Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C@@H:6]1[C@@H:19]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:18](O)[C@@H:17]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:16][C@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].CCN(S(F)(F)[F:42])CC>ClCCl>[Cl:1][CH2:2][C:3]([O:5][C@@H:6]1[C@@H:19]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:18]([F:42])[C@@H:17]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:16][C@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(=O)CCl)[C@@H](OC(=O)C(C)(C)C)[C@H]1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(=O)CCl)[C@@H](OC(=O)C(C)(C)C)[C@@H]1F
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
Compound (19) (300 mg, 0.583 mmol) was dissolved in dichloromethane (5.8 ml), and diethylaminosulfatrifluoride (DAST) was added to the solution with stirring under an argon stream at −15° C. The mixture was returned to room temperature 10 minutes after the addition of DAST and reacted for 1 hour. Disappearance of the material was confirmed by TLC, the DAST was quenched with methanol (3 ml), and the reaction mixture was concentrated in a vacuum. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:6), giving Compound (20) (in an amount of 211 mg, yield 70%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Cl:44][C:45]1[CH:46]=[C:47]([OH:52])[CH:48]=[CH:49][C:50]=1[F:51]>>[Cl:44][C:45]1[C:50]([F:51])=[CH:49][C:48]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])=[C:47]([OH:52])[CH:46]=1
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(F)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3-chloro-4-fluorophenol, the title compound was obtained (14%): MS (ES+) m/z 346 (M−17), 386 (M+23).
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.C(O[C:12](=[N:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:24])=[O:23])[CH3:13])C>>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][N:14]=[CH:12][C:13]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)([OH:24])=[O:23]
Reactant: O=Cc1ccccc1
Reactant: CCOC(C)=NOc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1ON=Cc1ccccc1
Yield: 61.8 %

Procedure:
70% HClO4 (14.0 μL, 0.163 mmol), benzaldehyde (18.0 mL, 0.177 mmol), and 20 (39.0 mg, 0.175 mmol) were subjected to the representative coupling procedure as outlined above (method 3), yielding 2a as a white solid (26.1 mg, 62%). 1H-NMR (500 MHz, d6-Acetone) δ 7.15 (dt, J=0.9, 7.8 Hz, 1H), 7.48-7.55 (m, 3H), 7.59 (dt, J=1.8, 7.8 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.83-7.89 (m, 3H), 8.66 (s, 1H), 10.8-11.5 (broad s, 1H); 13C-NMR (125 MHz, d6-DMSO) δ 115.7, 119.7, 122.1, 127.8, 129.0, 130.8, 130.9, 131.1, 133.1, 153.4, 157.7, 166.8; MALDI-FTMS (DHB) 242.0811 m/z [MH]+, C14H12NO3 requires 242.0812. RP-HPLC: >99% pure.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[C:16]1([CH:26]=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH:33]=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1cccs1
Reactant: O=Cc1cccc2ccccc12
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccs3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-naphthaldehyde, followed by thiophene-2-carbaldehyde. Mass: 444.88 (M+H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[NH2:9][C:10]1[C:15]([N:16]([CH3:18])[CH3:17])=[N:14][C:13]([Br:19])=[CH:12][N:11]=1.[CH3:20][N:21]([CH3:36])[C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32](Cl)(=[O:34])=[O:33].CCOCC>O1CCCC1>[CH3:20][N:21]([CH3:36])[C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[C:27]2[S:32]([NH:9][C:10]1[C:15]([N:16]([CH3:17])[CH3:18])=[N:14][C:13]([Br:19])=[CH:12][N:11]=1)(=[O:34])=[O:33]
Reactant: CN(C)c1nc(Br)cnc1N
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)c1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: -60 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A 2M solution of lithium diisopropylamide in tetrahydrofuran (THF)/heptane (1:1 v/v; 2.3 ml) was added over 10 minutes to a stirred solution of 2-amino-5-bromo-3-dimethylaminopyrazine (0.45 g) in dry THF (25 ml) at -60° C. The solution was stirred at -60° C. for 1 hour and then 5-dimethylamino-1-naphthalenesulphonyl chloride (0.62 g) was added portionwise over 5 minutes. The solution was allowed to warm to ambient temperature and then stirred for 18 hours. Ether (20 ml) was added and the solution was extracted with water (2×20 ml). The aqueous extracts were neutralised to pH 7 with 10% citric acid solution and extracted with ethyl acetate (2×20 ml). The organic extracts were combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column. The resulting solid was further purified by elution with dichloromethane through a fresh silica gel Mega Bond Elut column to give 5-dimethylamino-N-(5-bromo-3-dimethylamino-2-pyrazinyl)-1-naphthalenesulphonamide (0.125 g), m.p. 180°-182° C. (after trituration with ether); mass spectrum (+ve FAB, methanol/dichloromethane/DMSO/NBA): 450 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23]O)[CH2:19][C@H:18]2[NH:25][C:26](=[O:34])[O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:13]1=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg+].[Br-]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:2]([CH3:7])([CH3:3])[CH3:1])[CH2:19][C@H:18]2[NH:25][C:26](=[O:34])[O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:13]1=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1C[C@H](NO)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: CC(C)=O
Product: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
Example 1, Alternative Preparation, Step 5: A solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(hydroxyamino)cyclohexylcarbamate (350 mg, 0.69 mmol) in acetone (5 mL) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in anhydrous THF (7 mL) and cooled to 0° C. A solution of MeMgBr (1.1 mL, 3M in diethyl ether, 5 eq) was added dropwise. The mixture was stirred at room temperature for 1.5 h. The reaction was quenched with water (5 mL) at 0° C. The mixture was diluted with ethyl acetate (100 mL) and filtered through a pad of celite. The filtrate was washed with brine (30 mL). The solution was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 2 ml of acetonitrile and 1 ml of CS2 was added. The mixture was stirred at room temperature for 1 hours. The solvent was removed and the crude product was purified by silica gel column chromatography, using 1.5% of methanol in dichloromethane as the eluant, to provide the desired 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexylcarbamate (160 mg, 42%). LC/MS found [M+H]−=547.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[C:6](I)=[CH:5][N:4]=1.[C:11]1([CH2:17][C:18]#[CH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.CN1C(=O)CCC1.C(OCC)(=O)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:19]=[C:18]([CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:7]=2[N:8]=1
Reactant: C#CCc1ccccc1
Reactant: CSc1ncc(I)c(O)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CSc1ncc2cc(Cc3ccccc3)oc2n1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A mixture of 2-methylthio-4-hydroxy-5-iodopyrimidine (2.65 g), 3-phenyl-1-propyne (1.49 mL), copper (I) iodide (90 mg) and bis(triphenylphosphine) Palladium (II) dichloride (Fluka, 160 mg) in 20 mL of triethylamine and NMP (7 mL) was stirred at 40° C. for 6 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (3×50 mL), concentrated and purified by column chromatography (5% EtOAc/hexanes) to give 0.57 g of a solid product. MP: 69–72.2° C. MS: 257.2 (M+H).
Reaction SMILES: [NH3:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:13])[C:8](OCC)=[O:9]>>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:13])[C:8]([NH2:1])=[O:9]
Reactant: CCOC(=O)C(=O)c1cccs1
Reactant: N
Product: NC(=O)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.6 g of ammonia are passed into a cooled solution of 73.6 g of ethyl 2-thienylglyoxylate, and the resulting mixture is stirred at room temperature for 2 h. The solvent is stripped off in vacuo, and the residue is recrystallized from water:ethanol (80:20).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[H-].[Na+].Br[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CS(C)=O.C(OCC)(=O)C>[CH:11]1([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH:6]=[O:7])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc[nH]1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1cccn1C1CCCC1
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (12.0 g) in DMSO (252 mL) was added sodium hydride (55% dispersion in mineral oil, 8.26 g) at 0° C., and the mixture was stirred for 30 min. To the reaction mixture was added bromocyclopentane (22.6 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (500 mL), and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (9.34 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][CH:6]1[C:11]([CH3:13])([CH3:12])[O:10][C:9]2[CH:14]=[CH:15][S:16][C:8]=2[CH:7]1[N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22].[K+].[Br-]>C(O)(=O)C>[OH:5][CH:6]1[C:11]([CH3:12])([CH3:13])[O:10][C:9]2[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[S:16][C:8]=2[CH:7]1[N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22]
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(N2CCCC2=O)C1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Nitric acid (90%, 1.2 mL, 26.9 mmol) was added to a solution of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (1.0 g, 3.74 mmol) in acetic acid (30 mL) at 18° C., and stirred at rt for 1.5 h. The resultant solution was poured into ice water (200 mL). Within 10 min a yellow solid crystallized which was collected by filtration, washed with water and triturated in diethyl ether to give the product, 0.487 g (42%), as a yellow solid: mp 214°-217° C.; IR (KBr): 3216, 1655 and 1512 cm-1 ; MS: m/z 313 (MH+); 1H NMR (DMSO-d6): δ1.23(s, 3H), 1.43(s, 3H), 2.00(m, 2H), 2.36(m, 2H), 3.16(m, 1H), 3.20(m, 1H), 3.80(d, J=9.5 Hz, 1H), 4.98(d, J=9.5 Hz, 1H), 5.92(bs, 1H, exchanges with D2O) and 7.75(s, 1H).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].C(OP(C[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])(=O)OCC)C.[CH2:30]([N:37]1[CH2:42][CH2:41][O:40][CH:39]([C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=O)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:30]([N:37]1[CH2:42][CH2:41][O:40][CH:39]([CH:43]=[C:45]([C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:1]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:27])([F:29])[F:28])[CH2:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: CCOP(=O)(Cc1ccccc1C(F)(F)F)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1C(=CC1CN(Cc2ccccc2)CCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a cooled solution of KHMDS (0.5M in toluene, 50 ml, 25 mmol) at 0° C. in dry tetrahydrofuran (70 ml) under nitrogen is added freshly prepared neat (2-trifluoromethyl-benzyl)-phosphonic acid diethyl ester (5.7 ml, 25 mmol, 1 equiv.). The reaction is warmed to room temperature over 1 hour and then racemic (4-benzyl-morpholin-2-yl)-phenyl-methanone (7 g, 25 mmol in 25 ml of dry tetrahydrofuran) is added dropwise. The reaction is left at room temperature and stirred for 2 hours. At the end of this time the reaction solvent is removed under reduced vacuum and replaced with diethyl ether prior to quenching with water. After extraction with diethyl ether and drying (MgSO4) the solvent is again removed under reduced pressure. The resulting residue is purified by column chromatography on silica gel to yield a colourless oil (6.5 g, 61%).
Reaction SMILES: Br[CH:2]([CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]([O:5]C)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18]>>[CH3:10][CH:7]([CH:2]1[C:3](=[O:5])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]1)[CH2:8][CH3:9]
Reactant: Nc1ccccc1S
Reactant: CCC(C)C(Br)C(=O)OC
Product: CCC(C)C1Sc2ccccc2NC1=O
Yield: 72.6 %

Procedure:
In the same manner as in Reference Example 9, methyl 2-bromo-3-methylvalerate (1:1 diastereomer mixture) and 2-aminothiophenol were allowed to react followed by ring closure reaction, to give 2-(1-methylpropyl)-2H-1,4-benzothiazin-3(4H)-one (1:1 diastereomer mixture) as colorless prisms. mp 99°-100° C. (recrystallized from ethanol). Yield 72.6%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:12]([N:19]1[CH2:26][CH:25]2[CH2:24][N:23]([C:8]([C:7]3[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=3[CH3:11])=[O:10])[CH2:22][CH:21]2[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncnc(C)c1C(=O)N1CC2CN(Cc3ccccc3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
step 1—To a mixture of 4,6-dimethyl-pyrimidine-5-carboxylic acid (0.85 g, 5.58 mmol, T. J. Kress et. al. Heterocycles 1994 38:1375) and 4a (1.13 g, 5.58 mmol, C. J. Ohnmacht et al. J. Heterocycl. Chem. 1983 20:321) in DCM (25 mL) at RT was added sequentially EDCI (1.43 g, 6.7 mmol), HOBt (0.9 g, 6.7 mmol) and DIPEA (3.9 mL, 22.34 mmol) and the mixture was stirred overnight at RT. The reaction mixture was washed with 5% NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH4OH)/DCM (0 to 4%) to afford 1.5 g of (5-benzyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4,6-dimethyl-pyrimidin-5-yl)-methanone: ms (ES+) m/z 337 (M+H)+. To a solution of amide from the previous step (1.5 g, 4.45 mmol) in MeOH (50 mL) was added ammonium formate (2.81 g, 44.58 mmol). Palladium on charcoal previously wetted with MeOH was slowly added and the mixture heated to reflux for 8 h. The catalyst was filtered and solvent evaporated. The residue was purified by flash chromatography on silica gel eluting with MeOH (containing 10% NH4OH)/DCM (0 to 4%) to afford 0.941 g of 44b: ms (ES+) m/z 247 (M+H)+.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:25][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)CCO
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(COCCC(C)C)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (10.0 g, 33 mmol) is suspended in a mixture of isoamyl alcohol (35 g, 0.4 mol) and acetone (5 g) and stirred at 80° C. for 30 minutes. Sodium carbonate (4.7 g, 44 mmol) is added and the reaction mixture is stirred at 80° C. for 30 minutes. Acetone is removed under vacuum, salts are filtered off and the reaction mixture is evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 7.0 g of 2-(2H-Benzotriazol-2-yl)-6-(3-methyl-butoxymethyl)-4-methyl-phenol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:5]1[CH:4]=[CH:3][C:2]([C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8])#[N:26]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: N#Cc1ccccc1COc1ccc(Br)cc1C(=O)Nc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccccc3C#N)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-{[(2-cyanophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in example 23; 172 mg, 0.42 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (96 mg, 0.46 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.84 ml, 0.84 mmol) and tetrakis(triphenylphosphine)palladium(0) (29.2 mg, 0.025 mmol). The vial was sealed and heated to 120° C. for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 58 mg.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14](S(CCC)(=O)=O)=[N:15][C:16]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CS(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([C:1]#[N:2])=[N:15][C:16]=2[N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CCCS(=O)(=O)c1nc(N2CCOCC2)c2ncn(-c3ccccc3Cl)c2n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1nc(N2CCOCC2)c2ncn(-c3ccccc3Cl)c2n1
Temperature: 60 °C

Procedure:
Sodium cyanide (0.086 g) was added to a solution of the product from step (v) (0.74 g) in dimethylsulphoxide (10 ml) and heated at 60° C. for 36 h. The mixture was partitioned between ethyl acetate and brine, the organics washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 16% ethyl acetate in toluene. Yield 0.152 g
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:13][CH:14]2[C:23]3[C:18](=[C:19]([O:27]C)[C:20]([CH:24]([CH3:26])[CH3:25])=[CH:21][CH:22]=3)[C:17]([CH3:30])([CH3:29])[CH2:16][C:15]2([C:32]([F:35])([F:34])[F:33])[OH:31])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[N:8]=[CH:7]2.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:13][CH:14]2[C:15]([C:32]([F:33])([F:35])[F:34])([OH:31])[CH2:16][C:17]([CH3:30])([CH3:29])[C:18]3[C:19]([OH:27])=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:22][C:23]2=3)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[N:8]=[CH:7]2
Reactant: COc1c(C(C)C)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2nc(C)ncc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ncc2c(NC3c4ccc(C(C)C)c(O)c4C(C)(C)CC3(O)C(F)(F)F)ccc(F)c2n1
Yield: 28.1 %

Procedure:
50 mg (0.102 mmol) of 1-(8-fluoro-2-methylquinazolin-5-ylamino)-6-isopropyl-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is treated with BBr3 in dichloromethane as already described several times. After working-up and chromatography, 13.7 mg (28.2%) of the desired phenol is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl.C(OCC)(=O)C>[CH3:16][S:17]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])(=[O:19])=[O:18]
Reactant: O=Cc1ccccc1O
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (0.30 mL, 2.8 mmol) and pyridine (0.91 mL, 11.2 mmol) in 5.6 mL of dichloromethane was added methanesulfonyl chloride (0.65 mL, 8.4 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 50/50) to obtain the title compound as a white solid (553 mg, 98%).
Reaction SMILES: [CH2:1]([C:4]#[N:5])[C:2]#[N:3].C(O)C.Cl.N[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>C(Cl)(Cl)Cl>[S:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:3]=[C:2]1[CH2:1][C:4]#[N:5]
Reactant: Nc1ccccc1S
Reactant: N#CCC#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N#CCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of malonodinitrile (13.22 g, 0.200 mole) in dry chloroform (100 mL) was added ethanol (9.2 g, 0.200 mole). Hydrogen chloride (8.0 g, 0.220 mole) was passed into the solution at room temperature and the resulting suspension was stirred for an additional 16 hours at room temperature. The excess of hydrogen chloride was removed by passing dry nitrogen into the reaction mixture. A solution of o-aminothiophenol (25 g, 0.200 mole) in chloroform was added to the reaction mixture dropwise during 30 min and the reaction mixture was stirred for 1 hour at 60° C. After that the reaction mixture was cooled to room temperature, washed with water (2×100 mL) and dried with magnesium sulfate. Chloroform was removed using a rotary evaporator. The solid residue was recrystallized from ethyl alcohol. White crystals. The yield was 26.1 g (75% of theory). Mp=101-103° C.