Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][N:27]=1)[C:23]#[N:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:24]=2)[CH:25]=[CH:26][N:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccnc(OCc2ccccc2)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccnc(OCc3ccccc3)c2)sc2ccccc12
Yield: 32.1 %

Procedure:
Methyl thiosalicylate (0.59 g, 3.5 mmol) and 2-(benzyloxy)isonicotinonitrile (0.37 g, 1.8 mmol) were dissolved in toluene (2.0 ml). Triethylamine (0.54 ml, 3.9 mmol) was added thereto and the mixture was refluxed for 6 hrs. The reaction mixture was subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.20 g, 32%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1>C(#N)C>[C:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: c1cn[nH]c1
Solvent: CC#N
Product: c1ccc(-n2cccn2)cc1

Procedure:
Operating protocol A (82° C., 24 hours) was followed using 120.8 mg of Chxn-Thio-Al (0.4 mmoles), 211 μl of bromobenzene (2 mmoles), 204 mg of pyrazole (3 mmoles) and 1.2 ml of acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1cnc(Br)cn1
Product: Nc1cnc(-c2ccc(F)cc2)cn1

Procedure:
Conducting the operations similar to those of Production Example 14 using 2-amino-5-bromopyrazine (2.7 g) and 4-fluorophenylboronic acid (3.4 g), 2-amino-5-(4-fluorophenyl)pyrazine was obtained as white solid.
Reaction SMILES: [Br:1][CH:2]1[CH:10](O)[CH2:9][C:8]2[C:7](=[O:12])[N:6]([C:13]3[CH:18]=[C:17]([O:19][CH2:20][C:21]#[CH:22])[C:16]([Cl:23])=[CH:15][C:14]=3[F:24])[C:5](=[O:25])[C:4]=2[CH2:3]1.CCN(S(F)(F)[F:32])CC.O>ClCCl>[Br:1][CH:2]1[CH:10]([F:32])[CH2:9][C:8]2[C:7](=[O:12])[N:6]([C:13]3[CH:18]=[C:17]([O:19][CH2:20][C:21]#[CH:22])[C:16]([Cl:23])=[CH:15][C:14]=3[F:24])[C:5](=[O:25])[C:4]=2[CH2:3]1
Reactant: C#CCOc1cc(N2C(=O)C3=C(CC(Br)C(O)C3)C2=O)c(F)cc1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C#CCOc1cc(N2C(=O)C3=C(CC(Br)C(F)C3)C2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 995 mg (2.32 mmol) of 5-bromo-2-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4,5,6,7-tetrahydro-6-hydroxy-1H-isoindole-1,3(2H)-dione in 15 mL of dichloromethane was added 430 μL of DAST at 0° C. The mixture was stirred at the same temperature for 1 h. The reaction mixture was then poured into 50 mL of cold water. The aqueous layer was extracted with three 50 mL portions of ethyl acetate. The organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel eluting with a 1:4 v:v mixture of ethyl acetate and n-hexane to give 626 mg of the title product of Example 4, a compound of the invention, as a whim solid melting at 135°-136.5° C.
Reaction SMILES: C([N:3]([CH2:13][CH3:14])[C:4](=O)[C:5]1[C:6](=CC=CC=1)O)C.Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCCCC1.[OH-].[NH4+].CCCCCCCCCCCC>[Cu]I.O.C(OCC)(=O)C.CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH2:4][CH2:5][CH2:6][CH2:14][CH2:13]2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CCN(CC)C(=O)c1ccccc1O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCCCCCCCC
Product: Clc1ccc(N2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
CuI (10 mg, 0.05 mmol), N,N-diethylsalicylamide (39 mg, 0.20 mmol), 4-bromochlorobenzene (191 mg, 1.0 mmol) and K3PO4 (425 mg, 2.0 mmol) were put into a screw-capped test tube with a Teflon-lined septum. The tube was then evacuated and backfilled with argon (3 cycles). Piperidine (148 μL, 1.5 mmol) and DMF (0.5 mL) were added by syringes. The reaction mixture was stirred at 90° C. for 20 h. The reaction mixture was allowed to reach room temperature. Ethyl acetate (˜2 mL), water (˜10 mL), ammonium hydroxide (˜0.5 mL) and dodecane (227 μL) were added. The organic phase was analyzed by GC and GC-MS. A 75% conversion of 4-bromochlorobenzene and 29% calibrated GC yield was obtained.
Reaction SMILES: [Cl:1]Cl.[Si:3]([O:10][CH:11]([CH:13]1[CH:16](SC)[N:15]([C:19](=[C:33]2[S:37][C:36](=[O:38])[CH2:35][S:34]2)[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:14]1=[O:39])[CH3:12])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Si:3]([O:10][CH:11]([CH:13]1[CH:16]([Cl:1])[N:15]([C:19](=[C:33]2[S:37][C:36](=[O:38])[CH2:35][S:34]2)[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:14]1=[O:39])[CH3:12])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: ClCl
Reactant: CSC1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C1SCC(=O)S1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C2SCC(=O)S2)C1Cl
Reaction time: 0.5 h

Procedure:
A solution of an equimolar amount of chlorine in carbon tetrachloride was added to a solution of p-nitrobenzyl 2-[3-(1-t-butyldimethylsilyloxyethyl)-4-methylthio-2-azetidinon-1-yl]-2-(4-oxo-1,3-dithiolan-2-ylidene)acetate (134 mg) in methylene chloride (3 ml), with ice cooling. The solution was stirred at that temperature for 30 minutes and then solvent was distilled off to afford the desired product quantitatively.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[S:20][C:19]([CH3:21])=[N:18][C:17]=2[C:22](=[O:31])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:30][C:26]1[CH:25]=[C:24]([NH:23][C:22]([C:17]2[N:18]=[C:19]([CH3:21])[S:20][C:16]=2[NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][NH2:7])[CH:10]=2)=[O:31])[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(Nc2cccc(CNC(=O)OC(C)(C)C)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(Nc2cccc(CN)c2)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.6 %

Procedure:
A solution of {3-[4-(3-chloro-phenylcarbamoyl)-2-methyl-thiazol-5-ylamino]-benzyl}-carbamic acid tert-butyl ester (0.02 g, 0.04 mmol) in dichloromethane (0.50 ml) was treated with trifluoroacetic acid (0.10 ml) and stirred at room temperature for 5 min. The reaction mixture was diluted with dichloromethane and quenched with saturated sodium hydrogenocarbonate. The organic layer is separated, dried over sodium sulphate and evaporated, to yield the title compound (0.015 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][PH:8](=[O:14])[O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][C:3]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([C:37]([F:40])([F:39])[F:38])=[CH:22][N:21]=1>>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[NH:1][C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29](=[O:30])[NH:31][CH3:32])[C:23]([C:37]([F:40])([F:38])[F:39])=[CH:22][N:21]=1)[CH2:6][CH2:7][PH:8](=[O:14])[O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: COCCO[PH](=O)CCc1ccc(N)c(OC)c1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CC[PH](=O)OCCOC)cc2OC)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure for Example 102 using 2-methoxyethyl (4-amino-3-methoxybenzyl)methylphosphinate and 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A). 1H NMR (DMSO-d6, 400 MHz): δ=1.33 (d, J=14.15 Hz, 3 H), 2.76 (d, J=4.55 Hz, 3 H), 3.21 (d, J=17.94 Hz, 2 H), 3.26 (s, 3 H), 3.48-3.52 (m, 2 H), 3.77 (s, 3 H), 4.03 (ddt, J=6.19, 4.48, 3.13, 3.13 Hz, 2 H), 6.81-6.87 (m, 1 H), 7.02 (s, 1 H), 7.07 (t, J=7.45 Hz, 1 H), 7.38 (t, J=8.08 Hz, 1 H), 7.51 (d, J=7.33 Hz, 1 H), 7.64-7.70 (m, 1 H), 8.37 (s, 1 H), 8.72 (d, J=4.29 Hz, 1 H), 8.79 (br. s., 1 H), 11.43 (s, 1 H). MS (ES+): m/z 568.15 [MH+] (TOF, polar).
Reaction SMILES: Br.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:23])[CH2:11][N:12]2[CH2:15][CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)=[CH:6][CH:5]=1)#[N:3].[BH4-].[Na+]>CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:23])[CH2:11][N:12]2[CH2:13][CH:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:15]2)=[CH:8][CH:9]=1)#[N:3]
Reactant: CC(C)(C)OC(=O)C1CN(CC(=O)c2ccc(C#N)cc2)C1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C1CN(CC(O)c2ccc(C#N)cc2)C1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a mixture of tert-butyl 1-(2-(4-cyanophenyl)-2-oxoethyl)azetidine-3-carboxylate, hydrobromide (170 mg, 0.446 mmol) in MeOH (5 mL) was added sodium borohydride (25 mg, 0.661 mmol). The reaction mixture was stirred for 1 hour. The reaction was quenched with water. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated to yield 100 mg of tert-butyl 1-(2-(4-cyanophenyl)-2-hydroxyethyl)azetidine-3-carboxylate. MS (m+1)=303. HPLC Peak RT=0.90 minutes (Analytical Method B).
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([S:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:18])[CH3:17])[CH3:16]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: SC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC1CCCCC1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a solution of 2.5 g (21.5 mmol) of cyclohexyl thiol in ethanol (75 mL) were added 1.2 g (21.5 mmol) of KOH pellets, followed by 4.2 g (21.5 mmol) of ethyl α-bromoisobutyrate. The reaction was heated to reflux for 18 h and then cooled to room temperature. The solid (KBr) was separated by filtration and rinsed with ethanol (20 mL). The filtrate was concentrated under reduced pressure and the residue dissolved in DCM (50 mL). The organic layer was washed with water (2×20 mL). The aqueous washes were back-extracted with DCM (10 mL). The combined organics were washed with brine, dried over Na2SO4. Filtration and concentration under reduced pressure afforded 4.15 g of 2-cyclohexylsulfanyl-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH3:10][C:11]1([CH3:20])[NH:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:13](=[O:14])[CH2:12]1.C([Li])CCC.Cl>CCCCCC.CCOCC>[OH:8][CH:7]([CH:15]1[C:13](=[O:14])[CH2:12][C:11]([CH3:20])([CH3:10])[NH:17][C:16]1([CH3:19])[CH3:18])[C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc(C(O)C2C(=O)CC(C)(C)NC2(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 12g. of p-tolualdehyde, 15.5 g. of triacetone amine and 50 ml. of anhydrous ether was added dropwise 42.6g. of butyl lithium (as a 15% solution in n-hexane) at -50° to -60°C. under a nitrogen gas stream. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was poured into 5% dilute hydrochloric acid with ice-cooling. The aqueous layer was separated and saturated with potassium carbonate. Then, the ether layer was separated and concentrated to yield crude crystalline mass. The mass was recrystallized from benzene to give the desired product as white crystals having a decomposition point of 160° - 161°C.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.OCC1C=C2C(=CC=1)C(NC(=O)C1C=CC=CC=1)=NC=C2>C(O)C.[Pd]>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCOc3ccccc3C2)cc1
Agent: [Pd]
Agent: O=C(Nc1nccc2cc(CO)ccc12)c1ccccc1
Solvent: CCO
Product: c1ccc2c(c1)CNCCO2
Reaction time: 5 h

Procedure:
10.2 g of 4-benzyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine were dissolved in 100 mL of ethanol and hydrogenated for 5 hours at room temperature using 1.2 g of palladium (10% on carbon) as catalyst. Filtration followed by removal of the solvent in vacuo gave 6. 1g of 2,3,4,5-tetrahydro-benzo[f][1,4j]oxazepine as an oil. EI-MS: 149 (M+).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH3:36][S:33]([C:30]1[CH:29]=[CH:28][C:27]([C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:32][CH:31]=1)(=[O:34])=[O:35]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3[nH]2)cc1
Yield: 7.9 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.45 g, 8.6 mmol) in ethanol (8 mL), tetrahydrofuran (8 mL) and an aqueous sodium hydroxide solution (10%, 3 mL) was heated at 50° C. for 2 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (260 mg, 78%) which was used in the next step without further purification: LC/MS m/e calcd for C21H22N2O3S [M+H]+ 383.49, observed 383.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2cccc(C)c2n1
Product: Cc1cccc2nn(CCC#Cc3ccccn3)nc12

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (66 mg, 0.42 mmol) and 2-but-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole (70 mg, 0.38 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 50 mg (0.19 mmol, 50%) of 4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]thiazole as a yellow semi-solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O>[Pd].CO.C(Cl)Cl>[CH3:16][C:14]1([CH3:17])[C:13]([CH3:18])([CH3:19])[O:12][B:11]([C:9]2[CH:10]=[C:4]([NH2:1])[C:5]([NH2:6])=[CH:7][CH:8]=2)[O:15]1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(N)c(N)c2)OC1(C)C
Yield: 100.4 %

Procedure:
2-Nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.00 g) was stirred under hydrogen balloon with palladium on carbon (10%, 150 mg) in a mixture of MeOH and DCM (1:1, 10 ml) at room temperature overnight. The reaction mixture was then filtered through Celite®, volatiles removed in vacuo, and the residue purified by flash chromatography to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (890 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#N.C(O[C:15]([C:17]1[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)=[O:16])C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:10])[C:15]([C:17]1[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1)([OH:16])[C:23]([F:26])([F:25])[F:24]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc(C(F)(F)F)nc1
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccc(C(F)(F)F)nc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 2, steps 1-4, from 2,4-dichlorobenzeneacetonitrile [CAS Reg. No. 6306-60-1] and 6-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester [CAS Reg. No. 597532-36-0]. MS (m/e)=418.1 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:18]([NH2:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOCC.[Cu](I)I>[CH:18]([NH:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8])([CH3:20])[CH3:19]
Reactant: O=Cc1cncc(Br)c1
Reactant: CC(C)N
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Nc1cncc(C=O)c1
Temperature: 90 °C

Procedure:
To 5-bromonicotinaldehyde (1.5 gm, 8.06 mmol) in DMF (5 ml), N,N-diethylsalicylidiamide (311 mg, 1.61 mmol), copper iodide (77 mg, 0.403 mmol), potassium phosphate (3.42 gm, 16.12 mmol) and isopropylamine (715 mg, 1.21 mmol) were added and the reaction mixture was heated overnight at 90° C. Then reaction mixture was diluted with ether and filtered. Ether layer was washed with water, brine and dried. Crude residue was column chromatographed (40% ethylacetate/60% Hexanes) to yield 5-(isopropylamino)nicotinaldehyde.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:21]1(=O)[CH2:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:21]1([N:16]2[CH2:17][CH2:18][C:19]3=[CH:20][N:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[N:12]=[C:13]3[CH2:14][CH2:15]2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCC1
Reactant: CS(=O)(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[4-(methylsulfonyl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 38) (4 mg, 0.014 mmol) in dichloromethane (2 ml) was added cyclobutanone (7 mg, 0.096 mmol) and acetic acid (1 drop). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (20 mg, 0.096 mmol) was added and stirring continued overnight. The resulting reaction mixture was diluted with methanol and purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E28). MS (ES+) m/e 346 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH:11]([O:12]C(=O)C)[CH:10]([O:16]C(=O)C)[CH:9]([O:20]C(=O)C)[CH:8]([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:7]1)(=O)C.C[O-].[Na+]>CO>[OH:4][CH2:5][CH:6]1[CH:11]([OH:12])[CH:10]([OH:16])[CH:9]([OH:20])[CH:8]([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[CH:30]=[CH:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[O:7]1
Reactant: COc1ccc(C=Cc2sccc2OC2OC(COC(C)=O)C(OC(C)=O)C(OC(C)=O)C2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C=Cc2sccc2OC2OC(CO)C(O)C(O)C2O)cc1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
150 mg of 3,4,5-triacetoxy-6-{2-[2-(4-methoxy-phenyl)-vinyl]-thiophen-3-yloxy}-tetrahydropyran-2-ylmethyl acetate were suspended in 10 ml of dry methanol. 1.0 ml of a methanolic NaOMe solution (10 mg/ml) was added. The solution was stirred at 22° C. for 18 h. Amberlyst 15 (H+ form) was added and the solution was diluted with 10 ml of MeOH and filtered, and the residue was washed with 20 ml of methanol. The organic phase was concentrated, and the residue was purified by chromatography on silica gel. 100 mg of the product with the molecular weight: 394.45 (C19H22O7S), MS (ESI): 417 (M+Na+); 412 (M+NH4+) were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][N:26]=[C:27]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]=O)=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])/[CH:22]=[CH:36]/[C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[C:27](=[N:26][O:25][CH3:24])[CH2:28][CH2:29]4)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON=C1CCc2cc(C=O)ccc21
Reactant: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3)ccc21
Yield: 75 %

Procedure:
The title compound (0.9 g, 75%) was prepared from the product of Step 1 and the product of Example 1 Step 2 using the method of Example 2 Step 1. 1H NMR (CDCl3) 8.03 (2H, d, J 8.8 Hz), 7.80 (1H, d, J 15.6 Hz), 7.72 (1H, d, J 8.4 Hz), 7.56 (3H, m), 6.98 (2H, d J 8.8 Hz), 4.6 (1H, m), 4.01 (3H, s), 3.70 (2H, m), 3.35 (2H, m), 3.07 (2H, m), 2.92 (2H, m), 1.95 (2H, m), 1.80 (2H,m), 1.47 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13](S(C)(=O)=O)[N:14]=1.[NH2:30][C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33]([NH:40][CH2:41][CH2:42][NH2:43])[N:32]=1>>[NH2:30][C:31]1[N:32]=[C:33]([NH:40][CH2:41][CH2:42][NH:43][C:13]2[N:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=3[N:12]=2)[CH:34]=[CH:35][C:36]=1[N+:37]([O-:39])=[O:38]
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(-c3ccc(Cl)cc3Cl)c2C1

Procedure:
Reaction of tert-butyl 4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate and 2-amino-3-nitro-6-(2-aminoethylamino)pyridine gave tert-butyl 2-({2-[(6-amino-5-nitro(2-pyridyl))amino]-ethyl}amino)-4-(2,4-dichlorophenyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10](Cl)([F:12])[F:11])=[N:6][C:5]=1[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[H][H]>CO.C(N(CC)CC)C.[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:11])[F:12])=[N:6][C:5]=1[CH2:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: [H][H]
Reactant: COCCCc1nc(C(F)(F)Cl)ccc1C(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COCCCc1nc(C(F)F)ccc1C(=O)OC
Yield: 113.4 %

Procedure:
A solution of 194 g of 6-(Chloro-difluoro-methyl)-2-(3-methoxy-propyl)-nicotinic acid methyl ester (prepared according to WO 04/078729) in methanol (ca. 2 liter) and triethylamine (100 ml) is hydrogenated at 1 Atm hydrogen pressure in the presence of 2 g of 5% palladium supported on carbon. After completion of the reduction the reaction mixture is filtered through hyflo, and the filtrate diluted with water and the water/methanol mixture then extracted with ethyl acetate. The combined ethyl acetate extracts are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated in vacuo to give 194.2 g 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid methyl ester as a pale coloured oil.