Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]1([C:17]2[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=2)[NH2:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Product: Nc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of phenylboronic acid (10.5 g, 86.4 mmol) in 100 mL of MeOH, Na2CO3 (18.3 g, 172.2 mmol) and 3-bromoaniline (14.9 g, 86.4 mmol) were added sequentially. To the so obtained suspension, Pd(OAc)2 (500 mg, 2.16 mmol) was added and the reaction was heated to reflux of solvent until a black suspension appeared; the suspension was cooled at room temperature, diluted with MeOH and the black precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was splitted in water and CH2Cl2. The organic phase was dried on Na2CO3 and concentrated under reduced pressure to give 3-phenylaniline as a brown oil (14.6 g, yield 100%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C@@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C@@H:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: Cl
Product: COC(=O)[C@H](C)NCc1cccc(O[Si](C)(C)C(C)(C)C)c1
Yield: 80 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and (S)-methyl 2-aminopropanoate hydrochloride. Yield 80%, colorless liquid. MS 324 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOC(CCl)C1)C1C=CC=CC=1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@:33]2([C:51]3[C:42](=[CH:43][C:44]4[O:49][CH2:48][CH2:47][O:46][C:45]=4[CH:50]=3)[O:41][CH2:40]2)[C:32]1=[O:52].N1C2C(=CC=CC=2)C2(C3C(=CC4OCCOC=4C=3)OC2)C1=O>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@@:33]3([C:51]4[C:42](=[CH:43][C:44]5[O:49][CH2:48][CH2:47][O:46][C:45]=5[CH:50]=4)[O:41][CH2:40]3)[C:32]2=[O:52])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: ClC[C@@H]1CN(Cc2ccccc2)CCO1
Agent: ClCC1CN(Cc2ccccc2)CCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Product: O=C1N(C[C@@H]2CN(Cc3ccccc3)CCO2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 9.60 and making non-critical variations using (S)-4-benzyl-2-(chloromethyl)morpholine (Toshiya, M. et al., Heterocycles (1994), 38(5):1033-1040) to replace 4-benzyl-2-(chloromethyl)morpholine, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (8S)-1′-{[(2S)-4-benzylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (99%): MS (ES+) m/z 485.0 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]#[N:7])=[CH:2]1.[CH2:8]([Mg]Br)[CH3:9].B(F)(F)F.CCOCC.[OH-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2([NH2:7])[CH2:9][CH2:8]2)=[CH:2]1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccoc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1(c2ccoc2)CC1
Reaction time: 0.25 h

Procedure:
To solution of 3-furonitrile (5 g, 53.71 mmol, 1.0 eq) in dry THF at r.t. under an argon atmosphere was added slowly titanium isopropoxide (18.9 ml, 64.4 mmol, 1.2 eq). The reaction mixture was stirred for 15 min. A solution of 1.0 M ethyl magnesium bromide in THF (129 ml, 128 mmol, 2.4 eq) was added via syringe slowly to the mixture at 0° C. After addition, the reaction mixture was stirred at r.t. for 2 hour. BF3.Et2O (10.4 ml) was then added slowly to the mixture at 0° C. After completion of the addition, the reaction mixture was stirred at r.t. for 30 min. 10% NaOH solution was added slowly till the reaction mixture becomes basic and then extracted with EtOAC. The organic was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 35% EtOAC/pet ether as eluent. Yield: 2.5 g (38%). 1F NMR (400 MHz, CDCl3): δ 7.32 (m, 2H), 6.10 (s, 1H), 0.98-0.95 (m, 2H), 0.83-0.78 (m, 2H). LCMS: (ES+) m/z=123.7 (M)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH2:21]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=O)=[CH:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].CS(C)(=O)=O>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([CH:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH2:21]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[S:30])=[CH:2]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2ccccc2C1(c1c[nH]c2ccccc12)C1CNc2ccccc21
Agent: CS(C)(=O)=O
Solvent: O
Product: S=C1Nc2ccccc2C1(c1c[nH]c2ccccc12)C1CNc2ccccc21

Procedure:
3-(1H-indol-3-yl)-3,3′-biindolin-2-one (728 mg, 2 mmol), crystalline P2S5.2 C5H5N (228 mg, 0.6 mmol) and dimethylsulfone (3.05 g) were heated (165-170° C.) for 20 min. The melt was allowed to cool and then heated in water for 10 min. The solid formed was collected, 766 mg (94%), mp>260° C. 1H NMR (300 MHz, DMSO-d6) δ 7.09-7.15 (m, 2H), 7.18-7.20 (m, 5H), 7.24-7.30 (m, 7H), 13.00 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ 72.7 (s), 111.2 (d), 124.4 (d), 126.5 (d), 127.5 (d), 128.6 (s), 128.7 (s), 129.0 (d), 129.1 (d), 129.1 (d), 139.2 (s), 143.0 (s), 143.5 (s), 145.3 (s, 2C), 208.4 (s). Elemental analysis calcd for C24H17N3S; C, 75.96; H, 4.51; N, 11.07. Found C, 76.10; H, 4.46; N, 11.00.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([NH:14][CH:15]([CH3:17])[CH3:16])(=[O:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ClC1C=C(C=CC=1S(NC(C)C)(=O)=O)C(O)=O.Cl.Cl.[CH3:37][C:38]1[N:42]([CH:43]2[CH2:49][CH:48]3[N:50]([CH2:51][CH2:52][C:53]4([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)[CH:45]([CH2:46][CH2:47]3)[CH2:44]2)[C:41]2[CH:65]=[CH:66][CH:67]=[CH:68][C:40]=2[N:39]=1.CC1N(C2CC3N(CCC4(C5C=CC=CC=5)CCN(C(C5C=CC=CC=5S(NC(=O)OC(C)(C)C)(=O)=O)=O)CC4)C(CC3)C2)C2C=CC=CC=2N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([NH:14][CH:15]([CH3:17])[CH3:16])(=[O:13])=[O:12])=[C:6]([C:7]([N:56]2[CH2:55][CH2:54][C:53]([CH2:52][CH2:51][N:50]3[CH:45]4[CH2:46][CH2:47][CH:48]3[CH2:49][CH:43]([N:42]3[C:41]5[CH:65]=[CH:66][CH:67]=[CH:68][C:40]=5[N:39]=[C:38]3[CH3:37])[CH2:44]4)([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:58][CH2:57]2)=[O:9])[CH:10]=1
Reactant: CC(C)NS(=O)(=O)c1ccc(Cl)cc1C(=O)O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: CC(C)NS(=O)(=O)c1ccc(C(=O)O)cc1Cl
Agent: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2cc(Cl)ccc2S(=O)(=O)NC(C)C)CC1
Yield: 22 %

Procedure:
The title compound was prepared from a mixture of 5-chloro-2-[(isopropylamino) sulfonyl]benzoic acid and 3-chloro-4-[(isopropyl amino)sulfonyl]benzoic acid 2d and endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford 4-chloro-N-isopropyl-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]benzenesulfonamide 4 as a white solid (30 mg, 22% yield). 1H NMR (400 MHz, CDCl3) δ 8.13 (d, 1H, J=8.0 Hz), 7.65 (d, 1H, J=7.3 Hz), 7.52 (m, 1H), 7.40-7.11 (m, 9H), 4.99 (d, 1H, J=7.32 Hz), 4.60 (m, 1H), 4.20 (m, 1H), 3.49-3.22 (m, 6H), 2.56 (s, 3H), 2.40-2.32 (m, 3H), 2.18 (m, 1H), 1.98-1.66 (m, 1H), 1.62 (m, 2H), 1.10 (d, 6H, J=6.59 Hz). ES-LCMS m/z 690.45 (M+2H). Analytical HPLC (Method Y) Rt 5.03 (88.43%).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][S:5][S:6][CH2:7][CH:8]([OH:11])[CH2:9]Cl.CO.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:11]1[CH2:9][CH:8]1[CH2:7][S:6][S:5][CH2:4][CH:3]1[O:12][CH2:2]1
Reactant: OC(CCl)CSSCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: C1OC1CSSCC1CO1
Temperature: 5 °C

Procedure:
Next, a mixed solution of bis(3-chloro-2-hydroxypropyl)disulfide described above and 250 g of methanol was dripped into a reaction vessel containing a mixed solvent consisting of 500 g of toluene and 240 g of 47% aqueous solution of sodium hydroxide with the temperature of the solution in the reaction vessel being maintained at 0 to 10° C. At the point of the completion, no scum-like insoluble matter was generated. 100 g of toluene was added to carry out extraction, the aqueous layer was removed, and the organic layer was washed with 180 g of water three times. After that, no scum-like insoluble matter was generated. After that, the solvent was distilled away, thereby obtaining 171 g of bis(β-epoxypropyl)disulfide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([CH3:15])[C:3]=1[O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([CH3:1])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]=2[CH3:15])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCOc2c(C)cc([N+](=O)[O-])cc2C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.8 %

Procedure:
2-(2,6-Dimethyl-4-nitrophenoxy)ethanol (22 g) was dissolved into chloroform (200 ml) and triethylamine (20 ml) was added into this solution. Further, p-toluenesulfonylchloride (24.5 g) solution in chloroform (100 ml) was added into this solution in an ice bath. After being stirred for 6 hours at room temperature, the reaction mixture was washed with water (150 ml), 1N HCl (150 ml) and then 1N sodium hydroxide (150 ml). After being dehydrated with anhydrous magnesium sulfate (20 g), the solution was concentrated under vacuum to remove chloroform and residue was dissolved into ethyl acetate (50 ml). Hexane (200 ml) was added into ethyl acetate solution and separated solids were collected by filtration. Solids were dried under vacuum to obtain 2-(2,6-dimethyl-4-nitrophenoxy)ethyl p-toluenesulfonate (21.6 g) as yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:6](OC(C)(C)C)=[O:7].C(OC(=O)C)(=O)C>C(O)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:6]=[O:7]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(OC)cc1
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: COC(=O)CN(C=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 250 ml of formic acid was dissolved 36.9 g of N-Boc-p-methoxyphenylglycine methyl ester, and the mixture was stirred at room temperature for 3 hours and subsequently at 40°-50° C. for 1 hour. After dropwise addition of 24.8 ml (2.1 eq.) of acetic anhydride, the mixture was stirred at room temperature overnight and 40°-50° C. for 2 hours. After the solvent was distilled off, the residue was neutralized with an aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off. The crystals were collected by filtration with hexane.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([OH:21])=[O:20])[CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1cccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)c1
Yield: 74.8 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and m-aminobenzoic acid (0.714 g, 0.0052 mol) were refluxed as above overnight. Crystallisation of the product from MeOH yielded 1.21 g (72%) of 106 as a white solid: mp=>380° C.; Rf 0.87 (A): Rf 0.75 (C): Rf 0.27 (D):IR (cm−1): 2700–3125 (OH), 3090 (C═CH), 2665 (C—H), 1780 (C═O), 1731 (C═O), 1699 (C═O), 1610 (C═C), 1589 (C═C), 1484 (C═C), 1452 (C═C), 1383 (C—O), 1310 (C—O), 1222 (C—O), 722 (C═CH); MS m/z (rel intensity) 311 (22), 310 (100).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18](Br)[C:19]([C:22]#[N:23])=[N:20][CH:21]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH3:33])[N:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH3:33])[N:27]=2)[C:19]([C:22]#[N:23])=[N:20][CH:21]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)cc1Br
Reactant: CCc1cccc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C#N)n1
Temperature: 80 °C

Procedure:
A mixture of 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-bromopyridine-2-carbonitrile TFA salt (62 mg, 0.15 mmol), 2-amino-6-ethylpyridine (19 mg, 0.15 mmol), Xantphos (13 mg, 0.023 mmol), Pd2(dba)3 (14 mg, 0.015 mmol), and cesium carbonate (197 mg, 0.606 mmol) was evacuated and backfilled with nitrogen (3×). Dioxane (1 mL) was added, and the reaction mixture was heated to 80° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, filtered, and concentrated under reduced pressure to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carbonitrile. The material was used without further purification in the subsequent transformation. MS ESI calc'd. for C19H25N6 [M+H]+ 337. found 337.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.[ClH:25]>C(Cl)Cl.CCOCC>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(F)cccc2C(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1cccc(C(F)(F)F)c1C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carboxylate (22, 0.219 g, 0.63 mmol) in CH2Cl2 (4 mL) was added 2 N HCl (2.0 N solution in Et2O, 4 mL), and the mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with Et2O (50 mL) and the solids were collected by filtration to give 4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine hydrochloride (23) as an offwhite solid (158 mg, 88%): 1H NMR (300 MHz, DMSO-d6) δ 8.82 (br s, 1H), 8.50 (br s, 1H), 7.66-7.48 (m, 3H), 3.42-3.33 (m, 2H), 3.24-2.95 (m, 3H), 2.35-2.15 (m, 2H), 1.87-1.74 (m, 2H); ESI MS m/z 248 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13](=[N:16][C:17]#[N:18])SC)[N:3]=1.[CH3:19][NH2:20]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:13]([NH:20][CH3:19])=[N:16][C:17]#[N:18])[N:3]=1
Reactant: CN
Reactant: CSC(=NC#N)NCCSCc1nccc(N)n1
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nccc(N)n1
Reaction time: 18 h

Procedure:
A solution of 4-amino-2-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]pyrimidine (0.75 g.) in 33% w/v methylamine in ethanol (15 ml.) was left at room temperature for 18 hours. The solution was concentrated to 5 ml., cooled in ice, and the crystalline precipitate collected to give 4-amino-2-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]pyrimidine (0.52 g.), m.p. 189°-190°.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27].CCN(C(C)C)C(C)C>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2ccccn2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (pyridin-2-ylmethyl)-amine and DIEA to give 2-[(pyridin-2-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 347 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Br:12])=[CH:4][N:3]=1.[CH:13]1([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:12][C:5]1[C:6]([N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH:13]3[CH2:15][CH2:14]3)[CH2:18][CH2:19]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: C1CN(CC2CC2)CCN1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(CC3CC3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-amino-5-bromo-4-chloro-3-nitropyridine (0.126 g, 0.50 mmol) and isopropanol (6 ml) was added 1-cyclopropylmethylpiperazine (0.078 g, 0.55 mmol) with the aid of isopropanol (3 ml), followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and diluted with isopropanol (4 ml). The resulting yellow precipitate was collected by filtration, washed with isopropanol (2×4 ml), diethyl ether (3×4 ml), and dried. The title compound was obtained as a yellow solid (0.096 g). The filtrate was concentrated in vacuo, and purification of the resulting residue by chromatography (10 g isolute column) eluting with a gradient of methanol (2 to 4%) in dichloromethane/ethyl acetate (v/v; 1:1) afforded an additional 0.038 g of the product (overall yield: 76%). 1H-NMR (500 MHz, DMSO-d6) 0.08 (m, 2H) and 0.46 (m, 2H), (cyclopropyl CH2), 0.86 (m, 1H, cyclopropyl CH), 2.22 (d, J=6.6 Hz, 2H, N—CH2cyclopropyl), 2.57 (br s, 4H, piperazine N(CH2)2), 3.06 (br s, 4H, piperazine N(CH2)2), 6.96 (s, 2H, NH2), 8.15 (s, 1H, pyridine 6-H);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:25]=[N:24][N:23]=[N:22]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:32][C:29]3[CH:30]=[CH:31][C:26]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[CH:27][CH:28]=3)[N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(CCl)cs2)C1
Reactant: Oc1ccc(-n2cnnn2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1

Procedure:
A mixture of 3-(4-Chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (From Step 1) (300 mg, 0.946 mmol), 4-tetrazol-1-yl-phenol (155 mg, 0.946 mmol), CsCO3 (467 mg, 1.42 mmol) and KI (16 mg, 0.095 mmol) in acetonitrile (10 mL) was heated under reflux for 4 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 8.91 (1H, s), 7.63 (2H, d), 7.26 (1H, s), 7.17 (2H, d), 5.24 (2H, s), 4.30 (1H, br), 4.02 (1H, m), 3.20 (1H, m), 3.10 (1H, br), 2.88 (1H, t), 2.21 (1H, m), 1.77 (2H, m), 1.61 (1H, m), 1.47 (9H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[NH2:39][O:40][CH2:41][CH2:42][OH:43]>C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([NH:39][O:40][CH2:41][CH2:42][OH:43])=[O:14])=[C:5]([F:21])[CH:4]=1)[CH3:2]
Reactant: NOCCO
Reactant: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
The title compound was prepared from the reaction of the product of Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (93 mg, 0.32 mmol) dissolved in dry THF (5 mL), and carbonyldiimidazole (CDI) (102 mg, 0.63 mmol). Within 10 minutes, a bright yellow solution was obtained and conversion to the imidazolide was confirmed by TLC (50% EtOAc/hexanes). A solution of 2-(aminooxy)ethanol (97 mg, 1.26 mmol) in THF (5 mL) was then added and the mixture stirred for 15 hours at room temperature. The reaction solvent was removed under reduced pressure and the residue partitioned between 1 M HCl (50 mL) and EtOAc (50 mL). The EtOAc layer was then washed with water (50 mL) and saturated NaCl solution (50 mL), dried (Na2SO4), and the solvent removed under reduced pressure to afford an oil which was purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a cream solid (65%); m.p. (EtOAc/hexanes) 134–138° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.76 (br s, 1 H), 7.43–7.37 (m, 1 H), 7.14–7.02 (m, 2 H), 6.90 (dd, J=8.3, 1.5 Hz, 1 H), 6.83. (td, J=8.6, 4.4 Hz, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 2 H), 2.54 (q, J=7.6 Hz, 2 H), 1.15 (t, J=7.6 Hz, 3 H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:34]=[CH:33][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=3)[S:17][C:13]=2[CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:35]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([CH3:35])[C:11]1[CH:34]=[CH:33][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=3)[S:17][C:13]=2[CH:12]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccc(NC(=O)OC(C)(C)C)cc3s2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc2nc(-c3ccc(CNC(=O)OC(C)(C)C)nc3)sc2c1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
NaH (95%, 4.5 mg, 0.18 mmol) was added to a solution of tert-butyl (5-{6-[(tert-butoxycarbonyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)methylcarbamate (66 mg, 0.14 mmol) in DMF (2 mL). The mixture was cooled to 0° C. and MeI (10 μL, 0.16 mmol) was added. The reaction was stirred at rt on. Water was added and the mixture was extracted with EtOAc (3×) The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (Heptane/EtOAc gradient) gave the product (60 mg) as a white solid. MS m/z (M+H) 471.