Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH3:14][O:15]C(Cl)Cl.Cl.CCOC(C)=O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([CH:14]=[O:15])[CH:8]=1
Reactant: COC(=O)Oc1ccc(OC)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Oc1ccc(OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirred solution of 4-methoxyphenyl methyl carbonate (5, 16.5 g. 91 mmol) in CH2Cl2 (205 mL) at 0° C. was added dropwise TiCl4(23.5 mL, 210 mmol) in CH2Cl2 (20 mL) over 30 min. Then MeOCHCl2 (9.3 mL, 104 mmol) in CH2Cl2 (20 mL) was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction material was poured into a mixture of ice (210 g) and concentrated HCl (8.5 mL). EtOAc (200 mL) was added and the mixture was stirred vigorously for 30 min. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from EtOAc/hexanes to afford the title compound (16.6 g, 87%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H), 7.63 (d, J=3.1 Hz, 1H), 7.37 (dd, J=9.0, 3.1 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H); ESI MS m/z 228 [M+H2O]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24](Br)=[CH:23][C:10]=1[CH2:11][N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]([C:33]2[CH:34]=[CH:35][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=2)=[CH:23][C:10]=1[CH2:11][N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCC(=O)N(C)Cc1cc(Br)ccc1OCc1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CCCCCCCC(=O)N(C)Cc1cc(-c2ccc(C=O)cc2)ccc1OCc1ccccc1

Procedure:
In a manner similar to that of Example 1(e), by reacting 8 g (18.5 mmol) of N-(2-benzyloxy-5-bromo benzyl)-N-methyloctanamide and 3.6 g (24 mmol) of 4-formylbenzene boronic acid, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 5.8 g (69%) of the expected product are obtained in the form of a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[SH:34].CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1
Reactant: Fc1ccc(S)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCSc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 2,4-difluorobenzenethiol (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(2,4-difluorophenylthio)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=412.91). 1H NMR (DMSO-d6, 400 MHz) δ 3.40 (m, 2H), 4.32 (m, 2H), 6.56 (m, 1H), 6.72 (m, 1H), 7.05 (m, 1H), 7.12 (m, 1H), 7.22 (m, 2H), 7.53 (m, 3H), 7.92 (s, 1H). Anal. calculated for (C19H14F2N6OS): C, 55.33; H, 3.42; F, 9 21; N, 20 38; O, 3.88; S, 7.77. Found C, 55.01; H, 3 75; N, 21.95; S, 6.89.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:18]([NH2:20])=[O:19])[CH3:13].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:18]2[O:19][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=3)[N:20]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[CH3:13]
Reactant: O=C(CBr)c1ccncc1
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccncc3)co2)cc1OCC
Temperature: 170 °C
Yield: 2.7 %

Procedure:
In a microwave vial were dissolved 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (134 mg, 0.478 mmol) and 3,4-diethoxybenzamide (100 mg, 0.478 mmol) in DMF (5 ml) and the reaction was heated at 170° C. for 40 min. The reaction mixture was poured in a saturated solution of NaHCO3 and extracted with EtOAc (50 ml×3). The combined organic phases were washed with a saturated solution of NaCl (2×30 ml) and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (95:5) to yield 4 mg (2.7%) of the product. MS (EI) m/z: 311 (M+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:41][C:42]([Cl:47])([Cl:46])[C:43](Cl)=[O:44]>ClCCl>[Cl:41][C:42]([Cl:47])([Cl:46])[C:43]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:44]
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanone of Step C (1.5 g, 3.67 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethyl amine (1.28 mL, 7.35 mmol) followed by slow addition of trichloroacetyl chloride (1.23 mL, 11.0 mmol). The reaction mixture was stirred overnight at room temperature then quenched with water. The organic phase was washed with 0.1 N hydrochloric acid followed by water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a green oil. Purification by flash chromatography on silica gel using a solvent system of 20% ethyl acetate in hexane provided 2.1 g of title compound. The material was redissolved in dichloromethane and evaporated to dryness to provide a yellow foam, which was used in the next step.
Reaction SMILES: [CH2:1]([O:11][C:12]([CH:14]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:21])[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[Cl:33]Cl>C(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([C:14]([C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:13])([Cl:33])[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:21])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: ClCl
Reactant: CC(C)CCCCCCCOC(=O)C(C(=O)OCCCCCCCC(C)C)n1cncn1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClP(Cl)Cl
Product: CC(C)CCCCCCCOC(=O)C(Cl)(C(=O)OCCCCCCCC(C)C)n1cncn1

Procedure:
1-[bis(isodecyloxycarbonyl)methyl]-1,2,4-triazole, which is the product of Example 12 (15.6 g), was dissolved in carbon tetrachloride (20 ml). Phosphorus trichloride (3 drops) was added and the solution was stirred and heated at 60° whilst a slow stream of chlorine was bubbled through it for 1 hour. The solution was then cooled, washed with aqueous sodium sulphite solution and with water, and the solvent was distilled under reduced pressure yielding 1-[bis(isodecyloxycarbonyl)chloromethyl]-1,2,4-triazole (12.9 g), which had a purity of 82.4% as measured by non-aqueous titration with perchloric acid. This compound was evaluated as an extractant for copper by the procedure of Example 1 and the results are presented in Table 1.
Reaction SMILES: [C:1]([N:20]1[C:24]([CH3:25])=[C:23]([CH2:26]Cl)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[Cl-].[NH4+]>C1COCC1>[C:1]([N:20]1[C:24]([CH3:25])=[C:23]([CH2:26][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(CC(c2ccccc2)c2ccccc2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 48 h

Procedure:
Then it is cooled again to -78° C. and a solution of 1-trityl-4-chloromethyl-5-methylimidazole 3 in 10 ml of anhydrous THF is added thereto. After stirring for an hour at -78° C. the reaction mixture is kept at -20° C. for 48 hours. Then 30 ml of an aqueous 10% ammonia solution saturated with ammonium chloride are added and the mixture is extracted with ether. The organic phase is washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residual oil is dispersed in heptane and cooled with an ice bath. This causes the precipitation of a yellow solid which is recrystallised in isopropanol. The 1-trityl-4-(2,2-diphenyl ethyl)-5-methylimidazole 4 is so obtained in the form of a white solid.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].[C:14]([CH:17]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24])[C:18](OC)=[O:19])(=O)[CH3:15]>CO>[CH3:15][C:14]1[N:9]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:10][C:18](=[O:19])[C:17]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: N=C(N)c1ccccc1
Reactant: CCCC(C(=O)OC)C(C(C)=O)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 119.9 %

Procedure:
To a solution of benzamidine hydrochloride (9.2 g; 50 mmol) in methanol (46 mL) was slowly added a solution of sodium methoxide (25%) (23 mL; 100 mmol) and dimethyl 2-acetyl-3-propylsuccinate (60%) (19.2 g; 50 mmol). The reaction mixture was heated at reflux for 18 h, and after cooling, the white precipitate was filtered and washed with a small volume of methanol. The solid was dried and carefully added to a cold hydrochloric 12N solution (25 mL). The suspension was stirred for one minute at 0° C., filtered and washed with a small amount of methanol. The precipitate was dried under reduced pressure over phosphorus pentoxide to provide 17.16 g of the expected 2-(4-methyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)pentanoic acid as a white powder which was used without further purification. ESI/APCI(+): 287 (M+H); ESI/APCI(−): 285 (M−H). 1H NMR (DMSO-d6) δ 8.08 (2H, d, Harom.); 7.70 (1H, m, Harom.); 7.60 (2H, m, Harom.); 3.76 (1H, m, CHα); 2.48 (3H, s, CH3); 1.98 (1H, m, CHβ); 1.72 (1H, m, CHβ′); 1.14 (2H, m, CH2γ); 0.87 (3H, t, CH3δ).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:24]#[N:25])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2].F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].ClCCl>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:33][CH3:34])[NH:12][C:11]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:24]#[N:25])=[C:5]([O:26][CH3:27])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1C1C(C#N)=C(C(F)(F)F)Nc2cc[nH]c(=O)c21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C#N)=C(C(F)(F)F)N2

Procedure:
390 mg (1.05 mmol) of 4-(4-cyano-2-methoxyphenyl)-5-oxo-2-(trifluoromethyl)-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile and 398 mg of triethyloxonium tetrafluoroborate (2.1 mmol) are mixed under a dry argon atmosphere. After addition of dichloromethane (32 ml), the suspension is stirred until a solution is obtained (about 2 h), and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 250 mg (59% of theory) of the title compound as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH2:8].[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:32]1[N:31]=[C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:23]([NH:22][CH2:21][CH2:20][C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[NH:13][CH:12]=[C:11]4[C:9]#[N:10])=[O:37])=[CH:29][CH:28]=2)[CH:35]=[CH:34][N:33]=1
Reactant: NC1CC2CCC1C2
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NC5CC6CCC5C6)n4)cc3)cc12

Procedure:
Using Bicyclo[2.2.1]hept-2-ylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 477 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].CC(C)([O-])C.[K+].[C:13]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([NH:21][C:22](=[O:25])[CH2:23][CH2:24][O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])([CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:14])[CH3:15]
Reactant: C=CC(=O)NC(C)(C)CC(C)(C)C
Reactant: CCN(O)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)OCCC(=O)NC(C)(C)CC(C)(C)C

Procedure:
The procedure of Example I is repeated using diethylhydroxylamine, potassium-tert-butoxide and N-tertoctylacrylamide in tetrahydrofuran to afford the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:22])=[C:12]([CH3:21])[C:13]=2[CH2:19]O)[N:8]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH2:19][C:13]1[C:12]([CH3:21])=[C:11]([CH3:22])[CH:10]=[C:9]2[C:14]=1[N:15]=[C:16]([O:17][CH3:18])[C:7]([O:6][CH3:5])=[N:8]2
Reactant: O=S(Cl)Cl
Reactant: COc1nc2cc(C)c(C)c(CO)c2nc1OC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1nc2cc(C)c(C)c(CCl)c2nc1OC
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
Thionyl chloride (0.44 mL, 6.0 mmol) was added dropwise to a solution of 2,3-dimethoxy-6,7-dimethyl-5-hydroxymethylquinoxaline (0.50 g, 2.0 mmol) in toluene (30 mL) and pyridine (0.81 mL, 10.0 mmol) under nitrogen at 5° C. After 20 minutes, water (20 mL), and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic solutions were washed with 2M hydrochloric acid, dried (MgSO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (eluting with dichloromethane) gave 5-(chloromethyl)-2,3-dimethoxy-6,7-dimethylquinoxaline (0.18 g, 34%) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].[Br:13]Br>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:9]([O:11][CH3:12])=[O:10])[C:2]1=[O:1]
Reactant: COC(=O)C1CCCCCC1=O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1CCCCC(Br)C1=O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
Methyl 2-oxo-1-cycloheptanecarboxylate (50 g, 294 mmole) was dissolved in carbon tetrachloride (200 mL) and chilled to 0° C. Bromine (46.8 g, 294 mmole) was added via addition funnel over ˜30 minutes. The cooling bath was then removed and the reaction was allowed to warm to rt. The reaction was stirred under nitrogen at room temperature for 4 days. After 4 days the solution was poured into a separatory funnel containing water (1 L). The organic was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield). The material was carried on without further purification.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[OH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].FC(F)(F)S(O)(=O)=O.C(N(CC)CC)C>ClCCl>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10])([CH3:3])([CH3:1])[CH3:4]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC)c(OC(C)(C)C)c1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
A stirred solution of isobutylene (33 mL) in dichloromethane (60 mL) at -70° C. is treated dropwise with a cooled solution of methyl 3-hydroxy-4-methoxybenzoate (6 g) in dichloromethane (60 mL), followed by trifluoromethanesulfonic acid (0.3 mL). The reaction mixture is vigorously stirred at -70° C. for 3 hours and then between -70° C. and -50° C. overnight. It is then treated with triethylamine (0.6 mL) and allowed to warm to room temperature. The resulting yellow solution is concentrated, and the residue is subjected by mplc, using diethyl ether as eluent, to give methyl 3-tert-butoxy-4-methoxybenzoate (4.93 g), m.p. 98-100° C. [Elemental analysis: C,65.7; H,7.8%; calculated: C,65.5; H,7.6%].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].Cl.[H-].[Na+].Cl[C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[O:28])=[CH:25][C:24]=2[O:39][CH3:40])[N:13]=1>O1CCOCC1.O>[NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:16]1[C:17]([C:18]([F:19])([F:21])[F:20])=[CH:12][N:13]=[C:14]([NH:22][C:23]2[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)=[O:28])=[CH:25][C:24]=2[O:39][CH3:40])[N:15]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(O[C@@H]2CCC[C@H]2N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R,R)-2-aminocyclopentanol×HCl (155 mg) is added to a suspension of NaH (135.2 mg) in dioxane (0.75 mL) and stirred for 30 min at RT. Then 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (250 mg) is added. After 18 h, H2O (50 mL) is added. The precipitate formed is filtered off, washed with H2O, dissolved in CH2Cl2 and extracted with aqueous KHSO4 solution (10%). The aqueous phase is made basic again with K2CO3 and extracted with CH2Cl2. The organic phase is dried on magnesium sulphate, filtered to remove the desiccant and the solvent is eliminated in vacuo.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=3[CH:13]([O:15][CH2:16][C:17]3([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH3:14])[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=3[CH:13]([O:15][CH2:16][C:17]3([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH3:14])[CH:6]=[N:5]2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2c(cnn2C2CC2)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2c(cnn2C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(1-cyclopropyl-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (10 mg, 0.02 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (6.2 mg, 0.1 mmol) and formalin (54 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 3 mg (36%) as a clear oil. LC/MS (HPLC method 1): tR=2.46 min, 422.37(MH)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[C:9]([N:17]1[CH2:22][CH2:21][C:20]2([S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[S:1]2)[CH2:19][CH2:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Sc1ccccc1S
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC2(CC1)Sc1ccccc1S2
Reaction time: 15 h

Procedure:
500 mgs (3.52 mmol) of 1,2-dimercaptobenzene and 610 mgs (3.00 mmol) of N-benzoyl-4-piperidone were stirred in CH2Cl2 while anhydrous HCl gas was introduced Na2SO4 (2 grams) was added and the mixture stirred 15 hours. The mixture was diluted with CH2Cl2 filtered and washed with H2O, and 10% NaOH. The organics were dried (Na2SO4) and concentrated to a solid (yield 740 mgs).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:4]=2[N:3]1[CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1.Cl.CN(C)CCCN=C=NCC.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CC(N(C)C)=O>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]([NH:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:15])[C:4]=2[N:3]1[CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: COc1cc(Cn2c(=O)[nH]c3cccc(CCC(=O)O)c32)cc(OC)c1OC
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cc(Cn2c(=O)[nH]c3cccc(CCC(=O)NCc4ccccc4)c32)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
3-[2-Oxo-3-(3,4,5-trimethoxybenzyl)-benzimidazolyl]propionic acid (1.77 mmol, 0.69 g) (example 14) in DMA (5 ml) is charged with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl (2.66 mmol, 0.51g). Benzylamine (2.48 mmol, 0.27 ml) is added to the suspension, and the mixture is stirred at room temperature for 17 hours. The solution is added dropwise into ice (50 g) and the colorless precipitate is filtered off and dried in vacuo. Recrystallisation from ethyl acetate yields the title product. (R1=(CH2)2—C(O)—NHR5, x=2. R5=benzyl, R2=3,4,5-trimethoxybenzyl, n=0).