Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(Cl)(=O)=O)=CC=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].N1C=CC=CC=1.CC1C=CC(S(OCCC#C)(=O)=O)=CC=1.[O:38]=[CH:39][C:40]1[CH:48]=[CH:47][C:45](O)=[C:42]([O:43][CH3:44])[CH:41]=1>C(Cl)Cl>[CH2:12]([O:16][C:45]1[CH:47]=[CH:48][C:40]([CH:39]=[O:38])=[CH:41][C:42]=1[O:43][CH3:44])[CH2:13][C:14]#[CH:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: C#CCCO
Agent: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCCOc1ccc(C=O)cc1OC
Yield: 33.5 %

Procedure:
4-Methylbenzenesulfonyl chloride (5.7 g, 30 mmol), 3-butyn-1-ol (1.5 mL, 20 mmol) and pyridine (3.2 mL, 40 mmol) in CH2Cl2 (20 mL) were treated according to Procedure 4 giving but-3-ynyl 4-methylbenzenesulfonate (4.15 g, 93%) as a colourless oil. Vanillin (0.86 g, 5.7 mmol) was alkylated with but-3-ynyl 4-methylbenzenesulfonate (1.9 g, 8.5 mmol) according to Procedure 4 and the crude product was recystallised from EtOAc/petrol to provide 4-(but-3-ynyloxy)-3-methoxybenzaldehyde (0.39 g, 34%) as a colourless crystalline solid; mp 101-102° C.; δH (400 MHz, CDCl3) 2.07 (t, J=2.8 Hz, 1H, C≡CH), 2.79 (td, J=7.2, 2.8 Hz, 2H, CH2C≡CH), 3.93 (s, 3H, OCH3), 4.25 (t, J=7.2 Hz, 2H, OCH2), 7.00 (d, J5,6=8.0 Hz, 1H, H5), 7.42 (d, J2,6=2.0 Hz, 1H, H2), 7.45 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.86 (s, 1H, CHO); δC (100 MHz, CDCl3) 13.3, 56.1, 67.0, 70.5, 79.6, 109.6, 112.0, 126.6, 130.5, 149.9, 153.3, 190.9; vmax 1021, 1269, 1586, 1677, 2940, 3246 cm−1.
Reaction SMILES: [F:1][CH:2]([F:9])[C:3]([NH:5][CH2:6][CH2:7][OH:8])=O.Cl.ClCCl>C1COCC1>[NH3:5].[F:1][CH:2]([F:9])[CH2:3][NH:5][CH2:6][CH2:7][OH:8]
Reactant: O=C(NCCO)C(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: N
Product: OCCNCC(F)F
Temperature: 25 °C
Yield: 77.5 %

Procedure:
Borane-tetrahydrofuran complex (40 ml of a 1.0 N solution in THF, 40 mmol) was added dropwise at 0° C. to a solution of 2,2-difluoro-N-(2-hydroxyethyl)acetamide (2.78 g, 20 mmol) in tetrahydrofuran (30 ml). The mixture was warmed to ambient temperature and then heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated hydrochloric acid (6 ml) was added dropwise. The solvent was evaporated and the crude product was purified by chromatography on silica gel. Elution with dichloromethane:methanolic ammonia (96:4) then dichloromethane:methanolic ammonia (94:6) yielded 2-((2,2-difluoroethyl)amino)ethanol (0.97 g, 39% yield):
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49]([OH:51])=O.CCN(C(C)C)C(C)C.[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH2:66]>CN(C=O)C>[CH3:61][N:62]([CH3:67])[CH2:63][CH2:64][CH2:65][NH:66][C:49]([C:27]1[S:28][C:29]2[N:30]=[CH:31][N:32]=[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)[C:34]=2[C:26]=1[CH3:25])=[O:51]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
HATU (0.105 g, 0.28 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.097 g, 0.25 mmol) and Hünig's base (44 μL, 0.25 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 3-Dimethylamino-1-propylamine (138 μL, 1.25 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the product purified by reverse phase preparative HPLC to yield off-white solid (0.029 g, 24%).
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=S)C.[CH2:12](C1C=CC=CC=1)[CH3:13]>>[CH2:12]([C:10]1[CH:11]=[CH:3][C:4]([C:5]#[N:7])=[CH:8][CH:9]=1)[CH3:13]
Reactant: CCc1ccccc1C(N)=S
Reactant: CCc1ccccc1
Product: CCc1ccc(C#N)cc1

Procedure:
In a polyethylene vessel having a capacity of 1 liter, at -20° C and with agitation, 46 g of ammonium thiocyanate (0.6 mol) and subsequently 53 g of ethylbenzene (0.5 mol) are added in portions to 0.5 l of 98% hydrofluoric acid. Subsequently, agitation is continued for 20 hours at room temperature, and the reaction mixture is then poured onto ice, thus causing the separation of a precipitate which slowly crystallizes. The precipitate is suction-filtered and washed with water. By steam distillation, about 10 g of ethylbenzene are recovered from the precipitate. After drying, 66 g (0.4 mol) of ethyl-thiobenzamide having a slightly yellow color and a melting point of 115 - 117° C are obtained, which corresponds to a conversion rate of 80% relative to the ethylbenzene used. The yield, relative to converted ethylbenzene, is 95% of the thoeretical yield. The product can be recrystallized from toluene or chlorobenzene. The gas chromatogram shows that substitution by the thioamide group has occured in p-position at a rate of more than 95%. The 4-ethylbenzonitrile may be obtained from the thioamide in known manner using alkali, thereby splitting off H2S.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(OC2NC(N)=C3C(N=2)=NC(OC)=N3)CCC1.[CH:25]1([O:30][C:31]2[N:39]=[C:38]3[C:34]([N:35]=[C:36]([O:46][CH3:47])[N:37]3C3CCCCO3)=[C:33]([NH2:48])[N:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:25]1([O:30][C:31]2[NH:32][C:33]([NH2:48])=[C:34]3[C:38]([N:39]=2)=[N:37][C:36]([O:46][CH3:47])=[N:35]3)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COc1nc2c(N)nc(OC3CCCC3)nc2n1C1CCCCO1
Agent: COc1nc2nc(OC3CCC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2nc(OC3CCCC3)[nH]c(N)c-2n1

Procedure:
Prepared similarly to Intermediate 58 from 2-(cyclopentyloxy)-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1>>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:18]([O:19][CH:2]([CH3:3])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)CCCC(C)Br
Product: COC(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1

Procedure:
By the procedure described in Example 1, 2-bromo-6-methyl-heptane is reacted with vanillic acid methyl ester to produce 4-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-benzoic acid methyl ester (boiling point = 198°-200°C/0.1 mmHg).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:6]=1)[NH2:4].C(N(CC)CC)C.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=O)=[CH:31][CH:30]=1>ClCCl>[CH3:10][C:8]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:33]([C:32]3[CH:36]=[CH:37][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=3)[O:1][N:2]=2)[CH:9]=1
Reactant: Cc1ccc(Cn2nc(C(N)=NO)cc2C)cc1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cn2nc(-c3noc(-c4ccc(OC(F)(F)F)cc4)n3)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of N′-hydroxy-5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboximidamide (Intermediate KK, 110 mg, 0.45 mmol) and triethylamine (188 μL, 1.35 mmol) in dichloromethane (4 mL) was added 4-(trifluoromethyoxy)benzoyl chloride (101 mg, 0.45 mmol) at a temperature of 0° C. After stirring at rt for 1 h, when analytical HPLC indicated complete conversion of the starting materials, all volatiles were removed in vacuo. The residue was re-dissolved in DMSO (6 mL) and heated to 140° C. for 30 minutes in a microwave oven (CEM Discover). Then, the reaction mixture was diluted with a few mL of methanol and subjected to preparative HPLC. The title compound was obtained in pure form (110 mg, 59%): 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 2H), 7.37 (d, 2H), 7.12 (d, 2H), 7.05 (d, 2H), 6.71 (s, 1H), 5.40 (s, 2H), 2.31 (s, 3H), 2.23 (s, 3H); ES-MS m/z 415 (MH)+; HPLC RT (Method K) 1.58 min.
Reaction SMILES: [F:1][C:2]1[C:11]([C:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:30][Mg]Br>C1COCC1>[F:1][C:2]1[C:11]([C:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)([OH:13])[CH3:30])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cn1cc(-c2ccc3ncc(C(=O)c4c(F)cc5ncccc5c4F)n3n2)cn1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3ncc(C(C)(O)c4c(F)cc5ncccc5c4F)n3n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(5,7-Difluoro-quinolin-6-yl)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanone (Stage 191.2, 666 mg, 1.706 mmol) was dissolved in THF (13 mL) and the mixture was cooled down to 0° C. with an ice bath. A solution of methylmagnesium bromide (1.4 M, 3.05 mL) was added slowly. The RM was stirred at 0° C. for 15 min then it was warmed up to rt. After 4 h stirring, more methylmagnesium bromide (1.4 M, 1.0 mL) was added and after 1 h stirring, the reaction was quenched with a few mL of water. The RM was mixed with 10% Na2CO3 solution and the aqueous layer was extracted with EtOAc. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was triturated with Et2O and the yellow solid was filtered off to give the title compound (tR 1.28 min (conditions 12), MH+=407).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15].C(N(CC)CC)C.[CH3:26][C:27]([CH3:35])([O:29][C:30]([NH:32][NH:33][CH3:34])=[O:31])[CH3:28]>O1CCCC1.CN(C1C=CN=CC=1)C>[CH3:26][C:27]([CH3:35])([O:29][C:30]([NH:32][N:33]([CH3:34])[C:14](=[O:15])[C:13]([O:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11])([CH3:18])[CH3:17])=[O:31])[CH3:28]
Reactant: CNNC(=O)OC(C)(C)C
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(NC(=O)OC(C)(C)C)C(=O)C(C)(C)ON1C(=O)c2ccccc2C1=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A solution of 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-2-methylpropanoyl chloride (5.3 g, 22 mmole) in 40 ml of dry tetrahydrofuran was treated with triethylamine (4.10 ml, 30 mmole) and 4-(N,N-dimethylamino)pyridine (5 mg). A solution of 1-[(1,1-dimethylethoxy)carbonyl]-2-methylhydrazine (2.90 g, 20 mmole) in 20 ml of tetrahydrofuran was added dropwise at 0° C. and the resulting mixture was stirred at 20° C. overnight. The solvent was evaporated and the solid residue was partitioned between ethyl acetate and water. The organic phase was washed successively with 0.5N hydrochloric acid, 5% sodium bicarbonate, and water. Drying over magnesium sulfate and evaporation gave 6.6 g of the title compound as a colorless solid, m.p. 140°-145° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:33])[CH:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C@@H:17]([O:30][CH3:31])[C:16]1=[O:32])[C:12](=[CH2:14])[CH3:13]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:33])[C:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C@@H:17]([O:30][CH3:31])[C:16]1=[O:32])=[C:12]([CH3:14])[CH3:13]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)[C@H](OC)[C@H]1SSc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC)[C@H]1SSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
0.1 ml of triethylamine is added to a solution of 432 mg of 2- [(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylenebutyric acid methyl ester in 25 ml of methylene chloride and the mixture is stirred at room temperature for 100 minutes. The reaction mixture is diluted with methylene chloride, washed twice with aqueous citric acid solution and water, dried over sodiun sulphate and freed of solvent in vacuo. The residue is purified by chromatography over silica gel with toluene/ethyl acetate (9:1 and 4:1) and yields the title compound in the form of an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH-].[Na+].[O:10]1[CH2:12][CH2:11]1>O>[NH2:1][CH:2]([CH2:3][S:4][CH2:12][CH2:11][OH:10])[C:5]([OH:7])=[O:6]
Reactant: C1CO1
Reactant: N[C@@H](CS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(CSCCO)C(=O)O
Temperature: 10 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
36.3 g of L-cysteine was dissolved in 300 ml of water. 24 ml 1 mol/L of NaOH solution was added into above solution and cooled by ice-water bath in order to adjust pH value to 7. And then at 0° C. 30 mL of epoxy ethane was added dropwise to the above solution and then mixture was cooled to 10° C. After the mixture was stirred for 1.0 hour, it was warmed to room temperature and then stirred for 1.5 hours. The resultant mixture was extracted with ethyl ether three times (60 ml, 45 ml, 45 ml) to remove the residual epoxy ethane. Water layer was removed on a rot-vap to obtain a buff solid. The solid was recrystallized in 95% ethanol to obtain a white lamellar crystal (33.9 g). Yield 69.4%□mp 195-196° C. (Dec.).
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:2]1.[F:10][C:11]([F:33])([F:32])[O:12][C:13]([F:31])([O:18][C:19]([F:30])([O:24][C:25]([F:29])([F:28])[CH2:26][OH:27])[C:20]([F:23])([F:22])[F:21])[C:14]([F:17])([F:16])[F:15].ClC[C@H](O)CCCCC=C.[OH-].[K+]>O.COCCOC>[F:10][C:11]([F:32])([F:33])[O:12][C:13]([F:31])([O:18][C:19]([F:30])([O:24][C:25]([F:29])([F:28])[CH2:26][O:27][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([OH:1])[CH3:2])=[CH2:9])[C:20]([F:22])([F:21])[F:23])[C:14]([F:17])([F:16])[F:15]
Reactant: C=CCCCC[C@@H]1CO1
Reactant: OCC(F)(F)OC(F)(OC(F)(OC(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: C=CCCCC[C@@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: C=C(CCCCC(C)O)OCC(F)(F)OC(F)(OC(F)(OC(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 45 °C
Reaction time: 1 h

Procedure:
This chlorohydrin was converted in situ to (R)-1,2-epoxy-7-octene and reacted with 2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol using the following procedure: (R)-8-chloro-7-hydroxy-oct-1-ene (100 g, 0.61 mol), aqueous potassium hydroxide (45 mL of 45 wt.%), 2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol (291 g, 0.733 mol), Adogen™ 464 (60 g), and 1,2-dimethoxyethane (60 mL) were added to a one liter flask fitted with a mechanical stirrer, an addition funnel, a reflux condenser, and a thermometer. The resulting solution was stirred for one hour at 45° C. and then warmed to 60° C., at which time aqueous potassium hydroxide (70 mL of 45 wt %) was added dropwise. This solution was heated for 2 hours at 60° C. and then at 70° C. for 8 hours. Water (300 mL) was added, and the resulting organic phase was separated and washed with 7 weight % HCl (300 mL). The organic phase was again separated and was concentrated under reduced pressure (25 torr). The resulting crude product was then purified by silica gel chromatography using toluene as eluent to give 268 g of (R)-8-(2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-7-hydroxyoct-1-ene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C:14](=[O:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[N:21]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C:3]=12.Cl>CO.O.[OH-].[Pd+2].[OH-]>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:14]([OH:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH:11]=[N:12][CH:13]=2)=[CH:6][N:5]=[C:4]2[N:21]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:37])[CH3:38])[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[C:3]=12
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cncc(C(=O)C(=O)N(C)C)c3)c(Cl)c12
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(Cl)c12
Temperature: 23 °C
Reaction time: 15 h
Yield: 108 %

Procedure:
2-{5-[4-Chloro-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-2-oxo-acetamide (57 mg, 0.129 mmol) was dissolved in methanol (7 mL), and hydrochloric acid solution was added (774 μL, 0.774 mmol, 1.0 M solution in water). The flask was purged with nitrogen gas before and after addition of Palladium hydroxide (1.8 mg, 0.013 mmol, 20 weight % on carbon, wet) The flask was purged with hydrogen gas and allowed to stir for 15 hours at 23° C. under 1 atm of hydrogen gas. The reaction mixture was filtered through Celite® and concentrated to afford 2-{5-[4-Chloro-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (79 mg, quantitative yield) as an orange-brown oil. MS [MH+] m/z: 573.0
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:23]>>[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH:23][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-methyl-L-valine methyl ester hydrochloride (1:1) (CAN 63038-27-7) as starting materials, MS (ESI) 361.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19](Cl)(Cl)=[O:20].[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1>>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19]([N:23]3[CH2:28][CH2:27][S:26][CH2:25][CH2:24]3)=[O:20])[S:3][C:4]=2[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=1
Reactant: C1CSCCN1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)Cl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCSCC3)nc12
Yield: 73 %

Procedure:
Conversion of 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.377 mg) with phosgene (20% in toluene, 0.2 ml) and thiomorpholine (0.045 ml, 0.47 mmol) using the general procedure D affords the product as white solid in 73% yield. MS: m/e=395 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[C:16]([CH3:17])=[CH:15][N:14]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:13]=2)[C:9]2[C:4](=[C:5]([OH:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:26][C:27]1[C:28]([CH2:34][N:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]2=[O:45])=[N:29][CH:30]=[CH:31][C:32]=1[CH3:33].ClC1C=NC=C(Cl)C=1COC1C=CC=C2C=1N=C(C)C=C2N1C=CN=C1>>[CH3:33][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:34][N:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]2=[O:45])[C:27]=1[CH2:26][O:24][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]2[C:12]1[C:16]([CH3:17])=[CH:15][N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=1
Reactant: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1CCl
Reactant: Cc1cc(-c2nn(C3CCCCO3)cc2C)c2cccc(O)c2n1
Agent: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)cncc3Cl)c2n1
Product: Cc1cc(-c2nn(C3CCCCO3)cc2C)c2cccc(OCc3c(C)ccnc3Cn3cccc(C(F)(F)F)c3=O)c2n1

Procedure:
2-Methyl-4-[4-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-quinolin-8-ol and 1-(3-chloromethyl-4-methyl-pyridin-2-ylmethyl)-3-trifluoromethyl-1H-pyridin-2-one were coupled according to the procedure described for the synthesis of 8-(3,5-dichloro-pyridin-4-ylmethoxy)-4-imidazol-1-yl-2-methyl-quinoline to give the title compound which was used in the next step without purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=4)=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc[nH]1
Reactant: Cc1ccc(C(=O)Nc2ccc(N3CCNCC3)cc2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)Nc2ccc(N3CCN(Cc4ccc[nH]4)CC3)cc2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
To a solution of 5-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (329 mg) in 1,2-dichloroethane (20 mL) was added 1H-pyrrole-2-carboxaldehyde (86 mg) and acetic acid (54 mg). The solution was cooled at 0° C. and sodium triacetoxy borohydride (238 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH (95/5) and the oily residue obtained was crystallized from diisopropyl ether to give the title compound (210 mg) as white crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]1[C:20](=[O:21])[CH2:19][NH:18][C:17](=[O:22])[CH:16]=[C:11]12)=[CH2:5])C.C1C(=O)N([Br:30])C(=O)C1.CCOC(C)=O>C1COCC1.O.[Cl-].[Na+].O>[Br:30][CH2:3][C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]1[C:20](=[O:21])[CH2:19][NH:18][C:17](=[O:22])[CH:16]=[C:11]12)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C=C2c3cccc(C(=O)CBr)c3CCN2C(=O)CN1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
111-2. A solution of 9-(1-ethoxyvinyl)-3,4,7,8-tetrahydro -[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (1.2 g, 4.02 mmol) in a mixture of THF/H2O (3:1, 40 mL) was treated with NBS (716 mg, 4.02 mmol) and the mixture was stirred at 0° C. for 10 min. The mixture was partioned between AcOEt and brine and the org. phase was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (880 mg) that was used as it is in the next step. UPLC-MS: MS 349.0 (M+H+); UPLC rt 0.69 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:17]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[S:21])[CH3:18]>CC(C)=O>[ClH:1].[CH2:15]([O:14][C:12]([C:11]1[C:2]([S:21][C:20]([NH:22][CH2:23][CH3:24])=[N:19][CH2:17][CH3:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:13])[CH3:16]
Reactant: CCNC(=S)NCC
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Solvent: CC(C)=O
Product: CCN=C(NCC)Sc1nc2ccccc2nc1C(=O)OCC
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-3-quinoxalinecarboxylic acid, ethyl ester (7.100 g., 0.03 mole) and 3.967 g., (0.03 mole) of 1,3-diethylthiourea were dissolved in 150 ml. of acetone and boiled in an open flask for 1 hour. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to a volume of 50 ml. After standing at room temperature overnight, the mixture was filtered and the solid residue washed with acetone and ether. Recrystallized from a mixture of methanol, acetone and ether it gave 7.182 g. product, m.p. 144.5°-145° C.