Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[O:25]1[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH:27]2[CH2:28][CH2:29][O:25][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: NCC1CCOC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CCOC2)cn1
Yield: 81 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using (tetrahydrofuran-3-yl)methanamine hydrochloride instead of methylamine, to the title compound (103 mg, 81%) which was obtained as a white solid. MS: m/e=394.3 [M+H]+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:19]=[CH:18][C:9]([S:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[ClH:20]>O.C(O)(=O)C>[Cl-:20].[CH3:5][C:6]1[CH:19]=[CH:18][C:9]([S:10][C:11]2[CH:17]=[CH:16][C:14]([N+:15]#[N:1])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(Sc2ccc(N)cc2)cc1
Reactant: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Sc2ccc([N+]#N)cc2)cc1
Product: [Cl-]
Reaction time: 0.25 h

Procedure:
A solution of 2.8 g (0.04 mol) of sodium nitrite in 15 ml of water is added dropwise, at an internal temperature of max. 10° C., to 10.7 g (0.04 mol) of 4-(4-methylthiophenoxy)-aniline in 100 ml of glacial acetic acid and 7.5 ml of conc. hydrochloric acid. Then stirring is continued for 15 minutes.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[C:13]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]1[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1I.[CH:52]1([O:55][C:56]2[CH:57]=[C:58](B3OC(C)(C)C(C)(C)O3)[CH:59]=[CH:60][C:61]=2[O:62][CH:63]([F:65])[F:64])[CH2:54][CH2:53]1.C1(B(O)O)C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:58]2[CH:59]=[CH:60][C:61]([O:62][CH:63]([F:65])[F:64])=[C:56]([O:55][CH:52]3[CH2:53][CH2:54]3)[CH:57]=2)=[C:13]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]1[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cc2ccc(OC)nc2)c(Br)n(COCc2ccccc2)c1C=O
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Agent: OB(O)c1ccccc1
Product: CCOC(=O)c1c(Cc2ccc(OC)nc2)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Yield: 95.7 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 31 except for using 322 mg (0.66 mmol) of ethyl 1-benzyloxymethyl-5-bromo-2-formyl-4-(6-methoxy-3-pyridylmethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 43-(b) in place of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 323 mg (0.96 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in Reference example 1-(a) in place of phenylboronic acid, respectively, whereby 383 mg of the title compound was obtained as a slightly yellowish oil. (Yield: 96%)
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1.[C:27]1([NH2:34])[C:28]([NH2:33])=[CH:29][CH:30]=[CH:31][CH:32]=1.[C:35](O)(=O)[CH3:36]>>[CH3:20][CH:15]1[O:16][CH:17]([CH3:19])[CH2:18][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=[C:2]([N:33]2[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:34]=[C:35]2[CH3:36])[N:10]=3)[CH2:14]1
Reactant: CC1CN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC(C)O1
Reactant: CC(=O)O
Reactant: Nc1ccccc1N
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C)OC(C)C3)n(C)c2n1

Procedure:
Following the procedures for 157 and General Procedure J, where in Step 1, 4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-2,6-dimethylmorpholine and benzene-1,2-diamine were reacted, followed by condensation with acetic acid to give 194. LCMS m/z: 477.2 (MH+)
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([O:48]CC4C=CC=CC=4)=[C:43]([CH3:56])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:57]=[CH:58][CH:59]=[CH:60][C:4]=2[NH:3]1.[H][H]>CCO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([CH3:56])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:57]=[CH:58][CH:59]=[CH:60][C:4]=2[NH:3]1
Reactant: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
340 mg (0.41 mmol) (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-ethoxycarbonyl methoxy-1,4′-bipiperidinyl -1′-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 20 mL EtOH were combined with 100 mg 10% Pd/C and hydrogenated at 50° C. and 50 psi hydrogen for 2 h. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i. vac.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([OH:14])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][C:17]=1[OH:23].B(F)(F)F.CCOCC>>[Cl:15][C:16]1[C:17]([OH:23])=[CH:18][C:19]([OH:20])=[C:21]([C:12](=[O:14])[CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH:22]=1
Reactant: O=C(O)Cc1ccc2c(c1)OCCO2
Reactant: Oc1ccc(Cl)c(O)c1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(Cc1ccc2c(c1)OCCO2)c1cc(Cl)c(O)cc1O
Reaction time: 2 h
Yield: 68.4 %

Procedure:
This compounds was synthesised in the same manner as described above. (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-acetic acid (0.3 g, 1.55 mmol), 4-chlororesorcinol (0.22 g, 1.55 mmol), boron trifloride etherate (3 ml). After standing for two hours a precipitate formed which was filtered, washed (water), and dried to give 1-(5-Chloro-2,4-dihydroxy-phenyl)-2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone as a white solid (0.34 g, 68.3%); Rf 0.9 hexane/ethyl acetate (20/80).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].[I-].[K+].C[N:21]([CH3:24])C=O>>[C:24]([CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])#[N:21]
Reactant: CN(C)C=O
Reactant: COc1ccc(O)c(C=O)c1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: COc1ccc(OCC#N)c(C=O)c1
Temperature: 25 °C
Reaction time: 1.83 h
Yield: 90.9 %

Procedure:
To a cooled mixture of 2-hydroxy-5-methoxybenzaldehyde (500.0 g), potassium carbonate (908.4 g) and potassium iodide (272.8 g) in N,N-dimethylformamide (2.5 l) chloroacetonitrile (297.7 g) was added dropwise over 8 minutes below 10° C. under nitrogen. After being stirred at ambient temperature for 110 minutes, the mixture was poured slowly into ice-water (20 l) and stirred for 2 hours. The precipitates were cooled by centrifugal filtration, washed with water (1 l) 7 times and air-dried at ambient temperature to give 2-cyanomethoxy-5-methoxybenzaldehyde (571.4 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6].[N+](C1C=CC=C([N+]([O-])=O)C=1C#N)([O-])=[O:15].CS>[Ni]>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([S:2][CH3:1])[C:4]=1[C:5]([NH2:6])=[O:15]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CSc1cccc([N+](=O)[O-])c1C#N
Agent: [Ni]
Agent: CS
Product: CSc1cccc(N)c1C(N)=O

Procedure:
2-Amino-6-(methylthio) benzamide is prepared by Raney nickel reduction of 2-(methylthio)-6-nitrobenzonitrile which is prepared from 2,6-dinitrobenzonitrile and methylmercaptan following the procedure set forth in Example 75.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:51])[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[S:11]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([S:39]([C:42]1[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:43]=1[CH3:50])(=[O:41])=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:30]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=1[CH3:38])(=[O:29])=[O:28])(=[O:13])=[O:12].I[CH2:53][CH2:54][CH3:55].[CH3:56][CH2:57][CH2:58]CCC.CCOC(C)=O>CN(C=O)C>[C:5]1([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH3:51])[C:4]=1[S:11]([N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([S:39]([C:42]1[C:43]([CH3:50])=[CH:44][C:45]([CH3:49])=[CH:46][C:47]=1[CH3:48])(=[O:40])=[O:41])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([S:27]([C:30]1[C:31]([CH3:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=1[CH3:36])(=[O:28])=[O:29])[CH2:56][CH2:57][CH3:58])[CH2:53][CH2:54][CH3:55])(=[O:13])=[O:12]
Reactant: CCCI
Reactant: Cc1cc(C)c(S(=O)(=O)NCCCCCN(CCCCCNS(=O)(=O)c2c(C)cc(C)cc2C)S(=O)(=O)c2c(C)cc(C)cc2C)c(C)c1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CCCCCN(CCCCCN(CCC)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 95 %

Procedure:
NaH (80%, 198 mg, 6.6 mmol), 34 (1.51 g, 2.06 mmol), and 1-iodopropane (0.44 mL, 4.5 mmol) in DMF (40 mL) were reacted and worked up by the method of 43. Column chromatography (7:2/hexane/EtOAc) provided 1.61 g (95%) of 57 as an oil: NMR δ 0.75 (t, 6 H, J=7), 1.02-1.14 (m, 4 H), 1.36-1.52 (m, 12 H), 2.30 (s, 9 H), 2.60 (s, 18 H), 3.02-3.16 (m, 12 H), 6.95 (s, 6 H). Anal. (C43H67N3O6S3) C, H, N.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CC(=O)CC>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)-3-methyl-phenyl]methylamino]phenol (150 mg, 0.42 mmol, 1.0 eq) in 2-butanone (10 mL) was added Cs2CO3 (203 mg, 0.62 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 30 min then ethyl bromoacetate (83 mg, 0.50 mmol, 1.2 eq) was added. The reaction was stirred at room temperature 30 min then filtered and concentrated. The crude residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as a gum (150 mg, 81%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:51]([NH:53][CH2:54][C:55]([NH:57][C@H:58]([C:61]([NH:63][C@H:64]([C:69]([O:71]C(C)(C)C)=[O:70])[CH2:65][C:66](=[O:68])[NH2:67])=[O:62])[CH2:59][OH:60])=[O:56])=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])[CH3:11])=[O:8].C([O-])(=O)C>FC(F)(F)C(O)=O.O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][C@@H:46]([C:51]([NH:53][CH2:54][C:55]([NH:57][C@H:58]([C:61]([NH:63][C@H:64]([C:69]([OH:71])=[O:70])[CH2:65][C:66](=[O:68])[NH2:67])=[O:62])[CH2:59][OH:60])=[O:56])=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH3:11])=[O:8]
Reactant: CC(C)C[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCC(=O)N1)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)C[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@@H]1CCC(=O)N1)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reaction time: 1 h

Procedure:
In 8 ml of trifluoroacetic acid is dissolved 200 mg of pGlu-Ala-Lys(Boc)-Ser-Gln-(D)-Leu-Gly-Ser-Asn-OBut and the solution is allowed to stand at room temperature for 60 minutes. The trifluoroacetic acid is distilled off under reduced pressure and the residue is precipitated with ether and recovered by filtration. The powders thus obtained are dissolved in a small amount of water and passed through a column of Amberlite IRA-410 (acetate-form) (1.5×7 cm). The effluent is combined with washings and lyophilized. The powdery lyophilizate is dissolved in a small amount of 1 N-acetic acid and put onto a chromatographic column of Sephadex LH-20(2.5×125 cm), elution being carried out with 1 N-acetic acid. The fractions from 190-205 ml are pooled and lyophilized. Yield 65 mg; [α]D22 -45.4° (c=0.4, H2O); Rf4 (Avicel)=0.37; amino acid analysis (acid hydrolyzate): Lys, 1.04(1); Asp, 0.98(1); Ser, 1.86 (2); Glu, 2.14(2); Gly, 0.93(1); Ala, 1.00(1); Leu, 1.00 (1); average recovery, 71.2%.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18](=O)[CH2:19][CH2:20][O:21]4)=[CH:16][CH:15]=3)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:27][OH:28]>>[CH3:1][C:2]1([CH3:25])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:23]=[C:22]4[C:17](/[C:18](=[N:27]/[OH:28])/[CH2:19][CH2:20][O:21]4)=[CH:16][CH:15]=3)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1
Reactant: NO
Reactant: CC1(C)OCC(C)(c2csc(Sc3ccc4c(c3)OCCC4=O)c2)O1
Agent: Cl
Product: CC1(C)OCC(C)(c2csc(Sc3ccc4c(c3)OCC/C4=N\O)c2)O1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 68, 7-[4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-ylthio]chroman-4-one was reacted with hydroxylamine hydrochloride to give (E)-7-[4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-ylthio]chroman-4-one oxime in 65% yield as a gum.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]CC1.[CH:11]1[CH:16]=[C:15]([CH:17]=O)[C:14](O)=[CH:13][CH:12]=1>CN(C=O)C>[CH2:6]1[CH2:4][CH2:5][CH:10]2[O:1][CH:9]2[CH2:8][CH2:7]1.[CH:15]1[CH2:17][CH2:14][CH2:13][CH:12]=[CH:11][CH:16]=1
Reactant: O=Cc1ccccc1O
Reactant: c1ccc2c(c1)CCCO2
Solvent: CN(C)C=O
Product: C1=CCCCC=C1
Product: C1CCC2OC2CC1

Procedure:
According to the first pathway, the starting material for the preparation of chromane fragment d12 was the salicylic aldehyde d3, which was synthesized either by formylation of compound d1 or by reaction of the lithiated compound d2 at −60° C. with DMF. The allylic cycloheptene epoxide which could be obtained by epoxidation of cycloheptadiene was then reacted with aldehyde d4 to give the racemic compound d7 by a regioselective and stereoselective nucleophilic opening of epoxide d8. Protection of the hydroxyl group of d7 using TBSOT followed by treatment with 5 equiv EtMgCl and 10 mol % (R)-(EBTHI)Zr-binol delivered d8 in 44% yield and >98% ee. The Mo-catalyzed metathesis reaction under an ethylene atmosphere, followed by Wacker oxidation ofthe terminal double bond and subsequent catalytic hydrogenation, gave d10 in 83% overall yield. To synthesize d11 from d10, a photochemical Norrish type II cleavage was necessary. The following three-step sequence of ozonolytic cleavage, Mitsunobu reaction using tributylphosphine and phthalide followed by hydrazinolysis to remove the phthalimidyl group gave intermediate d12. The second pathway started with the synthesis of cis configured racemate d16, which was then resolved in the presence of the Zirconium catalyst (S)-(EBTHI)Zr-biphenol. The compound d17 was converted into compound d18 by Mo-catalyzed metathesis reaction. Wacker oxidation of the terminal double bond and subsequent catalytic hydrogenation delivered intermediate d19, which was further converted by a photochemical Norrish type II cleavage and ozonolysis into the aldehyde d21. D-Nebivolol was then obtained by reductive amination of compounds d12 and d21 followed by removal of the silyl ether protection groups.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[N:41]=[C:42](Cl)[O:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:34][C:27]1[CH:26]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[N:41]=[C:42]([C:6]3[CH:7]=[C:8]([CH:10]4[CH2:11][CH2:12]4)[CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)[O:43][CH:44]=2)=[O:39])[CH3:36])[CH:24]=[C:23]([F:22])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1(C)OB(c2cc(C3CC3)cc(C3CC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cc(C3CC3)cc(C3CC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 3.8 %

Procedure:
2-(3,5-Dicyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (74 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (100 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (254 mg, 0.78 mmol) as described above to give the title compound (5 mg, 4%) after purification by flash chromatography on silica gel (% EtOAc in hexane=30%˜70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=2[F:30])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:25]=[C:26]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][C:29]=3[F:30])[CH2:22][CH2:23]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 127 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.43–7.38 (m, 1H), 7.37–7.26 (m, 3H), 6.93–6.83 (m, 2H), 3.96–3.61 (m, 1H), 3.26–3.02 (m, 4H), 2.69–2.59 (m, 1H), 2.51–2.40 (m, 2H), 1.90–1.71 (m, 4H), 1.63–1.47 (m, 4H), 1.18 (d, 6H, J=6.9 Hz), 1.15 (s, 6H); ESMS m/e: 502.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[S:14]1C=CC=C1CC(O)=O.C1C[O:26][CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:13])[CH2:7][CH:8]([CH2:12][S:14][C:25](=[O:26])[CH3:24])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(CC(=O)OC(C)(C)C)C(=O)O
Reactant: C1CCOC1
Reactant: O=C(O)Cc1cccs1
Product: CC(=O)SCC(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.6 %

Procedure:
To a stirring solution of the compound of example 23 (3.00 g, 16.11 mmoles) in anhydrous THF (16 mL), was added drop wise thiolacetic acid (3.68 g, 48.34 mmoles). The mixture was stirred at room temperature for 24 hours. The solvent was then evaporated under vacuum and the residue was directly purified by flash chromatography (SiO2, 20% ethyl acetate:80% hexanes) to afford 1.80 g (42.6% yield) of the desired product as a yellow oil. IR (film) 2980, 2652, 1729, 1255, 1152 cm−1; HRMS (EI) Calcd for C11H19O5S: 263.0953, Found: 263.0944.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:30])=O>ClCCl>[Cl:30][CH2:25][C:21]1[CH:20]=[C:19]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:27])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH:24]=[CH:23][CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CO)c4)ccnc32)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CCl)c4)ccnc32)cc1
Yield: 99.3 %

Procedure:
To a solution of (G) (0.25 g, 0.66 mmol) in dichloromethane (5 mL) was added thionyl chloride (0.5 mL, 6.9 mmol) at RT. The solution was allowed to stir until complete as judged by HPLC (1 hour). The solvent was removed under reduced pressure to afford 0.26 g of (H) (99% yield) as a white solid. FIA MS expected for C21H17ClN2O2S: m/e 396.07, found: 396.8 ES+. The material was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]4[CH2:20][CH2:19]4)[CH2:13][CH2:12]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH2:46])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:39])([F:41])[F:40])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46][C:2]2[N:7]3[N:8]=[C:9]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH:18]5[CH2:20][CH2:19]5)[CH2:13][CH2:12]4)[N:10]=[C:6]3[CH:5]=[C:4]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:3]=2)[N:32]=1
Reactant: Clc1ccc(-c2cc3nc(C4CCN(CC5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1nc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(CC5CC5)CC4)nn23)ccc1C(=O)C(F)(F)F
Temperature: 130 °C

Procedure:
50 mg (0.10 mmol) of 5-chloro-2-[1-(cyclopropylmethyl)piperidin-4-yl]-7-(2,4-dichlorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine (Example 47A), 35 mg (0.12 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.110 ml (0.6 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 32 mg (48% of theory) of the product as a solid.