 76.2 mmol) were stirred for 18 hours at 80° C. The reaction mixture was allowed to cool to room temperature, then water was added thereto, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane/EtOAc=88/12 to 35/65) to obtain the title compound (8.2 g) (colorless oil).
Reaction SMILES: OC1C(=O)C(C(N)=O)=CN2CC3N4CCCCC4CN3C(=O)C=12.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32][NH:33][C:34]([C:36]1[C:37](=[O:62])[C:38]([O:54]CC2C=CC=CC=2)=[C:39]2[C:44](=[O:45])[N:43]3[CH2:46][C@@H:47]4[CH2:52][CH2:51][CH2:50][CH2:49][N:48]4[C@@H:42]3[CH2:41][N:40]2[CH:53]=1)=[O:35]>[Pd]>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32][NH:33][C:34]([C:36]1[C:37](=[O:62])[C:38]([OH:54])=[C:39]2[C:44](=[O:45])[N:43]3[CH2:46][C@@H:47]4[CH2:52][CH2:51][CH2:50][CH2:49][N:48]4[C@@H:42]3[CH2:41][N:40]2[CH:53]=1)=[O:35]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C[C@@H]3CCCCN3[C@@H]1C2
Agent: [Pd]
Agent: NC(=O)c1cn2c(c(O)c1=O)C(=O)N1CC3CCCCN3C1C2
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C[C@@H]3CCCCN3[C@@H]1C2
Yield: 86.8 %

Procedure:
(5aS,14aS)-N-[(2,4-Difluorophenyl)ethyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide. In a manner similar to that described in example Z-37, from (5aS,14aS)-N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)oxy]-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide (18 mg, 0.0337 mmol) and 10 w.t.% Pd/C (catalytic amount) was prepared the title compound as a white solid (13 mg, 87%) after purification by HPLC, 1H NMR (CDCl3) δ 11.71 (br s, 1H), 10.36 (br s, 1H), 8.31 (s, 1H), 7.34 (m, 1H), 6.78 (m, 2H), 4.64-4.57 (m, 2H), 4.28 (m, 1H), 4.12 (m, 1H), 3.92-3.89 (m, 2H), 3.22 (m, 1H), 3.04 (m, 1H), 2.49 (m, 1H), 2.28 (m, 1H), 1.97-1.89 (m, 2H), 1.78 (m, 1H), 1.66-1.60 (m, 2H), 1.43-1.36 (m, 2H); ES+MS: 445 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: CCCCc1cc(CCC=O)n(-c2cccc(Cl)c2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2cccc(Cl)c2)n1

Procedure:
312 mg (84.2%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(3-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (236.75 mg, 0.814 mmol), 1-(2-fluorophenyl)piperazine (192.9 mL, 1.221 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C:34]([C:36]2[N:37]=[CH:38][N:39]3[CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:41][C:40]=23)=[O:35])=[CH:30][CH:29]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:42]3[S:41][C:40]4=[C:36]([C:34]([C:31]5[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=5)=[O:35])[N:37]=[CH:38][N:39]4[CH:43]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3ccc(C)nc3)c2s1
Product: Cc1ccc(C(=O)c2ncn3cc(C4=C(C(=O)OCc5ccc([N+](=O)[O-])cc5)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)sc23)cn1
Yield: 77.3 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (499 mg) was prepared in the same manner as in step a) of Example 1, except that 398 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 923 mg of 7-(6-methylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][CH2:13]Br>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: N#CCc1ccccc1Br
Reactant: BrCCBr
Product: N#CC1(c2ccccc2Br)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using (2-bromo-phenyl)-acetonitrile and 1,2-dibromoethane.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:8][C:7]=1[C:33]([F:36])([F:35])[F:34]>C1COCC1.CCOC(C)=O.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:3]([NH:2][CH3:1])=[O:4])[N:27]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:8][C:7]=1[C:33]([F:34])([F:36])[F:35]
Reactant: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1

Procedure:
130 μl (2.2 mMol) methyl isocyanate are added to a solution of 300 mg (0.68 mMol) 6-(2-amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (Step 10.3) in 10 ml THF in a sealed vessel. The mixture is stirred at 100° C. for 11 days (another 1.1 eq. of Me-NCO is added on day 8 and 9). Then the reaction mixture is diluted with EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and partially concentrated. Precipitation with hexane, filtration and re-crystallization from boiling THF/CH3CN gives the title compound: m.p.: 233-234° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CS(C)=[O:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: O=C(Cc1ccc(F)cc1)c1ccc(F)cc1
Product: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
SeO2 (191 mg, 1.72 mmol, 4.00 equiv) was added in batches to a solution of 1,2-bis(4-fluorophenyl)ethanone (100 mg, 0.43 mmol, 1.00 equiv) in DMSO (4.5 mL). The resulting solution was allowed to react, with stirring, for 2 hrs while the temperature was maintained at 100° C. in an oil bath. The solids were filtered out and discarded.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:17]([O:19][N:20]([CH3:22])[CH3:21])=[O:18])=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.CS([C:27]1[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=1)(=O)=O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:17]([O:19][N:20]([CH3:22])[CH3:21])=[O:18])=[C:12]([O:16][C:27]3[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=3)[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CN(C)OC(=O)c1c(O)cccc1-c1ccc(Br)cc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(-c3ccc(Br)cc3)c2C(=O)ON(C)C)n1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
At 10° C., 0.30 g (0.01 mol) of sodium hydride (80% strength) is added to a solution of 3.35 g (10 mmol) of 3-(4-bromophenyl)-2-(N,N-dimethylaminooxycarbonyl)-phenol in 25 ml of dried dimethylformamide, and the mixture is stirred for 3 hours at 30° C. Subsequently, 2.18 g (0.01 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine is added and the mixture stirred for 12 hours at room temperature. Working up in accordance with Example 4 gives a colorless solid.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)[CH2:6][CH:7]=[CH2:8])C=C.N1CCC1>C(Cl)Cl>[O:4]1[CH2:1][CH:8]=[CH:7][CH2:6][CH:5]1[CH:9]1[CH2:10][CH2:11][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:17][CH2:18]1
Reactant: C=CCOC(CC=C)C1CCC2(CC1)OCCO2
Agent: C1CNC1
Solvent: ClCCl
Product: C1=CCC(C2CCC3(CC2)OCCO3)OC1
Temperature: 40 °C

Procedure:
A solution of 8-(1-(allyloxy)but-3-en-1-yl)-1,4-dioxaspiro[4.5]decane (454 mg, 1.80 mmol), prepared in the previous step, and the Grubbs Generation II catalyst (76 mg, 0.09 mmol) in DCM was degassed and heated to 40° C. under argon for 4 hours. After extraction with saturated NaHCO3 solution, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, ether) to afford the product.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[CH2:21][CH2:22][OH:23].CCOCC>C(Cl)Cl>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:13]1[CH2:21][CH:22]=[O:23]
Reactant: OCCC1Cc2ccccc2C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Suspended in 220 ml of methylene chloride were 18.5 g (85.8 mmol) of pyridinium chlorochromate and 70 g of Celite (No. 545). While chilling with ice water, a solution of 4.30 g (26.6 mmol) of 2-(indan-2-yl)ethanol in 15 ml of methylene chloride was added dropwise to the suspension. After stirring the mixture for 1 hour while chilling with ice water, it was further stirred at room temperature for 2 hours. The reaction product was added with 250 ml of ether to dilute it. The diluted reaction product was passed through 100 g of silica gel layer to remove inorganic matter. The solvent was distilled off to obtain 3.97 g of (indan-2-yl)acetaldehyde as a colorless oily substance. Yield: 93%.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:6][CH:7]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([Sn](C)(C)C)=[CH:24][CH:23]=1.[Cl-].[Li+].N>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:13]4[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=4[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=3)=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: CC1(C)C=C(c2ccc(I)cn2)c2cc(C#N)ccc2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C3=CC(C)(C)Oc4ccc(C#N)cc43)nc2)cc1
Yield: 67.1 %

Procedure:
440 mg of 4-(5-iodo-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile, 386 mg of p-tolyltrimethyltin, 144 mg of lithium chloride and 16 mg of bis(triphenylphosphine)palladium dichloride in 4 ml of dimethylformamide were heated at 100° C. for 2 hours. After cooling to room temperature 10% aqueous ammonia and ethyl acetate were added, the phases were separated and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution to give 268 mg of 4-[5-(4-methylphenyl)-2-pyridyl]-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile which was used without further purification.
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.O.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)CCC>[N+:12]([C:11]1[C:2]2[NH:19][CH2:16][CH2:17][NH:18][C:4](=[O:6])[C:3]=2[CH:8]=[CH:9][CH:10]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: NCCN
Solvent: CCCCO
Solvent: O
Product: O=C1NCCNc2c1cccc2[N+](=O)[O-]

Procedure:
A mixture of 11.7 parts of methyl 2-bromo-3-nitrobenzoate, 8.1 parts of 1,2-ethanediamine monohydrate and 40 parts of 1-butanol was stirred for 1/2 at reflux temperature. The reaction mixture was evaporated and the residue was diluted with 50 parts of water. The precipitate was filtered off and washed with water and 2-propanol. It was then recrystallized from 2-methoxyethanol, yielding 6.5 parts of 2,3,4,5-tetrahydro-9-nitro-1H-1,4-benzodiazepin-5-one; mp. 191°-195° C. (interm. 1).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+].[NH4+].[Cl-]>C(O)C.O.CCOC(C)=O>[CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10]/[C:11](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:27]\[OH:28])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(CC(=O)c2ccncc2)c2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(C/C(=N\O)c2ccncc2)c2ccccc2)cc1
Yield: 47.9 %

Procedure:
A solution of 3-(4-dimethylamino-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one (838 mg), hydroxylamine hydrochloride (353 mg) and sodium hydrogencarbonate (426 mg) in ethanol/water (21 mL, 20:1) was heated under reflux for 2 hours. A saturated aqueous solution of NH4Cl was added to the reaction mixture and extraction was made with EtOAc (2×). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography on silica gel (EtOAc/n-heptane 2:1) gave (E)-3-(4-dimethylamino-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (420 mg, 48%) as a white foam, MS (ESI+): m/z=346.1 ([M+H]+), (Z)-3-(4-dimethylamino-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (20 mg, 2%) as a colorless oil, MS (ESI+): m/z=346.1 ([M+H]+) and 3-(4-dimethylamino-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime as a mixture of isomers (313 mg, 36%), MS (ESI+): m/z=346.1 ([M+H]+).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[C:18]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:17]=[CH:16][C:15]=2[N+:27]([O-])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CCO>[NH2:27][C:15]1[CH:16]=[CH:17][C:18]([CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:19][C:14]=1[NH:13][C@@H:10]1[CH2:11][CH2:12][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:8][CH2:9]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(CN3CCCCC3)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(CN3CCCCC3)ccc2N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added cis-N-isopropyl-4-(2-nitro-5-(piperidin-1-ylmethyl)phenylamino)cyclohexanecarboxamide (1.400 g, 3.48 mmol) under nitrogen. Palladium on carbon (0.370 g, 0.348 mmol) was added, followed by EtOH (28.3 mL) via syringe. To the reaction was added ammonium formate (2.193 g, 34.8 mmol), and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered through Celite® brand filter aid, concentrated and diluted with 90:10:1 DCM:MeOH:NH4OH and water. The layers were separated, and the aqueous layer was washed once more. The organics were dried over sodium sulfate, filtered and concentrated to yield cis-4-(2-amino-5-(piperidin-1-ylmethyl)phenylamino)-N-isopropylcyclohexanecarboxamide (1.18 g, 3.17 mmol, 91% yield) as a dark red solid.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C=CC=CC=1C=C.Cl[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(=O)(O)(O)O>ClC1C=CC=CC=1Cl>[CH3:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: ClCCc1ccccc1
Reactant: C=Cc1ccccc1
Agent: C=Cc1ccccc1Cl
Agent: O=P(O)(O)O
Solvent: Clc1ccccc1Cl
Product: CC1CC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 90 parts of styrene, 156 parts of o-chlorostyrene and 114 parts of o-chloroethylbenzene is added to an emulsion of 680 parts of 90 per cent strength by weight phosphoric acid and 150 parts of o-dichlorobenzene at 35° to 40° C over 5 hours, whilst stirring vigorously. The mixture is stirred for a further 2 hours at 35° to 40° C and the organic phase is separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation at 10 mm Hg gives 34 parts of 1-methyl-3-phenylindan, 71 parts of 1-methyl-3-(o-chloro)-phenylindan (b.p. 165° to 168° C (10 mm), nD25 : 1.5890) and 23 parts of 1-methyl-3-(o-chloro)-phenyl-7-chloroindan (b.p. 195° to 200° C (10 mm)).
Reaction SMILES: BrC(C)C(OCC)=O.Cl.C1([CH:16]([N:20]2[CH2:25][CH2:24][CH:23](C3C=CC(NC(C4C=CC=CC=4C4C=CC(C(F)(F)F)=CC=4)=O)=CC=3)[CH2:22][CH2:21]2)[C:17]([OH:19])=[O:18])C=CC=CC=1.C(NC(=S)N(CCCC)CCCC)CCC>CCN(C(C)C)C(C)C>[N:20]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1ccc(C2CCN(C(C(=O)O)c3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCCCNC(=S)N(CCCC)CCCC
Agent: CCOC(=O)C(C)Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CN1CCCCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Ethyl 2-bromopropionate (0.0001 mol) was added to a mixture of intermediate (12) (0.000084 mol) and tri-n-butylthiourea (TBTU) (0.000168 mol) in DIPEA (4 ml). The reaction mixture was shaken for 2 hours at 70° C. The reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated. The residue was dissolved in DCM (4 ml), then washed with water (2 ml). The mixture was filtered through Extrelut™ and the filter residue was washed with DCM (2×3 ml). The filtrate was evaporated. The residue was purified by HPLC (Waters column, with Xterra MS C18; eluent: [(0.5% NH4OAc in H2O)/CH3CN 90/10)]/CH3CN (0 min) 85/15, (10 min) 10/90, (16 min) 0/100, (18.10-20.00 min) 85/15), yielding 1-piperidineacetic acid, α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-, 2-ethoxy-1-methyl-2-oxoethyl ester (compound 111).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:9][C:10]3([CH2:15][CH2:14][N:13](C#N)[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(O)(=O)C.[OH-].[Na+].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>Cl.CCOCC>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: N#CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A suspension of 2.5 g of 6-chloro-1'-cyano-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], Example 31, in 40 ml of 3N hydrochloric acid and 20 ml of glacial acetic acid is refluxed for 16 hours under nitrogen. Thereafter, the mixture is permitted to cool before sequentially being basified with dilute sodium hydroxide and extracted with ether. The combined ether extracts are successively washed with water, dried and concentrated under vacuum leaving an oil residue. The residue, in ether, is converted to its maleic acid salt which is recrystallized from an acetone-ether mixture to provide orange prisms, mp 153°-155° C. of 6-chloro-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine] maleate.