Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[CH2:24]>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([CH:23]=[CH2:24])=[CH:26][CH:27]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: C=Cc1ccc(B(O)O)cc1
Product: C=Cc1ccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)cc1
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-vinylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-4′-vinylbiphenyl-5-yl)-imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (3 mg, 3%): m/z (ES+) 391 [MH+].
Reaction SMILES: O.[OH-].[Li+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:41])=[C:12]([CH2:14][O:15][C:16]2[CH:40]=[CH:39][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:18][CH:17]=2)[N:13]=1.O.Cl>O1CCCC1>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[O:10][C:11]([CH3:41])=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:39][CH:40]=2)[N:13]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
Lithium hydroxide monohydrate (163 mg) was added to a solution of ethyl E-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate (670 mg) in tetrahydrofuran (6 ml)-water (4 ml)-etbanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (3.9 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoic acid (625 mg, yield 98%) as colorless crystals. m.p. 112-113° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N+:11]([C:14]1[C:19]2[NH:20][C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)([C:24]#[N:25])[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]>C1(C)C=CC=CC=1>[N+:11]([C:14]1[C:19]2[NH:20][C:21]([CH2:24][NH2:25])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: N#CC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: NCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
1.0 M Diisobutylaluminum hydride in toluene (200 μL, 0.2 mmol) was added drop-wise to a solution of 5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile (50 mg, 0.2 mmol) (Example 71, Step 1), in toluene (5 mL) at room temperature. The reaction mixture was stirred for 10 min, then quenched with methanol. The resulting mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 1-(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methanamine solid (0.05 g. 100%). LCMS calculated for C14H15N4O3 (M+H)+: m/z=287.1. found: 287.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[C:35]1([NH:41]N)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:41][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(C(F)(F)F)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and phenylhydrazine: ESMS m/e: 548.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][NH2:11].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22](=[O:35])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][NH:11][C:32]([C:28]1[S:27][C:26]([N:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][C:22]2=[O:35])=[N:30][C:29]=1[CH3:31])=[O:33]
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1cc2ccccc2[nH]1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cc2ccccc2[nH]1
Yield: 22 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1H-indol-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 22% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.73 (t, J=5.6 Hz, 1H), 8.62 (d, J=8.1 Hz, 1H), 7.45-7.29 (m, 7H), 7.01-6.87 (m, 2H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.25-6.22 (m, 2H), 5.16 (s, 2H), 4.53 (d, J=5.6 Hz, 2H), 2.56 (s, 3H); MS (ES+) m/z 471.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2-c2ncccn2)cn1
Temperature: 210 °C
Yield: 87.3 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 27 mg 0.10 mmole) and 2-bromopyrimidine (24 mg, 0.15 mmole) were dissolved in DMA (0.7 ml) and potassium carbonate (20 mg, 0.14 mmole) and copper(I) iodide (4.0 mg, 0.022 mmole) were added. The reaction was placed under argon and heated by microwave at 210° C. for 60 minutes. The reaction was taken up in ethyl acetate (25 mL) and the solution washed with water (3×7 mL) and brine. The combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with ethyl acetate to afford the title compound (31 mg). 1H-NMR (CDCl3, 500 MHz): 3.95 (s, 3H), 6.73 (d, J=0.95 Hz), 7.34 (s, 1H) under 7.34 (t, J=5.04 Hz, 1H), 7.53 (s, 1H), 8.11 (t, J=0.95 Hz, 1H), 8.66 (d, J=0.95 Hz, 1H), 8.85 (d, J=5.04 Hz, 2H),
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH:21]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(C2=CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.142 mmol) in DCM (1 mL) was added TFA (0.35 mL) and the resulting mixture was stirred at room temperature for 2 hr. The reaction was concentrated and dried under the high vacuum to yield 6-(bis(4-chlorophenyl)methyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one, which was used in the next step without further purification. (ES, m/z) 461, 463 [M+H]+
Reaction SMILES: C(=O)([O-])OCC[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1>[Pd].C(O)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][OH:13])=[CH:7][CH:8]=1
Reactant: O=C([O-])OCCC(=O)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: OCc1ccc(Cl)cc1
Reaction time: 10 h
Yield: 82.1 %

Procedure:
100 ml of glacial acetic acid and 5 g of 5% Pd on C are added to a solution of p-chlorobenzoyl-ethyl carbonate (22.8 g=0.1 moles). The mixture is reduced in a PARR apparatus for 10 hours at 60° and under a pressure of 200 psi (14 atm) of H2. We proceed as in Example II. We obtain 11.7 g (82%) of a product having the following characteristics:
Reaction SMILES: C1CO[C:3]2([CH2:15][C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[CH2:5][CH2:4]2)[O:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:5]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH2:15][C:3](=[O:2])[CH2:4]1
Reactant: c1ccc2c3c([nH]c2c1)CCC1(C3)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: O=C1CCc2[nH]c3ccccc3c2C1

Procedure:
165 g (0.72 mol) of 3,3-ethylenedioxy-1,2,3,4-tetrahydrocarbazole are dissolved in 2 l of acetone, and 3 g of p-toluenesulphonic acid are added. After the reaction solution has been heated under reflux for 4 h it is concentrated, 2 l of ethyl acetate are added, and the mixture is extracted 3 times with 1 l of saturated bicarbonate solution each time. The organic phase is dried with sodium sulphate and evaporated. The residue crystallizes from ether. In this way 118.7 g (89.1% of theory) of the product are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[C:19](Cl)=[O:20]>C(C(C)=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:1][C:19]([C:10]1[C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=[CH:18][C:9]=1[Cl:8])=[O:20]
Reactant: O=C(Cl)c1c(Cl)ccc2c1OCCO2
Reactant: Nc1ncccn1
Solvent: CCC(C)=O
Product: O=C(Nc1ncccn1)c1c(Cl)ccc2c1OCCO2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
280 ml of methyl ethyl ketone, 13 g of 2-amino-pyrimidine were put into a 500 ml balloon flask provided with a stirrer and a thermometer. The mixture was cooled to 10° C. and 28 g of ground 6-chloro-1,4-benzodioxane-5-carbonyl chloride was added and stirred for two hours, the temperature being allowed to rise to 20° C. The obtained solid was filtered off, washed with 30 ml of methyl ethyl ketone and then dissolved in 250 ml of boiling water. The solution was treated with 10 ml of 36° Bel caustic soda lye. After filtration 12 g of product were obtained and crystallized again from 150 ml of ethanol. 9.5 g of N-(2-pyrimidyl)-6-chloro-1,4-benzodioxane-5-carboxamide was obtained. (M.P.: 223° C. with decomposition). The structure was confirmed by nuclear magnetic resonance analysis.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:25]CC1C=CC=CC=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>CO.[Pd]>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[OH:25])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(Cc1cc(Cc2ccc(CC)cc2)ccc1OCc1ccccc1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(Cc1cc(Cc2ccc(CC)cc2)ccc1O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a solution of [2-benzyloxy-5-(4-ethylbenzyl)benzyl]phosphonic acid diethylester (1.03 g) in methanol (10.0 mL) was added 5% Pd—C (0.10 g), and the reaction mixture was stirred for 5 hr at room temperature under hydrogen gas atmosphere. After filtration and evaporation, the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=2/3) to give the title compound (0.80 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH2:23]([O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]1[CH:32]=[C:33]([NH:34][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH:35]=[CH:36][CH:37]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4cccc(OCc5ccccc5)c4)cc3)c2)o1

Procedure:
N-(3-Benzyloxyphenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-benzyloxyaniline using method I. LCMS; retention time 3.79 min, MH+ 476.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][O:7][CH:8]([CH3:10])[CH3:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:8]([O:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2][S:17][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)([CH3:10])[CH3:9]
Reactant: SCc1ccc(Cl)cc1
Reactant: CC(C)OCCC=CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)OCCC=CCSCc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
8.1 g (0.05 mol) of 1-chloro-5-isopropoxy-2-pentene are added dropwise at 20-25° during the course of 10 minutes and while stirring to a solution of 7.9 g (0.05 mol) of 4-chloro-benzylmercaptan and 5.6 g (0.05 mol) of potassium tert.butoxide in 150 cc of tert.butanol. The solution which is rendered turbid during the addition is stirred at 60° during the course of 1 hour and is then cooled and filtered. The solvent is distilled off at reduced pressure, the residue is dissolved in ether and the ether solution is washed with saturated salt solution. The ether phase is dried with sodium sulphate and then the ether is distilled off and the residue is chromatographed on silica gel with chloroform. The 4-[(5-isopropoxy-2-pentenylthio)-methyl]-chlorobenzol is obtained as colourless oil having a B.P. of 110°-112°/5.10-4 mm. nD20 = 1.5391.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:36]=[CH:35][C:22]4[N:23]([CH2:27][O:28]CC[Si](C)(C)C)[C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)=[CH:13][N:12]=2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:28][CH2:27][N:23]1[C:22]2[CH:35]=[CH:36][C:19]([O:18][CH2:17][C:14]3[CH:13]=[N:12][C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:38])([F:1])[F:37])=[CH:5][CH:6]=4)=[N:16][CH:15]=3)=[CH:20][C:21]=2[O:25][C:24]1=[O:26]
Reactant: C[Si](C)(C)CCOCn1c(=O)oc2cc(OCc3cnc(Nc4ccc(OC(F)(F)F)cc4)nc3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1oc2cc(OCc3cnc(Nc4ccc(OC(F)(F)F)cc4)nc3)ccc2n1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.3 %

Procedure:
To a solution of 6-((2-((4-(trifluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (0.05 g, 0.091 mmol) in DCM (3 mL) at 0° C., TFA (0.035 mL, 0.456 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under vacuum and the residue was washed with diethyl ether. The crude product was purified by preparative HPLC on an Inertsil ODS column (19×250 mm, 5μ) using 0 to 65% mobile phase B (ACN) in mobile phase A (0.1% TFA) over 6 min to give 3-(hydroxymethyl)-6-((2-((4-(trifluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)benzo[d]oxazol-2(3H)-one as a white solid (0.025 g, 61%). 1H-NMR: 400 MHz, DMSO-d6 δ ppm 5.03 (s, 2H), 5.19 (s, 2H), 6.92-6.95 (m, 1H), 7.21-7.32 (m, 4H), 7.86-7.88 (m, 1H), 8.62 (s, 2H), 9.96 (s, 1H). LCMS: R.T. 2.303 min; 449 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Reaction time: 2 h
Yield: 40.1 %

Procedure:
2,4-Difluoro-1-{(E)-2-[4-(phenylsulfonyl)phenyl]vinyl}benzene (Example 51, 57 mg, 0.16 mmol) and palladium (10% wt. on activated carbon, 20 mg) were combined in ethyl acetate (20 mL) and shaken in a Parr apparatus for 2 hours. The catalyst was removed by filtration and the filtrate evaporated in vacuo. The residue was purified by HPLC to yield the title compound as a white solid (23 mg, 40%). δH (400 MHz, CDCl3): 7.93–7.91 (2H, m), 7.84–7.82 (2H, m), 7.56–7.46 (3H, m), 7.27–7.24 (2H, m), 7.00–6.94 (1H, m), 6.76–6.70 (2H, m), 2.92–2.84 (4H, m).
Reaction SMILES: [N:1]([CH:4]([CH2:12][F:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-]>CO.[Pd]>[F:13][CH2:12][CH:4]([NH2:1])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NC(CF)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(CF)Cc1ccccc1
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of (2-azido-3-fluoro-propyl)benzene (0.6 g) in MeOH (50 mL) was added 10% Pd/C catalyst and the suspension was hydrogenated for 2 h at 3 atmospheres pressure. The filtered reaction mixture and MeOH washings were concentrated to an oil which was chromatographed over silica gel with an ammoniated mixture of MeOH/ether (1:9) to give 0.38 g of the title compound. MS ES (M++H)=154.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]ncc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 31 %

Procedure:
The title compound is prepared from 1H-indazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 31% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=318 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.I[CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:9][CH2:14][CH3:15])=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOc1cc(F)c(C)cc1[N+](=O)[O-]
Yield: 60.6 %

Procedure:
4-Methyl-5-fluoro-2-nitrophenol (11.1 g, 65.0 mmol) and iodoethane (12.2 g, 78.0 mmol) were dissolved in 100 mL of DMSO with stirring. K2CO3 (13.5 g, 97.5 mmol) was added. The reaction was stirred for 3 h and then diluted with DCM and filtered. The filtrate was poured into H2O and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound of step A (8.0 g, 39.4 mmol) as a pale yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.1 Hz, 1H), 6.70 (d, J=11.0 Hz, 1H), 4.10 (q, J=7.0 Hz, 2H), 2.22 (s, 3H), 1.45 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:34])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(Cl)C1CCCC1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C3CCCC3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and cyclopentanecarbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.32 (dq, J=14.97, 7.39 Hz, 2H) 1.54-1.63 (m, 2H) 1.65-1.77 (m, 4H) 1.82-1.92 (m, 2H) 2.20 (t, J=7.33 Hz, 2H) 2.83 (dt, J=15.41, 7.71 Hz, 1H) 6.73 (s, 1H) 7.59-7.70 (m, 3H) 7.83-7.94 (m, 4H) 8.13 (d, J=8.08 Hz, 1H) 10.26 (s, 1H); ESI-MS: m/z calc'd for C27H28N4O2S 472.6. found 473.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:12][C:13]([CH:17]([F:19])[F:18])=[CH:14][C:15]#[N:16]>C(O)(=O)C.C1COCC1>[F:18][CH:17]([F:19])[C:13]1[NH:12][C:13]([CH:17]([F:19])[F:18])=[C:14]([C:15]#[N:16])[CH:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[C:14]=1[C:15]#[N:16]
Reactant: N#CC=C(N)C(F)F
Reactant: O=Cc1ccc2[nH]ncc2c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CC1=C(C(F)F)NC(C(F)F)=C(C#N)C1c1ccc2[nH]ncc2c1

Procedure:
A mixture of 80 mg (0.55 mmol) 1H-indazole-5-carbaldehyde, 142 mg (1.21 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 1 (1984)] and a trace amount of powdered 4 Å molecular sieve in acetic acid (0.53 ml) was heated to reflux temperature for 5 h. After cooling, the reaction mixture was diluted with THF and filtered. The filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 95 mg (48% of th.) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([OH:26])(=[O:25])[C:22]([CH3:24])=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:22]([C:21]([OH:26])=[O:25])[CH3:24])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CC(=O)C(=O)O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: C1CCOC1
Product: CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Reaction time: 2.5 h

Procedure:
To a solution of 2.85 g. (0.01 mole) of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 100 ml. of tetrahydrofuran under nitrogen is added with stirring, 0.847 ml. (0.012 mole) of pyruvic acid. After 2.5 hours at room temperature and overnight at 0° C. 7-chloro-2-[(1-carboxyethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine is obtained.