Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[C:10]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:34]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[C:10]([CH2:25][N:26]([CH3:34])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CNS(C)(=O)=O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.1 %

Procedure:
To a stirred solution of the methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-(methylsulfonamidomethyl)phenoxy)benzoate (745 mg, 1.65 mmol) in DMF (10 ml) was added MeI (155 μL, 2.48 mmol) followed by K2CO3 (343 mg, 2.48 mmol). The reaction was stirred at ambient temperature for 3 hours, then diluted with ethyl acetate and 2M HCl. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over MgSO4. The crude mixture was purified by silica gel chromatography to give methyl 4-(4-(2-tert -butoxy-2-oxoethyl)-2((N-methylmethylsulfonamido)methyl)phenoxy)benzoate (0.368 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>O=P(Cl)(Cl)Cl>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[N:8]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nc3c(Cl)c(Cl)cnc3[nH]2)cc1
Temperature: 105 °C
Yield: 57.8 %

Procedure:
2,3-Diamino-4,5-dichloropyridine (Example 206a) (2.5 g, 14 mmol) and 4-nitrobenzoic acid (2.3 g, 14 mmol) were dissolved in POCl3 (40 ml) and heated to 105° C. for 5 h. The excess of POCl3 was evaporated off and the residue was dissolved in EtOAc and aqueous K2CO3. The aqueous phase was basified with 10M KOH and extracted three times with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo to afford the title compound (2.5 g, 58%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:53]=[CH:52][N:13]([C@@H:14]2[O:28][C@H:17]([CH2:18][O:19]C(=O)C3C=CC=CC=3)[C@@H:16]([NH:29][C:30]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C@H:15]2[F:51])[C:12](=[O:54])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>N1C=CC=CC=1.CO.O>[C:1]([NH:9][C:10]1[CH:53]=[CH:52][N:13]([C@@H:14]2[O:28][C@H:17]([CH2:18][OH:19])[C@@H:16]([NH:29][C:30]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C@H:15]2[F:51])[C:12](=[O:54])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(N[C@H]2[C@@H](F)[C@H](n3ccc(NC(=O)c4ccccc4)nc3=O)O[C@@H]2COC(=O)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(N[C@H]2[C@@H](F)[C@H](n3ccc(NC(=O)c4ccccc4)nc3=O)O[C@@H]2CO)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
N4 -benzoyl-2'-fluoro-3'-(4-methoxytrityl)amino-2',3'-dideoxycytidine 15 was prepared as follows: To 1.3 g (1.75 mmol) of 14 in 20 mL of 65/30/5 pyridine/methanol/water, cooled in an ice bath, was added 10 mL of cold 2M NaOH in 65/30/5 pyridine/methanol/water. The mixture was stirred cold for 20 min, then neutralized with pyridinium-H+ form Bio-Rad AG® 50W-X8 cation exchange resin. After 5 min, the resin was removed by filtration and washed with methanol. The combined filtrate and wash were concentrated in vacuo to an oil, which was dissolved in 100 mL ethyl acetate. The mixture was washed with 100 mL saturated aqueous NaHCO3 and with water (2×100 mL). After concentration in vacuo to a foam, the product was dissolved in 10 mL CH2Cl2 and pipetted into 75 mL rapidly stirred hexane/ether, 2/1. The product was collected by filtration and dried under vacuum, giving 1.13 g (102% yield) of product as a white powder. Mass-spectrometry, FAB+, M+Cs+, calculated: 753.1489, observed: 753.1499. 1H NMR δ 8.30 (br d, J=6.8 Hz, 1H), 7.89 (br d, J=6.7 Hz, 2H), 7.64 (dd, J=7.4, 7.4 Hz, 1H), 7.44-7.56 (mm, 9H), 7.22-7.32 (mm, 9H), 6.82 (d, J=8.8Hz, 2H), 5.80 (d, J=15.7Hz, 1H), 4.26 (mm, 2H), 4.13 (d, J=10.2 Hz, 1H), 3.81 (s, 3H), 3.26 (dddd, J=3.4, 10.7, 10.8, 26.5 Hz, 1H), 2.93 (dd, J =3.3, 50.5 Hz, 1H), 2.50 (dd, J=2.8, 11.0 Hz, 1H); 19F NMR δ -195.3 (m).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[CH3:15][N:16]([CH3:27])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH2:26])=[NH:25])=[CH:19][CH:18]=1.[OH-].[Na+]>O(CCO)C>[CH3:15][N:16]([CH3:27])[C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]2[N:26]=[C:8]([C:3]3[S:4][C:5]([CH3:7])=[N:6][C:2]=3[CH3:1])[CH:9]=[CH:10][N:25]=2)=[CH:21][CH:22]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: CN(C)c1ccc(NC(=N)N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N(C)C)cc3)n2)s1
Temperature: 120 °C

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (0.95 mmol, 0.19 g) and N-(4-dimethylamino-phenyl)-guanidine (2 mmol) in 2-methoxylethanol (5 mL) was added NaOH (40 mg). The reaction mixture was heated at 120° C. for 18 h. The solvent was evaporated and the residue was purified by chromatography, using EtOAc/PE to afford N,N-dimethyl-N′-{4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl}-benzene-1,4-diamine {119} (74 mg) as a reddish-brown solid. 1H-NMR (300 MHz, d6-DMSO) δ 2.62 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.86 (s, 6H, CH3), 6.73 (m, 2H, Ph-H), 6.97 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.56 (m, 2H, Ph-I), 8.44 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 9.33 (s, 1H, NH). DE MALDI-TOF MS: {M+H}+=329.51 (C17H19N5S requires 325.43).
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)CBr
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Agent: Cl
Product: COC(=O)CN1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 41 %

Procedure:
The title compound (135 mg, 41%) was prepared from 1-(4-Phenoxy-phenyl)-piperazine hydrochloride. (165 mg, 0.9 mmol) and methyl 2-bromo-acetate (140 mg, 0.92 mmol) by the procedure described in step 3 of Example 6 MS (ESI) m/z 327 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.76 (b, 2.67), 3.21 (t, J=3.2 Hz, 4H), 3.29 (s, 2H), 3.75 (s, 3H), 6.92-7.05 (m, 7H), 7.29 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.[C:33]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)#[N:34]>>[C:33]([C:35]1[CH:36]=[C:37]([O:41][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[N:6][CH:7]=2)[CH:38]=[CH:39][CH:40]=1)#[N:34]
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(O)c1
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4cccc(C#N)c4)cn3)cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D72) and 3-cyanophenol using a method similar to that described for D73 in Description 73 although the reaction was worked up after the first night of heating. MS (ES): MH+ 542.3.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@@H:21]4[CH2:23][O:22]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>O1CCCC1>[NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@@H:21]([OH:22])[CH2:23][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:26]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@@H]1CO1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C[C@H](O)COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1C#N
Temperature: 50 °C
Reaction time: 120 h
Yield: 91.1 %

Procedure:
After dissolving 4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2S)-oxiran-2-yl)methoxyquinoline (72 mg, 0.196 mmol) in tetrahydrofuran (2.0 ml) under a nitrogen atmosphere, diethylamine (0.4 ml) was added and the mixture was stirred at 50° C. for 5 days. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (78.6 mg, 0.178 mmol, 91.1%) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][CH2:18][OH:19])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:20]=1.O.CC([OH:25])C.[OH-].[Na+]>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][C:18]([OH:25])=[O:19])([C:12]([F:14])([F:15])[F:13])[C:6]=2[CH:20]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CCCO)(C(F)(F)F)O1
Reactant: CC(C)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
While stirring a solution of 6-chloro-4-(3-hydroxypropyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.0 g, 3.23 mmol) in acetone (20 mL), Jones reagent (8 N chromic acid, H2SO4—H2O solution, 2 mL) was added dropwise thereto at room temperature. Then water (20 mL) was added thereto and the solution was stirred at room temperature for 3 hours. Then, to the reaction solution, 2-propanol was added and the solution was stirred at room temperature for 5 minutes. After the reaction solution was diluted with ethyl acetate, a 8 N aqueous sodium hydroxide solution was added thereto, and the aqueous layer was separated. After the aqueous layer was acidified by adding 8 N hydrochloric acid thereto, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure, whereby the objective compound (726 mg, 70%) was obtained as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][C:8]([O:21]C)=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([OH:21])[CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][C:3]=1[OH:2]
Reactant: COc1ccc2c3ccccc3c3ccc(OC)cc3c2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2c3ccccc3c3ccc(O)cc3c2c1
Temperature: 220 °C
Yield: 93.8 %

Procedure:
A mixture of 2,11-dimethoxytriphenylene (8.8 g, 30.5 mmol) and pyridine hydrochloride (31.73 g, 274.6 mmol) was heated to 220° C. for 2 hours. The mixture was cooled and water was added. The resulting solid was filtered off, washed with water, and dried under high vacuum. 7.45 g (94%) desired product was obtained.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N:24]1([NH-:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO.[Pd]>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[N:24]1([NH-:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: [Pd]
Agent: [NH-]N1CCOCC1
Solvent: CO
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
A solution of 2.05 g (5.3 mmol) of Z-(L)-Tyr-morpholin-4-ylamide in 91 ml of methanol is hydrogenated for 1.5 h at RT in the presence of 0.5 g of 10% Pd/C. Filtration through ®Celite (filter aid of diatomaceous earth, John-Manville Corp.) and concentration of the filtrate by evaporation yields the title compound: TLC Rf (R)=0.34.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[C:37]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH2:51])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C(Cl)CCl.CN(C=O)C.C(N(CC)CC)C.O>[C:40]([O:39][C:37](=[O:38])[NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:17](=[O:18])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:11]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1

Procedure:
Starting materials: (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compound B2) (0.300 g), HOBt?H2O (0.130 g), triethylamine (668 μl), DMF (20 ml), EDC?HCl (0.508 g), N—BOC-1,2-phenylenediamine (0.176 g). Reaction conditions: room temperature, 1 hour; room temperature, 17 hours.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:28][S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:15])[F:14])[CH:7]=1.CO.[NH3:38]>C(O)CO.CCOC(C)=O>[CH3:32][C:31]([S:29]([NH:28][C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:15])[F:14])[CH:7]=1)[CH2:4][C:3]([NH2:38])=[O:2])=[O:30])([CH3:34])[CH3:33]
Reactant: COC(=O)CC(N[S@](=O)C(C)(C)C)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CC(C)(C)S(=O)NC(CC(N)=O)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 120 °C
Yield: 76 %

Procedure:
(R)-methyl-3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)propanoate (prepared as described for Procedure 11, 0.70 g, 1.33 mmol) was dissolved in 8N NH3 in ethylene glycol (6 mL) at room temperature in a microwave vial. The reaction mixture was heated at 120° C. for 1200 sec, and then at 130° C. for 1200 sec under microwave irradiation. After cooling, the cap was removed, and H2O was added. The mixture was extracted with EtOAc (3×), washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, then 10% MeOH in EtOAc) to give 3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)-propanamide as white solid (0.52 g, yield: 76%) LCMS: 3.88 min [M+1] 513.28 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.29 (m, 3H), 7.22-7.12 (m, 3H), 7.11-7.02 (m, 2H), 6.29 (m, 2H), 5.40 (s, br, 1H), 3.78 (d, J=14.50 Hz, 1H), 3.71 (s, 2H), 3.35 (d, J=14.50 Hz, 1H), 1.21-1.28 (m, 9H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21]#[C:22][CH3:23])[CH2:17][C:18]([NH2:20])=O)=[CH:12][CH:11]=1>CN(C=O)C>[CH3:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21]#[C:22][CH3:23])[CH2:17][C:18]#[N:20])=[CH:12][CH:11]=1
Reactant: CC#CC(CC(N)=O)c1ccc(OCc2ccccc2C)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC#CC(CC#N)c1ccc(OCc2ccccc2C)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
An oven-dried 50 mL round-bottomed flask was charged with DMF (8 mL) and a stir bar. The solution was cooled to 0° C. in an ice bath. Thionyl chloride (160 μL, 1.0 mmol) was added slowly via syringe. The mixture was stirred at 0° C. for an additional 45 minutes. Nitrile 23.2 (300 mg, 0.98 mmol) was then added to the mixture as solution in DMF (2 mL). The reaction was stirred at 0° C. for an hour, and was then allowed to gradually warm to room temperature overnight. The reaction mixture was partitioned between ice water and ethyl acetate. The aqueous layer was extracted 2 additional times with 25 mL ethyl acetate. Saturated NaHCO3 was then added to the aqueous layer and the aqueous layer was extracted a third time with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 and concentrated under reduced pressure. The resulting residue was purified via radial chromatography (15% ethyl acetate in hexanes) to yield 203 mg (72%) of 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynenitrile (23.3). 1H NMR (400 MHz) (acetone-d6) δ 7.44 (3H, m), 7.24 (3H, m), 7.05 (2H, m), 5.13 (2H, s), 4.09 (1H, m), 2.89 (2H, m), 2.39 (3H, s), 1.88 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([F:18])([F:35])[C:31]([F:32])([F:33])[F:34])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=495.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].N1C=CC=CC=1>O1CCCC1>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1noc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1noc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
1.0 g of benzo[d]isoxazole-3-carboxylic acid, 0.7 g of N,O-dimethylhydroxylamine hydrochloride, 2.3 g of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide) hydrochloride and 1 ml of pyridine in 40 ml of tetrahydrofuran are placed in a round-bottomed flask. The mixture is stirred at ambient temperature for 20 h. The mixture is concentrated and the residue is taken up in 40 ml of ethyl acetate and 20 ml of water. The organic phase is washed with 20 ml of a 1N solution of sodium hydroxide and 20 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 1.1 g of compound are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:21][CH2:20][CH2:19][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:10]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: NCCN1CCCCC1
Product: O=C(CN1CCCC1=O)NCCN1CCCCC1

Procedure:
From 12.8 g. of ethyl 2-oxo-1-pyrrolidineacetate and 19.2 g. of 2-(1-piperidinyl)ethylamine [Compt. rend. 233, 1121 (1951)], following the procedure of Example 1, there is obtained 2-oxo-N-[2-(1-piperidinyl)ethyl]-1-pyrrolidineacetamide; b.p. 185°-187° C./0.15 mm.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]2[S:11][C:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:5]=2[C:4]=1[C:18]1[C:19]([CH3:28])=[C:20]2[C:25](=[CH:26][CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:9][N:8]1[C:3]([CH:2]=[O:1])=[C:4]([C:18]2[C:19]([CH3:28])=[C:20]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][CH2:22][CH2:21]3)[C:5]2[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=3[S:11][C:6]=2[C:7]1=[O:10]
Reactant: Cc1c(-c2c(CO)n(C)c(=O)c3sc4c(c23)CCCC4)ccc2c1CCCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2c(C=O)n(C)c(=O)c3sc4c(c23)CCCC4)ccc2c1CCCO2
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a solution of 3-(hydroxymethyl)-2-methyl-4-(5-methylchroman-6-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-c]pyridin-1(2H)-one (60 mg, 0.15 mmol) in chloroform (15 mL) was added manganese(IV) oxide (132 mg, 1.5 mmol). The mixture was stirred at reflux for 18 h. After the reaction mixture was cooled to room temperature, the suspension was filtered through a pad of silica gel and the pad was washed with ethyl acetate (20 mL×3). The combined filtrates were concentrated to dryness to give crude title product (50 mg, 84% yield), which was used in the next step directly. LCMS (m/z) ES+=396 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:20](O)[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][O:25]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OCC1CCCO1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CC1CCCO1)c1cc(F)ccc1F

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.661 mmol) obtained in Example 5 and tetrahydrofurfuryl alcohol (0.13 ml, 1.34 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (0.320 ml). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was separated and purified by flash silica gel chromatography (using a hexane/ethyl acetate mixed solvent) to give a white solid. The white solid was washed with hexane, whereby obtained were the title Isomer 294-A (low polarity) (102 mg, 0.264 mmol, 40%) and the title Isomer 294-B (high polarity) (39 mg, 0.10 mmol, 15%), each as a white powder.