Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[C:18]([C:23]([OH:25])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1.[CH3:30]O>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[C:18]([C:23]([O:25][CH3:30])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: CO
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccnc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncccc1C1COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Temperature: 80 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylic acid (294 mg, 0.7493 mmol) in methanol (60.0 mL) was treated with one drop of concentrated sulfuric acid and heated in a sealed tube overnight at 80° C. The reaction mixture was then concentrated to a crude residue. This residue was diluted with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution and stirred at room temperature for 1 hour. After dissolution, the aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (300 mg, 99%) as a racemic mixture. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (dd, J=4.6, 1.5 Hz, 1H), 7.56 (dd, J=8.1, 4.6 Hz, 1H), 7.29 (dd, J=8.1, 1.4 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.00 (dd, J=2.9, 2.9 Hz, 1H), 4.53 (d, J=2.9 Hz, 2H), 3.91 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H); LCMS calculated for C21H19N4O5 (M+H)+: m/z=407.1. found: 407.0.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:9]2[CH2:8][C@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)=[CH:19][CH:20]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(OC(F)(F)F)cc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3ccc(OC(F)(F)F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (0.603 g, 1.51 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 11.87 mL, 67.78 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-50% Acetonitrile in H2O/AcN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. 5-(Trans-2-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (200 mg, 38.8%) was isolated as a white solid. 1H NMR (400 MHz, dmso) δ 1.47-1.60 (m, 1H), 1.68-1.87 (m, 3H), 2.43-4.01 (m, 6H), 5.73 (s, 1H), 7.20-7.40 (m, 4H). HRMS Calculated for [C16H17F3N2O3+H]+: 343.1270. Found: 343.1260
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[N:16][C:15]=1[CH3:22].[CH3:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCOCC>[OH:30][C:24]([CH3:23])([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][C:15]1[C:14]([CH3:13])=[N:19][C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=1
Reactant: Cc1nc(C)c(C)nc1C
Reactant: CCCCCC(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCCCCC(C)(O)Cc1nc(C)c(C)nc1C

Procedure:
The preparation is carried out in the manner described in Example VII using 10.1 grams (0.1 mole) of diisopropylamine in 80 milliliters of ether, 0.95 mole of butyllithium, 13.6 grams (0.1 mole) of tetramethylpyrazine, and 12.8 grams (0.1 mole) of 2-heptanone. The reaction is worked up as before, and the product is isolated by chromatography on silica gel.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[CH:11][C:12](OCC)=[O:13])=[CH:8][N:7]=[C:6]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=1)[CH3:2].N12CCCN=C1CCCCC2>C(N(CC)CC)C>[CH2:1]([N:3]1[C:4]2[N:5]=[C:6]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:7]=[CH:8][C:9]=2[CH:10]=[CH:11][C:12]1=[O:13])[CH3:2]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CCn1c(=O)ccc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of ethyl 3-(4-ethylamino-2-phenylamino pyrimidin-5-yl)acrylate (179 mg, 0.57mmol) in 10 mL of triethylamine was added 90 μL of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction mixture was heated at reflux for 8.5 hours then stirred at room temperature overnight. An additional amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (90 μL) was added, and the reaction mixture was heated at reflux for 9 hours then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by flash chromatography, followed by recrystallization from ethyl acetate:hexane, to provide 8-ethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one, mp 203-204° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[C:25]1[CH:30]=[C:29]([N+:31]([O-])=O)[C:28](=[O:34])[N:27]([CH3:35])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Ni]>[NH2:31][C:29]1[C:28](=[O:34])[N:27]([CH3:35])[CH:26]=[C:25]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)=[CH:16][C:11]=3[N:10]=2)[CH:30]=1
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)nc(-c1cc([N+](=O)[O-])c(=O)n(C)c1)n2Cc1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc2c(c1)nc(-c1cc(N)c(=O)n(C)c1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a hydrogenation apparatus is placed 6-[1-benzyl-2-(1-methyl-5-nitro-6-oxo-1,6-dihydro-pyridin-3-yl)-1H-benzoimidazol-5-yl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one F-1 (97 mg; 0.21 mmol) dissolved in 50 ml THF. A scoop of Raney-Nickel is added and the reactor filled up with H2 to 5 bar. The reaction mixture is stirred at room temperature for 1 hour. The Raney-Nickel is filtered off and the filtrate concentrated under reduced pressure. The residue is purified by using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: [CH2:1]=[C:2]([CH:5]([CH3:11])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=[O:4]>[Pd]>[CH3:1][CH:2]([CH:5]([CH3:11])[CH2:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH:3]=[O:4]
Reactant: C=C(C=O)C(C)CC(C)(C)C
Agent: [Pd]
Product: CC(C=O)C(C)CC(C)(C)C
Yield: 95.9 %

Procedure:
235 g of the propenal from Example 71 (1.48 moles) were hydrogenated on a Parr shaker with 2.5 g of 5% Pd on carbon. The resulting propanal, 231.8 g, was distilled to afford 221.7 g of purified product (96% yield). BP 59° C./5 mmHg; 1H-NMR (300 MHz), spectra consistent with assigned structures; 13C-NMR (75 MHz), spectra consistent with assigned structures; IR (Neat), 2980, 2700, 1730, 1480, 1370; MS (m/e), 141 (M+ -15), 123, 98, 83, 57 (Base);
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[CH2:19])[CH:17]=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:26])[CH2:23][N+:24]#[C-:25]>C1(C)C=CC=CC=1.[Cu-]=O>[CH3:20][O:21][C:22]([CH:23]1[CH:17]([C:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH2:19])[O:18][CH:25]=[N:24]1)=[O:26]
Reactant: C=C(C=O)CCCCNC(=O)OCc1ccccc1
Reactant: [C-]#[N+]CC(=O)OC
Agent: O=[Cu-]
Solvent: Cc1ccccc1
Product: C=C(CCCCNC(=O)OCc1ccccc1)C1OC=NC1C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.0 g (15.3 mmol) of 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal and 1.62 ml (16.8 mmol) of isocyanoacetic acid methyl ester are dissolved in 50 ml of toluene and added dropwise at 40° to a suspension of 0.12 g of 96.4% copper(I) oxide in 50 ml of toluene. The mixture is then stirred at room temperature for 2.5 hours, filtered, introduced into a column filled with 60 g of silica gel and extracted first with hexane/ethyl acetate (1:1) and then with ethyl acetate. 5-[6-(N-benzyloxycarbonylamino)hex-1-en-2-yl]-oxazoline-4-carboxylic acid methyl ester is obtained; oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH:23]1([CH2:26][C@H:27]([NH2:34])[C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][C@H:27]([NH:34][C:14]([C:12]2[CH:11]=[CH:10][C:9]([N:17]3[CH2:20][C:19]([F:21])([F:22])[CH2:18]3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:15])[C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)[CH2:25][CH2:24]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(N3CC(F)(F)C3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 140 a) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e=474.1 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]1[O:23][C:22](=[O:24])[C:21]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:20]=1>CN1CCOCC1>[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]([NH:20][C:21]1([C:22]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Reactant: CSCC[C@H](N)C(=O)O
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1)C(=O)O
Yield: 22.4 %

Procedure:
10 ml of N-methylmorpholine was added to 522 mg (3.5 mmol) of L-methionine and 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 170 mg (22%) of the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[ClH:1].[NH:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[CH2:14][N:11]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:13]=[N:12]1
Reactant: [N-]=[N+]=NCc1nc2ccccc2[nH]1
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3nc4ccccc4[nH]3)nn2)c[nH]1
Yield: 59 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.091 g, 0.576 mmol) was reacted with 2-azidomethyl-1H-benzimidazole, which was synthesized using previously reported methods (Hiales et al., Synthesis 1978, 4, 313-315), (0.120 g, 0.691 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(1H-Benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-ylmethyl]1Himidazol-2-ylamine dihydrochloride (0.125 g, 59%) of a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.01 (s, 1H), δ 7.58 (d, 2H), δ 7.31 (t, 2H), δ 6.44 (s, 1H), δ 5.98 (s, 2H) δ 3.84 (s, 2H) ppm; 13C (75 MHz, CD3OD) δ 135.6, 124.7, 123.7, 123.5, 122.8, 112.8, 112.3, 108.4, 83.6, 78.9, 74.0, 73.2, 44.2, 19.3 ppm; HRMS (ESI) calcd for C14H14N8 (M+) 295.1414. found 295.1420.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>>[CH2:18]([N:20]([CH2:21][CH3:22])[C:5](=[O:6])[C:4]1[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:3]=1[C:2]([F:17])([F:16])[F:1])[CH3:19]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: CCNCC
Product: CCN(CC)C(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F

Procedure:
N,N-Diethyl-2,5-bis(trifluoromethyl)benzamide was prepared from 2,5-bis(trifluoromethyl)benzoyl chloride and diethylamine according to General Method E1. The desired intermediate was isolated in quantitative yield (11.3 g) without additional purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]([C:37](OC)=[O:38])=[CH:27]2)=[CH:23][CH:22]=1.C(OCC)C.O1CCCC1>O>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:28]([CH2:37][OH:38])=[CH:27]2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
Lithium aluminium hydride (232 mg) was added to a mixture of methyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenylpyrrole-3-carboxylate (2.92 g), diethyl ether (50 ml), and tetrahydrofuran (25 ml) at 0° C., and the mixture was stirred at 0° C. for 3 hours. After water was added to the reaction mixture, the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]methanol (2.37 g, yield: 86%) was obtained as a colorless amorphous substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[Br:13].Cl[Sn]Cl.O.[OH-].[Na+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[Br:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(N)c1Br
Temperature: 25 °C
Yield: 100.1 %

Procedure:
2-Bromo-3-nitro-benzoic acid methyl ester (12.9 g, 49.5 mmol) (prepared from 2-amino-3-nitro-benzoic acid as described by Webber E. S., et al., see patent application number WO 01/16136 A2) and SnCl2 (42 g, 223 mmol) were refluxed in methanol (225 mL, 0.2 M) and H2O (5.3 g, 243 mmol) for 2 hours. After cooling at ambient temperature, diatomaceous earth (20 g) and dichloromethane (1 L) were added followed with 3N aqueous sodium hydroxide (150 mL) with vigorous stirring. The mixture was filtered and the organic phase was washed with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate, filtered and all volatiles were removed under reduced pressure to afford Intermediate 5(a) (11.4 g) in 98% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[CH3:18])=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:31]2[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=2)=[CH:13][C:12]=1[CH3:18])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1cc(Br)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(-c2cncc(F)c2)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[2-(4-bromo-2-methyl-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISP): 489.1 and 491.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([O:13]C)[C:10]2[C:9](=[O:15])[NH:8][C@H:7]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:6]3[C:5]=2[CH:4]=1)[CH3:2].C(C1C=C(OC)C2C(=O)N[C@@H]3CN(C(OC(C)(C)C)=O)C[C@H]3C=2C=1)C.B(Br)(Br)Br.[OH-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.Cl>[CH2:1]([C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[C:9](=[O:15])[NH:8][C@H:7]3[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:18][C@@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(OC)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCc1cc(OC)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Solvent: ClCCl
Product: CCc1cc(O)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (3aR,9bS)-tert-butyl 8-ethyl-6-methoxy-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Example 51, Part B (686 mg, 1.98 mmol) in 100 mL of methylene chloride was added boron tribromide (2.38 mL of a 1 M solution in methylene chloride, 2.38 mmol) dropwise at ambient temperature. The solution was allowed to stir for 8 h and then there was added 100 mL of 1 N sodium hydroxide followed by followed by di-tert-butyl dicarbonate (648 mg, 2.97 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction was diluted with 1 N HCl to give a pH of −5-6. The layers were separated and the organic layer was washed with water and brine, dried (MgSO4) and concentrated. The residue was purified (ISCO, elution with 0-50% EtOAc/hexane) to afford 413 mg (63%) of the title compound as a white solid. LRMS (ESI): 333.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:32]1([C:42](Cl)=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>ClCCl>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:42]([C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=[CH:34][CH:33]=3)=[O:43])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (0.80 g) was dissolved in dichloromethane (30 ml), and potassium carbonate (0.60 g) was added. Then, a solution of 1-naphthoyl chloride (0.33 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.45 g of 4-amino-5-chloro-2-methoxy-N-(1-(4-(1-naphthoylamino)butyl)piperidin-4-ylmethyl)benzamide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]2[NH:7][C:8](=[O:17])[C:9]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=3[NH:11][C:5]=2[CH:4]=1.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25]>C(OCC)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]2[C:8](=[O:17])[NH:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][N:24]([CH2:23][CH2:22][N:21]([CH3:26])[CH3:20])[CH3:25])=[CH:4][C:5]=3[NH:11][C:10]=2[CH:12]=1
Reactant: CNCCN(C)C
Reactant: O=C1Nc2ccc(CBr)cc2Nc2cc(Cl)ccc21
Solvent: CCOC(C)=O
Product: CN(C)CCN(C)Cc1ccc2c(c1)Nc1cc(Cl)ccc1C(=O)N2
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of Example 512A (50 mg, 0.15 mmol) and N,N,N′-trimethylethylenediamine (300 μL, 2.3 mmol) was heated at 50° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 31.5 mg (59%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:23]N1C(=O)CCC1=O>C(#N)C>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:23])[C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C(C)C
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of N-trifluoroacetyl-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.091 g, 0.29 mmol) in acetonitrile (3 mL) was treated with N-bromosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 20 C. After removing the solvent, flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.056 g of a clear oil. MS calculated for C16H19BrF3NO2+H: 394, observed: 394.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[Na+].[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[C:2]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCC#CCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC#CC(C(=O)OCC)C(=O)OCC
Reaction time: 1 h

Procedure:
A mixture of 16.5 g of 1-bromo-2-nonadecyne in 50 ml of ethanol is added to 3.0 g of 60% sodium hydride and 11.4 ml of diethyl malonate in 100 ml of ethanol. This mixture is stirred one hour and then evaporated. The residue is washed with ether, twice with dilute hydrochloric acid and brine. The residue is then purified by flash chromatography, (5% ethyl acetate:petroleum ether), to give 12.1 g of the desired compound as white needles, mp. 33°-34° C.