Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[NH:7][CH:6]=1.[C:17]([O:21][C:22]([NH:24][NH2:25])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CO>[C:17]([O:21][C:22]([NH:24][N:25]=[CH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][CH2:3][N:2]([CH3:16])[CH3:1])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Solvent: CO
Product: CN(C)CCc1c[nH]c2ccc(C=NNC(=O)OC(C)(C)C)cc12
Yield: 98.1 %

Procedure:
A 100 ml flask is charged with 3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde (Reference Example 9; 2.16 g, 10 mmol), hydrazinecarboxylic acid tert-butyl ester (1.32 g, 10 mmol), and methanol (10 ml). This mixture is heated at reflux for 18 hours, and then the solvent is removed on the rotavapor to leave the hydrazone (3.24 g, 98%). 1H-NMR (CDCl3, 300 MHz) δ 1.55 (s, 9H, C(CH3)3); 2.30 (s, 6H, N(CH3)2); 2.59, 2.87 (2 m, 2H each, CH2CH2NHMe2); 6.94 (d, 1H, J=2 Hz, H-2); 7.17 (d, 1H, J=8.5 Hz, H-7); 7.52 (dd, 1H, J=1.5 Hz, H-6); 7.68 (d, 1H, H-4); 7.84 (br s, 1H, N═CH); 8.42 (br s, NH); 9.10 (s, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 23.89 (CH2); 28.83 (C(CH3)3); 45.66 (N(CH3)2); 60.47 (CH2NMe2); 81.23 (OCMe3); 111.94 (C-7); 114.77 (C-3); 119.30 (C-4); 120.76 (C-6); 122.91 (C-2); 125.37 (C-5); 127.48 (C-9); 137.54 (C-8); 146.13 (N═CH); 153.13 (NC═O).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11])#[CH:2].[Cl:12][C:13]1[C:14]([C:20]#[N:21])=[N:15][CH:16]=[C:17](Cl)[CH:18]=1.C(N(CC)CC)C.CN(C=O)C>[Cu]I.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.CCOC(C)=O>[Cl:12][C:13]1[C:14]([C:20]#[N:21])=[N:15][CH:16]=[C:17]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=2[CH3:11])[CH:18]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1ccc(OC)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 60 °C

Procedure:
To a round bottom flask capped with septa was added 1-ethynyl-4-methoxy-2-methylbenzene (commercially available, 1.1 equiv.), 3,5-dichloropicolinonitrile (commercially available, 1 equiv.), triethylamine (5 equiv.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.05 equiv.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 equiv.) were added. The septum was replaced with a refluxing condenser and the flask was heated at 60° C. overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EtOAc (1:4%)) afforded 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:25]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])=[CH:33][C:32]=1[C@H:43]1[CH2:47][CH2:46][CH2:45][NH:44]1)(=[O:30])=[O:29])([CH3:27])[CH3:26]>>[CH3:41][N:39]([CH3:40])[C:38](=[O:42])[NH:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([CH:25]([CH3:26])[CH3:27])(=[O:30])=[O:29])=[C:32]([C@H:43]2[CH2:47][CH2:46][CH2:45][N:44]2[C:12](=[O:14])[C@H:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:1]([NH2:2])=[O:3])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH:33]=1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)N(C)C)cc1[C@H]1CCCN1
Reactant: COc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1F
Agent: Cl
Product: COc1cc([C@@H](Nc2cccc(C(N)=O)c2)C(=O)N2CCC[C@@H]2c2cc(NC(=O)N(C)C)ccc2S(=O)(=O)C(C)C)ccc1F

Procedure:
Example 59 was prepared according to the general coupling condition using 7D and 31A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.15 (d, J=6.57 Hz, 3 H) 1.40 (d, J=6.82 Hz, 3H) 1.64-1.80 (m, 1H) 1.92-2.20 (m, 2H) 2.39-2.57 (m, 1H) 2.97 (s, 6H) 3.62-3.76 (m, 4H) 3.81-3.95 (m, 1H) 4.06-4.18 (m, 1H) 5.38 (s, 1H) 5.63 (dd, J=8.08, 5.05 Hz, 1H) 6.78-6.89 (m, 2H) 6.93-7.08 (m, 3H) 7.09-7.22 (m, 3H) 7.25 (dd, J=8.72, 2.15 Hz, 1H) 7.69 (d, J=8.84 Hz, 1H), LC-MS 640 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH3:2].[NH4+:31].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[NH2:31][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl {3-[(2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.39 g, 3.35 mmol) in 35 mL of CHCl3 was treated with 15 mL of concentrated NH4OH solution and p-toluenesulfonyl chloride (0.67 g, 3.51 mmol). After 15 min, the reaction mixture was diluted with water and CHCl3 and the phases were separated. The organic portion was washed with 10% Na2CO3 solution and water. The combined aqueous washes were back-extracted with CHCl3. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield tert-butyl {3-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.30 g) as an orange foam.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][F:29]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][F:29])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCF)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.9 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 1-bromo-2-fluoroethane (0.05 ml, 0.7 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (100 mg, yield 64%).
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].O.[O:18]=[C:19]1[CH:26]2[CH:21]([CH2:22][CH:23]=[CH:24][CH2:25]2)[NH:20]1>C1C=CC=CC=1>[OH:4][CH:3]([N:20]1[C:19](=[O:18])[CH:26]2[CH:21]1[CH2:22][CH:23]=[CH:24][CH2:25]2)[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NC2CC=CCC12
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(O)N1C(=O)C2CC=CCC21
Reaction time: 3.5 h

Procedure:
p-Nitrobenzyl glyoxylate hydrate (9.08 g) was refluxed in benzene (150 ml) with provision for the removal of water. After 1 hour 8-oxo-7-azabicyclo [4.2.0]oct-3-ene (1) (2.46 g) was added and refluxing continued for 3.5 hours. The cooled solution was washed with water (x2), then brine. After back extraction of the first aqueous extract with ethyl acetate, the organic solutions were dried over magnesium sulphate, filtered combined, and evaporated. Chromatography on silica, eluting with ethyl acetate-petroleum ether mixtures gave two separate isomers of the alcohol (54) (43%). Less polar isomer I m.p. 153°-5° (crystalline plates ex ethyl acetate/ether). νmax (CHCl3) 3400 (broad), 1760, 1745, 1520, 1350 cm-1. δppm (CDCl3) 1.90-2.83 (4H, m, 2-CH2), 3.23-3.55 (1H, m, β-lactam proton), 4.00-4.20 (1H, m, β-lactam) proton), 4.27 (1H, d, J 8 Hz, exchangeable with D2O, OH), 5.33 (2H, s, CH2Ar)obscuring 1H, CHOH; 5.67-5.88 (2H, m, CH=CH), 7.55 (2H, d, J 8.5 Hz, Ar), 8.23 (2H, d, J 8.5 Hz, Ar) (Found: C, 58.07; H, 5.15; N, 8.51%, C16H16N2O6 requires C, 57.83; H, 4.85; N, 8.43%). More polar isomer II m.p. 118°-120° (fine crystalline needles ex ethyl acetate/ether). νmax (CHCl3) 3400 (broad), 1760-1745, 1520, 1350 cm-1. δ ppm (CDCl3) 1.83-2.77 (4H, m, 2-CH2), 3.25-3.55 (1H, m, β-lactam proton), 4.02-4.37 (2H, m, β-lactam proton and CHOH, --OH exchangeable with D2O), 5.31-5.98 [5H, 5.35 (2H, s, CH2Ar), obscuring, 1H, which sharpens to s, at δ 5.40 on D2O exchange, CHOH, and 2H, m, CH=CH], 7.56 (2H, d, J 8 Hz, Ar), 8.23 (2H, d, J 8 Hz, Ar) (Found: C, 57.95; H, 4.95; N, 8.50%. C16H16N2O6 requires C, 57.83; H, 4.85; N, 8.43%).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][N:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([O:20][N:21]=[CH:22][C:23](=[N:28][O:29][CH3:30])[CH2:24][C:25]([CH3:27])=[CH2:26])[CH3:19])[C:8]([NH:10][CH3:11])=[O:9]>CN(C=O)C>[CH3:4][O:5][N:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([O:20][N:21]=[CH:22][C:23](=[N:28][O:29][CH3:30])[CH:24]=[C:25]([CH3:26])[CH3:27])[CH3:19])[C:8]([NH:10][CH3:11])=[O:9]
Reactant: C=C(C)CC(C=NOC(C)c1ccccc1C(=NOC)C(=O)NC)=NOC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C(=NOC)c1ccccc1C(C)ON=CC(C=C(C)C)=NOC
Temperature: 30 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
34.7 g of solid sodium methoxide in 250 ml of DMF were stirred at 23° C. for 3 hours and 120 g of the amide from Example 6 in 250 ml of DMF were then added dropwise (temperature increase to up to 30° C.). The mixture was subsequently stirred at 23° C. for 12 hours and then worked-up as in Example 6. This gave 108 g of the title compound as a colorless solid which, according to NMR, GC and HPLC analysis, contains approximately 10% of the starting material (Example 6).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH:21](OCC)=[O:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:21]=[O:22])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Reactant: CCOC=O
Product: COC(=O)c1nc2n(c1C=O)C1CC(C1)c1ccc(Br)cc1-2
Yield: 74 %

Procedure:
Methyl 10-bromo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (4 g) was reacted with ethyl formate similarly to as described in example 8 with non-critical modifications to afford 3.2 g (74%) of methyl 10-bromo-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[N:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:12]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[N:3]=2)[CH2:14][CH2:13]1
Reactant: OB(O)C1CC1
Reactant: COc1nc(Cl)ccc1C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(C2CC2)ccc1C=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 58.4 %

Procedure:
6-Chloro-2-methoxynicotinaldehyde (200 mg, 1.17 mmol), cyclopropylboronic acid (200 mg, 2.33 mmol), sodium carbonate (371 mg, 3.50 mmol) and tetrakis(triphenylphosphine)palladium (0) (67.3 mg, 0.0583 mmol) were combined, diluted with toluene (2 mL) and water (200 μL). The reaction vial was purged with argon, heated to 90° C. and stirred for 12 hours. The reaction was cooled, loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield 6-cyclopropyl-2-methoxynicotinaldehyde (121 mg, 0.683 mmol, 58.6% yield).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:17])[CH:10]=[CH:9][C:8]1=[O:18].FC(F)(F)C(O)=O>>[CH3:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[N:7]([CH2:6][CH:2]=[O:1])[C:8](=[O:18])[CH:9]=[CH:10]2
Reactant: Cc1cccc2ccc(=O)n(CC3OCCO3)c12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2ccc(=O)n(CC=O)c12
Temperature: 40 °C
Reaction time: 72 h

Procedure:
To 0.17 g of 1-(1,3-dioxolan-2-ylmethyl)-8-methylquinolin-2(1H)-one, 2 mL of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 4 days, at 40° C. for 3 days, and at room temperature for 5 days. The solvent was removed under reduced pressure, and the reaction mixture was added with ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.14 g of a brown oily substance, (8-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(C=O)c1
Reaction time: 4 h

Procedure:
To a stirred solution of 5-bromonicotinaldehyde (1 g) and ethynyltrimethylsilane (792 mg) in Et3N (15 ml) was added tetrakis(triphenylphosphine)palladium (124 mg) and copper(I) iodide (51 mg). After 4 hours, the resulting mixture was filtrated and evaporated. The residue was dissolved in EtOAc and washed successively with dil. NH3aq, water and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified with silica gel column chromatography to give 5-[(trimethylsilyl)ethynyl]nicotinaldehyde as a slightly yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([F:9])[CH:4]=1.[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].CCOCC>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([CH2:2][O:18][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: O=C([O-])c1ccccc1
Reactant: Fc1cc(CBr)ccn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(OCc1ccnc(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
The mixture of 4-Bromomethyl-2-fluoro-pyridine (35) (4.85 g, 25.5 mmol) and sodium benzoate (5.51 g, 38.25 mmol) in DMF (60 ml) was stirred at room temperature for 3 hr. Ether was then added and the mixture was washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexane (1:4)) to afford 4.68 g (79%) of a colorless oil; 1H NMR (200 MHz, CDCl3) δ: 5.41 (2H, s), 7.11 (1H, m), 7.45-7.66 (3H, m), 8.08-8.12 (2H, m), 8.23 (1H, d, J=5.4 Hz); m/z (EI): 231 (M+).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]#[N:23])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1.CCN(C(C)C)C(C)C>CC(O)C>[C:22]([C:21]1[C:2]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:3][CH:4]=[C:5]([CH:20]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[O:7])#[N:23]
Reactant: N#Cc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Reactant: O[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 110 °C

Procedure:
A stirred mixture of 6-chloro-5-cyano-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 70.3, 4.50 g, 13.2 mmol), (R)-3-Pyrrolidinol (1.38 g, 15.8 mmol) and DIPEA (3.74 g, 29.0 mmol) in iPrOH (20 mL) was heated at 110° C. for 60 min. The cooled RM was then evaporated to dryness under reduced pressure and the residue was dissolved in EtOAc, washed with sat. aq. NaHCO3 and brine. The solution was dried over anhydrous Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by crystallization from DCM/TBME to afford the product as a colorless crystalline solid. m.p. 234-236° C., HPLC (Condition 4) tR=5.41 min, UPLC-MS (Condition 8) tR=1.01 min, m/z=393.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.25 (m, 1H), 1.80-2.06 (m, 1H), 3.67 (d, J=11.34 Hz, 1H), 3.82 (br. s, 3H), 4.01 (q, J=7.04 Hz, 1H), 4.40 (br. s, 1H), 7.34 (d, J=8.60 Hz, 2H), 7.83 (d, J=8.99 Hz, 2H), 8.51 (d, J=2.35 Hz, 1H), 8.83 (d, J=2.35 Hz, 1H), 10.23 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:8][CH2:7][N:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:5][CH2:4][CH:3]1[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:68]([O:72][C:73]([NH:75][C:76]1[S:80][C:79]([C:81]2[C:86]([F:87])=[CH:85][CH:84]=[CH:83][C:82]=2[F:88])=[N:78][C:77]=1[C:89](O)=[O:90])=[O:74])([CH3:71])([CH3:70])[CH3:69]>CO.C(Cl)Cl.[Pd]>[F:1][C:2]1([F:25])[CH:3]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:4][CH2:5][N:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH:15][C:89]([C:77]2[N:78]=[C:79]([C:81]3[C:82]([F:88])=[CH:83][CH:84]=[CH:85][C:86]=3[F:87])[S:80][C:76]=2[NH:75][C:73](=[O:74])[O:72][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:90])[CH2:7][CH2:8]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)C(F)(F)F)C(F)(F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: [Pd]
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)C(F)(F)F)C(F)(F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
A solution of N-(5,5-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide (0.29 g, 0.78 mmol) in MeOH (20 mL) was passed through the H-Cube® (Full H2 Mode, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give the crude amine. To a solution of this amine (0.26 g, 0.78 mmol) in DCM (15 mL) was added DIPEA (0.68 mL, 3.9 mmol), PyBOP (0.61 g, 1.17 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (0.30 g, 0.86 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 4-(5-(4,4-difluoro-5-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate as a white solid (0.37 g, 69%). 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.71 (s, 1H), 7.82 (s, 1H), 7.42-7.33 (m, 1H), 7.11-7.01 (m, 2H), 6.72 (d, J=9.0 Hz, 1H), 4.73-4.57 (m, 1H), 3.77 (s, 3H), 3.51-3.37 (m, 2H), 3.36-3.25 (m, 2H), 2.49-2.36 (m, 2H), 2.25-2.03 (m, 2H), 1.55 (s, 9H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[Cl:21])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: Clc1ccccc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 346.5 %

Procedure:
70.3 g of benzoyl chloride was added into the mixture of aluminium chloride (93.3 g) and 1,2-dichloro benzene (14.7 g) using 500 mL three necked flask, then reaction was carried out for 12 hrs. at 120° C. The reaction mixture was poured into 1000 g of ice water in a beaker (5000 mL), and further, 1000 g of toluene was added. The toluene layer was washed by 1000 g of water three times. After condensing the toluene layer under reduced pressure, 87 g of 3,4-dichlorobenzophenone was obtained (yield 69%)
Reaction SMILES: O=O.[CH:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]1[CH:15]=[C:14]([CH2:16][OH:17])[CH2:13][CH2:12][N:7]12>C1(C)C=CC=CC=1>[CH:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]1[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13][CH2:12][N:7]12
Reactant: OCC1=Cc2cc3ccccc3n2CC1
Agent: O=O
Solvent: Cc1ccccc1
Product: OC[C@@H]1CCn2c(cc3ccccc32)C1
Yield: 99.4 %

Procedure:
The glass attachment of a 30 ml autoclave is charged in a glove box (oxygen content <1 ppm) with 0.20 g (1.0 mmol) of 6,7-dihydropyrido[1,2-a]indole-8-methanol, 8 ml of toluene and 2 ml of the above-mentioned catalyst solution. The hydrogenation is carried out at 80° C., an initial pressure of 60 bar of H2 and while stirring vigorously. After a hydrogenation time of 18 hours, the conversion is 99.9% according to GC. The pale yellow hydrogenation solution is evaporated. The residue is dissolved in diethyl ether and the solution is allowed to flow through a 5 g silica gel column in order to separate the catalyst. Rinsing of the column with diethyl ether, evaporation of the eluate and drying of the pale brown crystalline residue, yields 0.20 g (100%) of (R)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol; GC 100 area %, 93.7% e.e.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[C:12]([C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:22][C:23]([O:25]C)=[O:24])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CO>[CH3:9][C:2]([C:10]1[CH:11]=[C:12]([C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:22][C:23]([OH:25])=[O:24])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1cc(-c2cccc(C=CC(=O)OC)c2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC(C)(C)c1cc(-c2cccc(C=CC(=O)O)c2)ccc1OC
Yield: 82.6 %

Procedure:
Methyl 3-[3-(1,1-dimethylheptyl)-4-methoxyphenyl]cinnamate (334.5 mg, 1.05 mmol), methanol (4 ml) and a 1N aqueous sodium hydroxide solution (1.2 ml, 1.2 mmol) were mixed, and this solution was refluxed under heating for 1 hour. Methanol was evaporated under reduced pressure. Conc. hydrochloric acid (0.3 ml) and saturated brine (5 ml) were added, and the aqueous layer was extracted 4 times with ethyl acetate (5 ml). The organic layers were combined, washed twice with saturated brine (5 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with hexane to give 3-[3-(1,1-dimethylheptyl)-4-methoxyphenyl]cinnamic acid (0.33 g, quant.) as colorless crystals.