Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9]O.P(Br)(Br)[Br:14].O>C(OCC)C>[Br:14][CH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:11])[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1cnccc1C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: FC(F)(F)c1ccncc1CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
A solution of 0.6 g (3.4. mmoles) of (4-trifluoromethylpyridin-3-yl)-methanol dissolved in 50 ml of diethyl ether was cooed to −30° C. Thereto was added 1.4 g (5.2 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.61 g (yield: 75.3%) of 3-bromomethyl-4-trifluoromethylpyridine as a yellow oily substance.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:54]=[CH:53][C:20]([CH2:21][O:22][C:23]([NH:25][C@@H:26]([CH2:46][S:47][S:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:35]([OH:37])=[O:36])=[O:28])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][C:23]([NH:25][C@@H:26]([CH2:46][S:47][S:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][C@H:34]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C:35]([O:37][CH2:2][C:1]#[N:4])=[O:36])=[O:28])=[O:24])=[CH:53][CH:54]=1)=[N+:15]=[N-:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reaction time: 15.5 h
Yield: 82.9 %

Procedure:
N,N-Diisopropylethylamine (34 μL, 0.197 mmol) and subsequently bromoacetonitrile (38 μL, 0.539 mmol) were added to a solution of (S)-6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk23) (110 mg, 0.180 mmol) in acetonitrile (0.3 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 15.5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoate (97.3 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:18]S(C(C)(C)C)=O)([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1.Cl.CCCCCC>C(Cl)Cl.O1CCOCC1>[ClH:1].[NH2:18][C:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6]2[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[CH:14][CH:13]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NS(=O)C(C)(C)C)c1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(N)c1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
Deprotection/protection: To a solution of N-(1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}-1-methylethyl)-2-methylpropane-2-sulfinamide (107 mg) in DCM (5 ml) was added dropwise a solution of hydrogen chloride in dioxane (4 M, 130 ul) at room temperature. The reaction mixture was stirred for 30 min. Hexane was added to the suspension and the solid was filtered to give N-[4-(1-amino-1-methylethyl)phenyl]-6-chloro-3-nitropyridin-2-amine hydrochloride. To a suspension of N-[4-(1-amino-1-methylethyl)phenyl]-6-chloro-3-nitropyridin-2-amine hydrochloride in THF (3 ml) chilled to 0° C. was added saturated sodium bicarbonate solution (6 ml) and followed by a solution of di-tert-butyl dicarbonate (167 mg) in THF (3 ml) dropwise. After being stirred at room temperature over night, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (3-30% ethyl acetate in hexanes) gave the product (99 mg, 2 steps 93%).
Reaction SMILES: [OH:1][CH:2]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[C:3]#[CH:4].C([Mg]Cl)#C.S1C=CC=C1C=O.Br[C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1/[C:24](=[CH:32]/[C:33]1[NH:34][CH:35]=[CH:36][C:37]=1[O:38][CH3:39])/[C:25](=[O:31])[NH:26]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[C:3]#[C:4][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1/[C:24](=[CH:32]/[C:33]1[NH:34][CH:35]=[CH:36][C:37]=1[O:38][CH3:39])/[C:25](=[O:31])[NH:26]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccs3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(2-thiophenyl)-1-propyne (102 mg, 0.74 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 2-thiophenecarboxaldehyde (Aldrich) according to Method A above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (126 mg, 0.39 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (35 mg) (Aldrich) and CuI (17 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(2-thiophenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 105 mg, 71%).
Reaction SMILES: COC1C=CC([O:7][C:8]2[CH:9]=[C:10]([C:14]3[N:19]4[N:20]=[C:21]([NH:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]6[CH2:37][CH2:36][CH2:35][CH2:34]6)=[CH:26][CH:25]=5)[N:22]=[C:18]4[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[N:33]1([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:21]3[N:22]=[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([C:10]5[CH:9]=[C:8]([OH:7])[CH:13]=[CH:12][CH:11]=5)[N:19]4[N:20]=3)=[CH:25][CH:26]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COc1ccc(Oc2cccc(-c3cccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 2 h

Procedure:
{5-[3-(4-Methoxy-phenoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (2.90 g, 5.41 mmol) was dissolved in dichloromethane (10 ml). Trifluoroacetic acid (10 ml) was added and the reaction mixture stirred for 2 hours. Neutralisation was performed by adding saturated aqueous sodium hydrogencarbonate. The aqueous was extracted twice with dichloromethane, then the combined organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired compound. Yield 2.01 g, 89%. 50 mg was purified by preparatory HPLC.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([C:33]3[C:28]([F:27])=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Reactant: OB(O)c1cccnc1F
Product: Fc1ncccc1-c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Yield: 75 %

Procedure:
The title compound was synthesized as described for Intermediate example I-4 in 75% yield, starting from (2R)-N,N-dibenzyl-8-bromo-1,2,3,4-tetrahydronaphthalen-2-amine and 2-fluoropyridine-3-boronic acid; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29-8.34 (m, 1 H), 7.78-7.89 (m, 1 H), 7.41-7.52 (m, 1 H), 7.21-7.30 (m, 8 H), 7.11-7.21 (m, 4 H), 7.01 (dd, 1 H), 3.51-3.61 (m, 4 H), 2.89-3.00 (m, 1 H), 2.83 (br. s., 1 H), 2.59-2.78 (m, 2 H), 2.34-2.46 (m, 1 H), 2.00-2.12 (m, 1 H), 1.64-1.79 (m, 1 H); MS (ESI) m/z 424[M+H+].
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([O-:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:30])[CH2:9]1)=[O:6])[CH3:4].[Na+].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.O.C(OCC)C>CN(C)C=O>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][O:26][C:25](=[O:27])[CH2:24][CH:23]([OH:28])[CH2:22][CH:21]([OH:29])[CH2:20][CH2:19][CH:14]1[CH:13]2[C:12](=[CH:11][CH:10]([OH:30])[CH2:9][CH:8]2[O:7][C:5](=[O:6])[CH:3]([CH3:4])[CH2:2][CH3:1])[CH:17]=[CH:16][CH:15]1[CH3:18]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Reactant: BrCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(C)C(=O)OC1CC(O)C=C2C=CC(C)C(CCC(O)CC(O)CC(=O)OCCCCBr)C21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of pravastatin sodium (9.25 g, 21 mmol) in N,N-dimethylformamide (70 ml) a mixture of 1,4-dibromobutane (3.68 ml, 31 mmol) in N,N-dimethylformamide (30 ml) was added dropwise. The reaction mixture was stirred at room temperature for 24 h. The solution was then treated with water and diethyl ether, the organic layers were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, with n-hexane/ethyl acetate 3/7 as eluent. The title compound was obtained as a white powder (7.8 g).
Reaction SMILES: [CH:1]1([O:6]/[N:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)/[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:1]1([O:6]/[N:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)/[C:9]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Cn1ccc(N)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ccc(NC(=O)/C(=N/OC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
(E)-Cyclopentyloxyimino-(3,4-dichloro-phenyl)-acetic acid (100 mg, 0.33 mmol) was dissolved in methylene chloride (1.6 mL). N,N-diisopropylethylamine (173 μL, 0.99 mmol) and 1-methyl-1H-pyrazol-3-ylamine (32 μL, 0.33 mmol) were added and the reaction mixture was cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (126 mg, 0.33 mmol) was added and the reaction mixture was allowed to warm to 25° C. After stirring 16 h, the reaction mixture was diluted with chloroform (2 mL) and washed with saturated aqueous sodium bicarbonate solution (1.5 mL). The aqueous phase was extracted with chloroform (1.5 mL) and the combined organic phases were filtered through sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-cyclopentyloxyimino-2-(3,4-dichloro-phenyl)-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (103 mg, 82%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C17H18Cl2N4O2 [M+] 380.08, found 381 [M+H+]; H1-NMR (400 MHz, CDCl3) □ ppm 1.64 (m, 4 H, 2×CH2), 1.85 (m, 4 H, 2×CH2), 3.83 (s, 3 H, NCH3), 4.84 (m, 1 H, OCH), 6.70 (d, J=2.3 Hz, 1 H, Ar), 7.26 (d, J=2.3 Hz, 1 H, Ar), 7.33 (dd, Jo=8.3, Jm=1.9 Hz, 1 H, Ar), 7.47 (d, Jo=8.3 Hz, 1 H, Ar), 7.61 (d, Jm=1.9 Hz, 1 H, Ar), 9.15 (s, 1 H, NH).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]2[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.[C-:17]#[N:18].[K+]>CN(C=O)C>[C:17]([CH2:2][C:3]1[N:8]2[CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)#[N:18]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cn2c(CCl)cccc2n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(CC#N)cccc2n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Title material is made by dissolving the title product of Example 5 in DMF and after cooling to 0° C., reacting with KI and KCN. The reaction is stirred for 6 h at 0° C. After warming to room temperature, title compound is obtained by diluting with CHCl3, washing with water, and removing all solvent in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:31]([C:26]1[NH:27][C:28]2[C:24]([CH:25]=1)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=2)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N)[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 12 h
Yield: 70.8 %

Procedure:
(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine (4.62 g) was dissolved in dichloromethane (50 ml), 5-chloroindole-2-carboxylic acid (3.63 g), 1-hydroxybenzotriazole monohydrate (2.43 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.45 g) were added at room temperature, and the mixture was stirred for 12 hours. After 0.1N hydrochloric acid was added, and the mixture was extracted with dichloromethane, the resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=2:3) to obtain the title compound (5.3 g) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@H:18]([C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=3[N:21]=2)[CH3:19])=[O:16])=[CH:13][C:12]=1[Cl:32])=[O:10].[C:33](OC(=O)C)(=[O:35])[CH3:34].[Cl-].[Na+].ClCl>C(O)(=O)C.CO>[C:33]([NH:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@H:18]([C:20]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=3[N:21]=2)[CH3:19])=[O:16])=[CH:13][C:12]=1[Cl:32])=[O:10])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CCN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)NCC[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 67 %

Procedure:
Prepared analogously to Example 124 from 4-[(2S)-2-(2-aminoethyl)pyrrolidin-1-ylcarbonyl]-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]benzamide and acetic anhydride in glacial acetic acid. Yield: 67%; Rf value: 0.32 (Reversed phase RP 8; methanol:5% sodium chloride solution=6:4); C25H27Cl2N5O3 (516.43); mass spectrum: (M+H)+=516/518/520 (chlorine isotope).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]1([CH3:20])[O:17][C@H:16]([CH2:18]O)[CH2:15][O:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:12][C:13]1([CH3:20])[O:17][C@H:16]([CH2:18][O:1][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=2[CH3:10])[CH2:15][O:14]1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1OC[C@@H]1COC(C)(C)O1
Reaction time: 3 h
Yield: 84.4 %

Procedure:
Nitrogen was bubbled in a solution of 4-hydroxy-3,5-dimethylbenzonitrile (5.0 g, 34.0 mmol) and (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (9.53 ml, 76 mmol) in THF (125 ml) at room temperature. The solution was made in a 500 ml flask w/3 necks fitted with a reflux condenser for 10 min. To this was added triphenylphosphine (20.05 g, 76 mmol) in one portion. Nitrogen was bubbled for an additional 10 minutes, followed by the dropwise addition of diethyl azodicarboxylate (12.04 ml, 76 mmol). The color of the reaction mixture changed from pale to a dark reddish brown and the reaction was exothermic. The reaction vessel was immersed in a preheated oil bath held at 65° C. The reaction was found to be nearly complete after 3 h. The contents of the reactor were cooled and evaporated. The semi solid residue was taken in ether and washed with water. The aqueous layer was extracted with ether (2×). The combined organic layer was then washed with brine. It was then dried over anhydrous MgSO4., and then concentrated. Triphenylphosphineoxide was crystallized out and filtered with ether and hexanes. The product was purified on a 330 g ISCo cartridge eluted with 0 to 30% EtOAc-hexanes. (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3,5-dimethylbenzonitrile (7.49 g, 28.7 mmol, 84% yield) was obtained as a clear oil. 1H NMR (400 MHz, CCl3D) δ ppm 7.27 (2H, s), 4.38-4.49 (1H, m), 4.08-4.19 (1H, m), 3.88 (1H, ddd, J=8.18, 5.99, 1.87 Hz), 3.73-3.84 (2H, m), 2.25 (6H, s), 1.41 (3H, s), 1.36 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:20])=[N:10]2.S(=O)(=O)(O)O.C1C(=O)N([Br:33])C(=O)C1.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[Br:33][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([C@:9]23[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]2[CH2:13][S:12][C:11]([NH2:20])=[N:10]3)[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CF)[C@H]2CS1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
(4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (700 mg, 2.32 mmol) was dissolved in TFA (2.1 mL) and sulfuric acid (864 μL, 16.2 mmol). NBS (453 mg, 2.55 mmol) was added and the reaction was stirred at 60° C. for 45 minutes. The reaction was cooled to room temperature and basified with 2N NaOH. The mixture was then extracted with EtOAc (×3). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified using column chromatography, eluting with 20-80% EtOAc in n-hexane to give the title compound. (620 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 7.67 (t, J=8.13 Hz, 1H), 6.94 (dd, J=8.01, 11.55 Hz, 1H), 4.65 (d, J=4.16 Hz, 1H), 4.47-4.57 (m, 3H), 3.84-3.98 (m, 1H), 3.01-3.20 (m, 2H), 2.77-2.91 (m, J=13.40 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH:14](OCC)=[O:15]>ClCCl>[CH:14]([NH:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:15]
Reactant: CCOC=O
Reactant: NC1(CO)CCc2ccccc2C1
Solvent: ClCCl
Product: O=CNC1(CO)CCc2ccccc2C1
Reaction time: 8 h

Procedure:
A solution containing 5.6 mmol of the compound obtained in Stage D of Example 35 in 5 ml of ethyl formate is left overnight at room temperature. The solution is then diluted with 25 ml of dichloromethane, the solid is filtered off and the tiltrate is evaporated. The residue is then purified by chromatography on a silica column using a dichloromethane/ethanol (95:5) mixture as eluent.
Reaction SMILES: C(NC(=O)NC1C=C[C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=CC=1)C.CC1(C)C(C)(C)OB(C2[S:49][C:48]([NH:50]C(=O)OC(C)(C)C)=[N:47][CH:46]=2)O1.ClC1N=C(N2CCOC[C@@H]2C)C2CCN(C)CC=2N=1>>[CH3:22][N:19]1[CH2:20][CH2:21][C:15]2[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])=[N:13][C:12]([C:9]3[S:49][C:48]([NH2:50])=[N:47][CH:46]=3)=[N:17][C:16]=2[CH2:18]1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C)C2
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)s2)nc2c1CCN(C)C2

Procedure:
Method as described for intermediate 5 using tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate and (S)-4-(2-chloro-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 13) as starting materials. The tert-butyl carboxylate group was removed under the reaction conditions. The mixture was concentrated in vacuo and purified by flash SCX2 chromatography affording (S)-5-(7-methyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)thiazol-2-amine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[F:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[F:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25][C:24]([F:29])([F:28])[F:23]
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2F)C(F)(F)OC3(F)F)n1
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2cc3c(cc2F)C(F)(F)OC3(F)F)c(N)c1SC(F)(F)F
Temperature: 55 °C
Reaction time: 10 h
Yield: 28.7 %

Procedure:
To a suspension wherein 5-amino-3-cyano-1-(6-fluoro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)pyrazole (900 mg, 2.85 mmol), sodium trifluoromethanesulfinate (890 mg, 5.70 mmol) and dimethylamine tosylate (1.550 g, 7.13 mmol) are in toluene (5 ml), thionyl chloride (678 mg, 5.70 mmol) was added dropwise under ice cooling over a period of about 10 minutes and stirred at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 340 mg of 5-amino-3-cyano-1-(6-fluoro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-4-trifluoromethylsulfenylpyrazole.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CN([CH:29]=[O:30])C>O.ClCCl.[OH-].[Na+]>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:12]([CH3:13])=[C:11]([CH:29]=[O:30])[C:10]([CH3:14])=[N:9]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)n(C(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1nn(C(c2ccccc2)c2ccccc2)c(C)c1C=O
Temperature: 100 °C

Procedure:
To a hot solution of 1-(diphenylmethyl)-3,5-dimethyl-(1H)-pyrazole (25.0 g) in DMF (22 ml) was added phosphoryl chloride (8.87 ml) dropwise with stirring under nitrogen and the resulting mixture heated at 100° C. for 3 hr. It was cooled, diluted with water and dichloromethane and basified with 50% sodium hydroxide with ice/water cooling. It was extracted with dichloromethane, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ethyl acetate/i-hexane (1:19) followed by ethyl acetate to give the sub-title compound as a solid (12.61 g).