Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([C:21]#[C:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(C#CCOC2CCCCO2)cc1F
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F

Procedure:
2,3,4-Trifluorobenzoic acid and 2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]aniline were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, followed by purification by chromatography on silica gel (50% EtOAc/PE as eluant), 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}benzoic acid was isolated as a cream-yellow solid (68%); m.p. (Et2O/hexane) 164-166° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.60 (v br s, 1 H), 9.27 (br s, 1 H), 7.83 (ddd, J=8.2, 6.1, 1.9 Hz, 1 H), 7.36 (dd, J=12.0, 1.7 Hz, 1 H), 7.21-7.11 (m, 2 H), 6.96 (td, J=8.8, 5.5 Hz, 1 H), 4.80 (br s, 1 H), 4.47 (d, J=16.0 Hz, 1 H), 4.38 (d, J=16.0 Hz, 1 H), 3.79-3.71 (m, 2 H), 3.51-3.45 (m, 2 H), 1.77-1.61 (m, 2 H), 1.56-1.44 (m, 4 H). Anal. calcd. for C21H18F3NO4: C, 62.2; H, 4.5; N, 3.5. Found C, 62.5; H, 4.4; N, 3.6. Step C: Preparation of 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}-N-(2-hydroxyethoxy)benzamide
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][N:40]=[C:41]=[O:42]>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:41]([NH:40][CH3:39])=[O:42])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN=C=O
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N(C)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 88 %

Procedure:
To a solution of 25 mg of amine prepared in Example 11 and 0.05 mL of DIPEA in 0.5 mL of methylene chloride was added 15 mg of methyl isocyanate. After 1.5 h in a sealed vial, the volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with ethyl acetate to afford 25 mg of title compound. Mass spec (NH3 /CI): 475 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([Cl:14])[C:8]2[C:9]([CH:13]=1)=[N:10][S:11][N:12]=2)=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[NH2:15][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[CH:13][C:9]2=[N:10][S:11][N:12]=[C:8]2[C:7]=1[Cl:14]
Reactant: COC(=O)c1cc2nsnc2c(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1c(C(=O)O)cc2nsnc2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution of 0.37 g (1.50 mmol) of 6-amino-7-chloro-benzo[1,2,5]thiadiazole-5-carboxylic acid methyl ester in 7.32 mL of dioxane and 0.92 mL of MeOH, is added 2.25 mL (2.25 mmol) of an aqueous solution of NaOH 1 N. The mixture is stirred at ambient temperature during 2 hours and then the solvents were evaporated. The residue is suspended in H2O and the mixture is acidified to pH 2-3 with an aqueous 1 N HCl solution. The reddish-violet precipitate obtained is filtrated and washed with a minimum of H2O. 291 mg (1.27 mmol) of the expected product can be isolated. The aqueous phase is extracted with EtOAc (2 times) and then the organic layer is washed once with brine, dried on Na2SO4, filtrated and concentrated under reduced pressure. 10 mg (43.54 ?mol) of the acid is obtained more giving a total amount of 301 mg (1.31 mmol, 87%) of a dark violet solid. LC/MS: 230/232 (M+1)+.
Reaction SMILES: [CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:4])[O-:3].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:3])[O:4][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CBr
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)[O-]
Product: CCOC(=O)COP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same way, P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate acid and ethyl bromoacetate are reacted together to give ethoxycarbonylmethyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:2]
Reactant: CCOC(=O)CCCBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(C#N)c1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
3-cyanophenol (2 000 mg; 16.79 mmol; 1 eq.) was dissolved in DMF (40 mL). Then ethyl 4-bromobutyrate (3 602.35 mg; 18.47 mmol; 1.10 eq.) and K2CO3 (3 480.55 mg; 25.18 mmol; 1.50 eq.) were added to the reaction mixture. The reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was cooled to RT and diluted with EtOAc. The organic layer was washed with water (3×), brine, dried over MgSO4 and concentrated affording the title compound as a colourless liquid (3.92 g, 96%). 1H NMR (DMSO-d6, 300 MHz) δ 7.51-7.38 (m, 3H), 7.29-7.26 (m, 1H), 4.10-4.03 (m, 4H), 2.48-2.43 (t, J=7.37 Hz, 2H), 2.02-1.93 (m, 2H), 1.20-1.15 (t, J=7.10 Hz, 3H). HPLC (Method A) Rt 4.49 min (Purity: 97.9%).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH:10]=1>CO.[Pd]>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1
Reactant: C1=C(c2ccccn2)C2CCN1CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc(C2CN3CCC2CC3)nc1
Yield: 39.8 %

Procedure:
A solution of 3-(2-pyridinyl)-1-azabicyclo[2.2.2]oct-2-ene dihydrochloride (0.28 g, prepared as in Example 5) in methanol (10 ml) was hydrogenated over 10% palladium on carbon (20 mg) in a Parr apparatus at 45 psi for 1 h. The suspension was filtered and concentrated. The crude product was recrystallised from methanol/ether to give 81 mg of the title compound as the dihydrochloride salt; m.p. 180°-190° C.; Found: C, 53.70; H, 7.04; N, 10.47. C12H18N2Cl2. 0.35 H2O requires C, 53.88; H, 7.05; N, 10.47; δ(360 MHz, D2O) 8.738 (1H, d, J=5.6 Hz, py-H), 8.555 (1H, t, J=8.0 Hz, py-H), 8.086 (1H, d, J=8.2 Hz, py-H), 7.934 (1H, t, J=6.5 Hz, py-H), 4.00- 3.75 (3H, m, H2 -2 and H-3), 3.60-3.30 (4H, m, H2 -6 and H2 -7) 2.54 (1H, m, H-4), 2.30-1.80 (4H, m, H2 -5 and H2 -8); m/e 188 (M+).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[C:15]([C:17]1([NH:26][C:27](=[O:35])[CH:28]([NH2:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]1)#[N:16]>>[C:15]([C:17]1([NH:26][C:27](=[O:35])[CH:28]([NH:34][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]1)#[N:16]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC(C)(C)C)NC2=NS(=O)(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-chloro-benzo[d]isothiazole 1,1-dioxide and 2-amino-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt according to the procedure from Example 10, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 460=M+1.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:14][CH:15]=3)[C:10]2=[O:24])[CH2:6][CH2:5]1)(=O)C.[ClH:25]>C(O)C>[ClH:25].[CH3:23][S:20]([NH:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][C:7]3([C:10]2=[O:24])[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=1)(=[O:21])=[O:22]
Reactant: CC(=O)N1CCC2(CCc3ccc(NS(C)(=O)=O)cc3C2=O)CC1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C1(CCNCC1)CC2
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 0.53 g (1.5 mmoles) 1'-acetyl-3,4-dihydro-7-methanesulfonamido-1-oxospiro[naphthalene-2(1H),4'-piperidine] in 15 ml ethanol and 5 ml 3N hydrochloric acid was heated at reflux for 18 hours. An additional 10 ml 3N hydrochloric acid was added and the solution was heatea at reflux for 5 hours, then cooled to room temperature. The solvents were removed in vacuo and the residue was stirred with 3 ml ethanol to give a solid which was filtered off and dried to give 0.35 g (67%) product, m.p 277°-279° C.; 1H NMR (DMSO-d6): δ1.70 (m, 2H), 2.00 (m, 2H), 2.06 (t, 2H), 2.94 (t, 2H), 2.98 (s, 3H), 3.13 (m, 4H), 7.37 (d, 1H), 7.41 (d of d, 1H), 7.73 (d, 1H), 8.75-8.95 (m, 2H), 9.91 (s, 1H, CH3SO2N H--).
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21].O>C1C=CC=CC=1>[CH2:18]([N:19]([CH2:22][CH2:23][CH:13]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:14]#[N:15])[CH2:20][CH3:21])[CH3:17]
Reactant: CCN(CC)CCCl
Reactant: N#CCc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCN(CC)CCC(C#N)c1cccc2ccccc12

Procedure:
7 g of sodium amide are added in small quantities to 27.11 g of 1-naphthylacetonitrile in 210 ml of anhydrous benzene. The mixture is heated for 2 hours to reflux and 22 g of 2-chlorodiethylaminoethane are added, the heating being continued to reflux for another two and a half hours. Then, the mixture is cooled and 200 ml of water are added. After decanting, the organic phase is extracted by HCl at 10%. The aqueous phase is washed in ether, neutralized with NaOH at 10%, then extracted with ether. After evaporation of the solvents, a red oil is obtained, which is distilled in vacuo.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[C:20]1([CH2:30]Br)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][CH2:30][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:10]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: BrCc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3cccc4ccccc34)[C@@H](CO)O2)cc1F
Yield: 17.8 %

Procedure:
The general procedures of Reference Examples 4 and 5 were followed using 1.3 g of potassium hydroxide, 1.00 g of 2'-deoxy-5-fluorouridine and 2.7 g of 1-naphthylmethyl bromide, thereby producing 0.28 g of the title compound in a yield of 18%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:27]3[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]3)=[CH:4][CH:5]=2)[C:12](=[O:26])[CH:13]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccccc4F)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(2-Fluoro-benzyloxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 9.1c from 80 mg (0.19 mmol) 1-[2-(4-bromomethyl-phenyl)ethyl]-4-(2-fluoro-benzyloxy)-1H-pyridin-2-one (example 9.1b), 41 mg (0.29 mmol) N-piperidin-4-yl-acetamide and 84 μL (0.48 mmol) N-ethyl-diisopropylamine as base.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[CH:9][C:10](/[C:15](/[C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=2)=[CH:16]/[C@@H:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])[C:20](=[O:33])[CH2:19][CH2:18]2)=[N:11][C:12]=1[O:13][CH3:14].O>CN(C)C=O>[C:40]([C:37]1[CH:36]=[CH:35][C:34](/[C:15](/[C:10]2[N:11]=[C:12]([O:13][CH3:14])[C:7]([C:4]#[N:5])=[CH:8][CH:9]=2)=[CH:16]\[C@H:17]2[CH2:18][CH2:19][C:20](=[O:33])[N:21]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])=[CH:39][CH:38]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: N#C[Cu]C#N
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C#N)c(OC)n2)c(OC)c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Copper cyanide (27 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (90 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at an external temperature of 180° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-carbonitrile (32 mg, 40%).
Reaction SMILES: [CH3:1][C:2]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=1)([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3].[H-].[Na+].I[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C=O>[CH3:3][C:2]([C:4]1[N:5]([CH2:9][CH2:7][CH2:6][CH2:12][CH3:11])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([C:13]1[N:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH3:1]
Reactant: CCCCCI
Reactant: CC(C)(c1nc2ccccc2[nH]1)c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1c(C(C)(C)c2nc3ccccc3n2CCCCC)nc2ccccc21
Reaction time: 4 h
Yield: 163.9 %

Procedure:
2.8 g 2,2′-Propane-2,2-diylbis(1H-benzimidazole) was added to 60 ml of N,N-dimethylformamide. 1.21 g Of a 60% sodium hydride dispersion in mineral oil was added in portions. 6.0 g Of 1-iodopentane was added and the mixture was stirred under nitrogen. After 4 hours, the reaction was quenched with 160 ml of water and then extracted with two 75 ml portions of ethyl acetate/methanol (˜99:1, v/v). The combined organic layers were washed twice with 75 ml of water. The cloudy organic layer was filtered. Following solvent removal to give a brown oil, the product was purified by silica gel chromatography increasing from 25% to 50% ethyl acetate in hexane by volume over the course of the elution. 3.46 g Of a yellow oil was obtained.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>CO>[CH:10]([NH:13][CH2:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:9])([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: c1ccc(C2CO2)cc1
Solvent: CO
Product: CC(C)NCC(O)c1ccccc1
Yield: 49.6 %

Procedure:
A mixture of 120 g (1 mole) styrene oxide and 59 g (1 mole) of isopropylamine are heated under reflux for 5 hours in 400 ml of methanol. The mixture is dry evaporated and the residue is dissolved in 500 ml of water. The desired free base which has precipitated is filtered and the solution is washed with 100 ml of hexane. The base is recrystallized from hexane, and the crystals are filtered and washed with 50 ml hexane and then dried. 89 g (yield=49%) of 2-isopropylamino-1-phenyl-1-ethanol are obtained. M.P. 90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14](=[O:31])[C@@H:15]([NH2:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14](=[O:31])[C@@H:15]([NH:30][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccc(O)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccc(O)c2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 36.2 %

Procedure:
A solution of 2-amino-5-chloro-benzoic acid (1.95 g, 11.38 mmol) in DMF (10.0 mL) was reacted with (2S)-amino-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester (3.50 g, 11.38 mmol), HBTU (3.98 g, 10.50 mmol), and DIEA (6.08 mL, 34.15 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silical gel using DCM/hexane 85:15 and increasing the gradient to DCM and finally DCM containing 0.25% methanol, to give 1.75 g of (2S)-(2-amino-5-chloro-benzoylamino)-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:31]3[CH:32]=[CH:33][N:34]=[C:29]([Cl:28])[N:30]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Yield: 54.1 %

Procedure:
A mixture of compound 1e (15.00 g), 2,4-dichloropyrimidine (7.56 g) and tetrakis(triphenylphosphine)palladium(0) (4.51 g) in a solution of ethylene glycol dimethyl ether (200 mL) and aqueous Na2CO3 (2M, 60 mL) was refluxed overnight. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was concentrated and the residue was purified on silica gel column (eluted with 100% dichloromethane and 3% acetone in dichloromethane) to provide 1-benzenesulfonyl-3-(2-chloro-pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (1f) (7.83 g, 54%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=8.0 Hz, 1H), 8.62 (d, J=5.6 Hz, 1H), 8.52 (d, J=4.8 Hz, 1H), 8.47 (s, 1H), 8.28 (d, J=7.6 Hz, 2H), 7.63 (t, J=7.6 HZ, 1H), 7.57 (d, J=5.2 Hz, 1H), 7.53 (t, J=8.0 Hz, 2H), 7.35 (dd, J=8.0 Hz, 4.8 Hz, 1H). MS (ESI) m/z: 371 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][O:9][C:10]=1[CH3:11])C.O.[NH2:15][NH2:16]>C(O)CCC>[CH3:12][C:7]1[C:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: NN
Reactant: CCOC(=O)Cc1c(C)noc1C
Solvent: CCCCO
Solvent: O
Product: Cc1noc(C)c1CC(=O)NN
Yield: 87 %

Procedure:
As described for example 112a, (3,5-dimethyl-isoxazol-4-yl)-acetic acid ethyl ester (Bacon, Edward R.; Daum, Sol J.; Singh, Baldev. 6-Substituted pyrazolo[3,4-d]pyrimidin-4-ones and compositions and methods of use as c-GMP phosphodiesterase inhibitors. PCT Int. Appl. (1996), WO 9628429 A1) in butanol was reacted with hydrazine hydrate (3.2 equivalents) and the resulting mixture was heated under reflux for 24 h. Evaporation of all volatiles and crystallization from n-butanol/toluene afforded the title compound as a white solid (yield: 87%). MS: m/e=170.2 [M+H]+.
Reaction SMILES: [C:1]([N:8]([CH3:41])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:43]1[CH:48]=[CH:47][C:46]([C:49](=[O:51])[CH3:50])=[CH:45][CH:44]=1>>[C:49]([C:46]1[CH:47]=[CH:48][C:43]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH3:37])=[C:29]([CH2:28][N:15]([C:16]([C:18]3[S:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[C:19]=3[Cl:27])=[O:17])[CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:41])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][CH2:11]3)[CH:30]=2)=[CH:44][CH:45]=1)(=[O:51])[CH3:50]
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)c1ccc(Br)cc1
Product: CCOc1ccc(-c2ccc(C(C)=O)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 12 (200 mg, 0.33 mmol) is coupled to 4′-bromoacetophenone (79 mg, 0.39 mmol) using Method B to give the title compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19])(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
8.1 g (28.1 mmol) of N-tert-butyl-2-methoxy-4-nitro-benzenesulfonamide is mixed with 350 ml of trifluoroacetic acid and stirred for 20 hours at room temperature. The trifluoroacetic acid is drawn off, and the remaining residue is then digested with ethyl acetate. 5.0 g (21.6 mmol, corresponding to 77% of theory) of the product is obtained. The ethyl acetate phase is concentrated by evaporation, and the residue that is obtained is purified by chromatography (DCM/EtOH 95:5, Flashmaster II). Another 0.84 g (3.6 mmol, corresponding to 13% of theory) of the product is obtained.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]>C(OCC)(=O)C.CCOCC>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(N)=O)[C@@H](C)CC
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC[C@H](N)C(=O)N[C@H](C(N)=O)[C@@H](C)CC
Reaction time: 1 h
Yield: 96 %

Procedure:
4.5 g (13.7 mmoles) of BOC-Nva-Ile-NH2 are suspended in 20 ml of ethyl acetate, and 12 ml of a 6 n hydrochloric acid solution in ethyl acetate are added to the suspension. After one hour of standing the reaction mixture is diluted with ether, and the separated precipitate is filtered off. The resulting 3.6 g of crude product are recrystallized from a mixture of methanol and ether to obtain 3.5 g (96%) of H-Nva-Ile-NH2.HCl; m.p.: 254°-255° C., Rf5 =0.45, [α]D25 =+3.8° (c=1%, in methanol).