Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH:31]=O)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]1([C:39]([CH2:41][N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:29]([C:28]1[C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:33])=[CH:22][CH:21]=2)=[N:24][CH:25]=[C:26]([CH2:31][N:45]2[CH2:44][CH2:43][N:42]([CH2:41][C:39](=[O:40])[N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:47][CH2:46]2)[CH:27]=1)#[N:30]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(C=O)cc2C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(CN3CCN(CC(=O)N4CCCC4)CC3)cc2C#N)cc1
Reaction time: 3 h
Yield: 70.9 %

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.3 g, prepared as described in Method 15 below) and 1-(pyrrolidinocarbonylmethyl)piperazine (0.14 g) were dissolved in dichloromethane (10 ml). Sodium triacetoxyborohydride (0.15 g) was added, and the mixture stirred for 3 hours before being washed with water (10 ml). The organic residues were separated and purified using flash column chromatography eluting with ethyl acetate, followed by (6-8%) MeOH in dichloromethane to give t-butyl (2-{[4-(3-cyano-5-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]methyl}pyridin-2-yl)benzoyl]amino}phenyl)carbamate (300 mg) as a pale yellow oil. The oil was dissolved in methanol (10 ml), and a 4M solution of hydrogen chloride in 1,4-dioxan (10 ml) added and the solution stirred at ambient temperature for 2 hours. The solvent was evaporated, methanol (5 ml) added and the resulting solution absorbed onto an SCX-2 column, which was then washed with methanol (2 column volumes) and the product eluted with a 2M solution of ammonia in methanol (2 column volumes). The ammonia/methanol was evaporated to give a foam. This was treated with diethyl ether (20 ml), stirred and filtered to give the product as a white solid (195 mg, 57%); NMR Spectrum: (DMSO-d6 373K) 1.82 (m, 4H), 2.50 (m, 8H), 3.11 (s, 2H), 3.40 (m, 4H), 3.66 (s, 2H), 4.74 (br s, 2H), 6.64 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.24 (d, 1H), 8.87 (d, 1H), 9.49 (br s, 1H); Mass Spectrum: M+H+ 524.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4=CC=CC=C4C3=O)[CH:8]=2)[N:3]=1.NN>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:8]=2)[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc2nc(Cl)ccc2c1
Agent: NN
Solvent: CCO
Product: NCCCOc1ccc2nc(Cl)ccc2c1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a suspension of 2-chloro-6-(3-phthalimidopropoxy)quinoline (9.0 g) in ethanol (250 ml) is added hydrazine.monohydrate (1.4 g), and the mixture is refluxed for 7.5 hours. The mixture is allowed to cool, and the precipitated crystals are collected by filtration, and suspended in water. The mixture is acidified with conc. hydrochloric acid, and stirred for one hour. The mixture is basified with a 10% aqueous potassium hydroxide solution, and extracted with chloroform. The extract is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent to give 2-chloro-6-(3-aminopropoxy)quinoline (4.7 g) as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].[OH-].[Na+]>CC#N.Cl>[CH2:1]([C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (1.50 g, 3.01 mmol) in MeCN (50 mL), 2 N aq. HCl (50 mL) was added slowly at rt. The resulting solution was stirred at room temperature overnight, then basified to pH=10 with 10 N aq NaOH aq, and MeCN was removed under vacuum. The aqueous residue was extracted with CH2Cl2 (4×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under vacuum to give (S)-1-(2-(2-ethylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (1.16 g, 97%) as a free amine. The crude product was used for next step without purification; MS m/z 398 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:25][C:26]1[C:27]([CH3:36])=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH:14]([CH2:20][OH:21])[CH2:15][OH:16])[N:9]=[CH:8][CH:7]=[C:6]2[O:25][C:26]1[C:27]([CH3:36])=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2
Reactant: CCOC(=O)C(Oc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OC(CO)CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
Diethyl 2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-malonate (compound 373) (50 mg) was dissolved in tetrahydrofuran (1 ml) to prepare a solution. Lithium aluminum hydride (10 mg) was added to the solution at 0° C., and the mixture was stirred at 0° C. for 3 hr and then at room temperature for 2 hr. Water was added to the reaction solution to stop the reaction. The mixture was filtered through Celite, water was then added to the filtrate, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (9.1 mg, yield 22%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:29]([N:18]1[C:19]2=[CH:25][S:24][CH:23]=[C:20]2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared by suspending the 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione (2.0 g, 5 mmol) of Example 10 in CH2Cl2 and treating it with acetyl chloride (469 mg, 6 mmol) and triethylamine (1 equivalent). After stirring at room temperature for 24 hours, the organic phase was washed with water and brine and dried over MgSO4. Solvent removal produced a crude product which was purified by flash silica gel chromatography using EtOAc/hexane (1/1). The title compound was crystallized from CH2Cl2 /hexane to give a white solid (337 mg, 15% yield), mp 150°-151° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]([CH2:18][CH2:19]Cl)[CH2:15][CH2:16]Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:30]([O:29][C:21]([C:22]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18][N:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CCN(Cc2ccccc2)CC1
Temperature: 80 °C

Procedure:
Potassium carbonate (79.22 g, 0.572 mol) and tetrabutylammonium bromide (6.16 g, 0.019 mol) are added to a solution of benzyl-bis-(2-chloroethyl)amine (47.5 g, 0.205 mol) and diethyl malonate (30.62 g, 0.191 mol) in N,N-dimethylformamide (450 mL). The reaction mixture is heated at 80° C. for 1.5 hours and then concentrated under reduced pressure. The residue is treated with demineralized water (200 mL) and the aqueous layer is extracted with ethyl acetate (3×100 mL). Combined organic layers are washed with brine (1×40 mL) and dried over sodium sulphate. Removal of solvent gives a viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate 80:20) to give 1-benzylpiperidine-4,4-dicarboxylic acid diethyl ester.
Reaction SMILES: [OH:1][CH:2]1[C:7]2([CH2:18][OH:19])[O:8][CH:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]3=[O:17])[CH:3]1[O:4][N:5]([CH3:20])[CH2:6]2.[CH3:21][O:22][C:23]1[CH:44]=[CH:43][C:26]([C:27](Cl)(C2C=CC=CC=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH:27]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:44][CH:43]=2)[O:19][CH:18]([C:23]2[CH:44]=[CH:43][CH:26]=[CH:25][CH:24]=2)[C:7]23[CH:2]([OH:1])[CH:3]([CH:9]([N:10]4[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]4=[O:17])[O:8]2)[O:4][N:5]([CH3:20])[CH2:6]3)=[CH:33][CH:32]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CN1CC2(CO)OC(n3ccc(=O)[nH]c3=O)C(O1)C2O
Solvent: c1ccncc1
Product: COc1ccc(C(OC(c2ccccc2)C23CN(C)OC(C(n4ccc(=O)[nH]c4=O)O2)C3O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
To a solution of compound 55 (1 mmol) in anhydrous pyridine (4 mL) was added 4,4′-dimethoxytrityl chloride (1.5 mmol). After stirring at room temperature for 6 hours the mixture was quenched with MeOH and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL), washed with saturated aqueous NaHCO3 (2×20 mL), brine (20 mL) and the organic layer dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography. Appropriate fractions were collected, concentrated to give compound 56 in 80% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([S:16](Cl)(=O)=O)=[CH:15][C:9]=2[N:8]=1)=[O:5].Cl[Sn]Cl>O>[CH3:2][O:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([SH:16])=[CH:15][C:9]=2[N:8]=1)=[O:5]
Reactant: COC(=O)Nc1nc2cc(S(=O)(=O)Cl)ccc2[nH]1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: COC(=O)Nc1nc2cc(S)ccc2[nH]1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
10.8 g. (0.033 moles) of 2-[(Methoxycarbonyl) amino]-1H-benzimidazole-5-sulfonic acid chloride hydrochloride are suspended in 35 ml. of water, 33 g. of SnCl2 are added and the mixture is stirred at 50° C. for 30 minutes. A clear solution is obtained and then the precipitation of a crystalline substance can be observed. The mixture is cooled to room temperature, filtered and the precipitate is washed with a small portion of ice water. 2-[(Methoxycarbonyl)amino]-1H-benzimidazole-5-thiol obtained is further treated as described in Example 6 to yield 5 g. of the title compound, melting at 210° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:32])[N:24]([CH2:28][CH2:29][C:30]#[N:31])[CH:25]([CH3:27])[CH3:26])[CH:20]=[C:19]([Cl:33])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[C:30]([CH2:29][CH2:28][N:24]([CH:25]([CH3:27])[CH3:26])[C:23](=[O:32])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=[C:19]([Cl:33])[CH:20]=1)(=[O:38])[NH2:31]
Reactant: CC(C)N(CCC#N)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCC(N)=O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 12 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-isopropyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.071 g) in a mixture of dichloromethane (4 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 12 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.045 g) was obtained as a yellow oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OCCc1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCc1ccccc1)c1cc(F)ccc1F
Yield: 74.5 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330 mmol) obtained in Example 5, and 2-phenylethyl alcohol (79.2 μl, 0.661 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (159 μl, 0.661 mmol). The resulting mixture was heated under reflux for 13 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column and the fraction obtained from the hexane:ethyl acetate=93:7 eluate was concentrated. The solid thus obtained was washed with hexane, whereby the title compound (100 mg, 0.246 mmol, 74%) was obtained as a white powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35](=[O:48])[CH:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:38]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35](=[O:48])[CH:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:38][I:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCI)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of triphenylphosphine (734 mg, 2.80 mmol) and imidazole (191 mg, 2.80 mmol) in CH2Cl2 (10 ml) at rt was added iodine (711 mg, 2.80 mmol) portionwise over 5 min. The mixture first turned yellow, then brown and developed precipitate. The mixture was stirred at rt until no pieces of iodine were visible (approx. 5 min.). A solution of alcohol from step (38b) (721 mg, 2.33 mmol) in CH2Cl2 (5 ml) was added and the resulting mixture was stirred at rt for 1 h. The reaction was filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0-25% EtOAc/Hexane) gave 2-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester (430 mg, 44%) as a slightly yellow oil: 1H NMR (500 MHz, Methanol-D) δ 7.24-7.42 (m, 5 H), 5.07-5.25 (m, 2 H), 4.16-4.31 (m, 1 H), 3.12-3.29 (m, 2 H), 2.01-2.35 (m, 2 H), 1.42 (s, 9 H). LC-MS (Method A, retention time: 1.71 min), MS m/z 420 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH:8]=[O:9].O.[SH-:12].[Na+].[BH4-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([SH:12])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: [SH-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1c(S)cncc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under argon atmosphere a mixture of 3,5-dichloro-pyridine-4-carbaldehyde (3.00 g, 17.05 mmol) and sodium hydrosulfide hydrate (flakes 70%, 1.37 g, 17.05 mmol) in DMF (20 mL) was stirred at 0° C. for 15 min. NaBH4 (8.52 g, 17.05 mmol) was added. After 30 min at 0° C. the solution was filtered and the solvent was removed in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 176.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].CC[N:14](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:14])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Cl)c1O
Reaction time: 0.25 h

Procedure:
A mixture of 3-chloro-2-hydroxybenzoic acid (335 mg, 1.94 mmol), DIPEA (2.98 mL, 17.08 mmol), HATU (849 mg, 2.232 mmol) was dissolved in DMF (1.94 mL)/THF (7.77 mL). The reaction was stirred for 15 min, then ammonium chloride (457 mg, 8.54 mmol) was added. The reaction mixture was stirred at room temperature overnight. The volatiles were evaporated under reduced pressure. The residue was diluted with saturated 1N HCl (20 mL) and extracted with EtOAc (3×5 mL). The combined organic fractions were washed with water (30 mL), sat. NaHCO3 (20 mL), brine (20 mL), dried over MgSO4 and evaporated under reduced pressure. The resulting residue was purified by Combiflash™ chromatography (SiO2, 12 g, elution with 10-70% EtOAc/hexanes over 40 min) to afford the title compound as solid.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.[C:45](=O)([O:56][CH:57]1[CH2:61][CH2:60][O:59][CH2:58]1)[O:46]C1C=CC([N+]([O-])=O)=CC=1>C(Cl)Cl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:45](=[O:46])[O:56][CH:57]3[CH2:61][CH2:60][O:59][CH2:58]3)[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNC(=O)OC2CCOC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (18 mg, 0.032 mmol) and triethylamine (22 μL, 0.16 mmol) in methylene chloride (1 mL) was added 4-nitrophenyl tetrahydrofuran-3-yl carbonate (9.8 mg, 0.039 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.8 mg, 12%). LCMS calculated for C22H29N4O4S (M+H)+: m/z=445.2. Found: 445.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:22][C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH4+].[OH-]>ClCCCl.O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:22][C:23]2[CH:24]=[N:25][C:26]([Cl:29])=[N:27][CH:28]=2)[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1cnc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C1(CCNc2cnc(Cl)nc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.2 %

Procedure:
To a mixture of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (324 mg, 1.08 mmol) and 5-amino-2-chloropyrimidine (140 mg, 1.08 mmol) in DCE (3 mL) was added AcOH (0.19 mL, 3.4 mmol) followed by NaBH(OAc)3 (687 mg, 3.24 mmol) and then stirred for 18 hours at ambient temperature. Water was added and the solution was brought to pH 9 with NH4OH. The two layers were separated and the aqueous was extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated to afford a solid which was purified by flash column chromatography (5 to 50% EtOAc/Heptane) to provide 188 mg (42% yield) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)(=[O:9])[CH3:8].[CH3:18][O:19][C:20](=[O:32])[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[CH2:30]Br>CC(C)=O>[CH3:18][O:19][C:20](=[O:32])[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[CH2:30][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:7](=[O:9])[CH3:8])[CH:12]=1
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1COc1cccc(NC(C)=O)c1
Reaction time: 0.25 h

Procedure:
In accordance with general method U, 1.50 g (10.86 mmol) of potassium carbonate are suspended in 15 ml of acetone, 1.80 g (11.90 mmol) of 3-acetamidophenol are then added and the mixture is stirred for 15 min. 2.44 g (8.91 mmol) of (2) are added to the mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[O:9])[S:5][C:6]=1[Cl:7].C([O-])([O-])=O.[Na+].[Na+].[CH3:41][N:42]1[C:46](B2OC(C)(C)C(C)(C)O2)=[C:45]([CH3:56])[CH:44]=[N:43]1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:7][C:6]1[S:5][C:4]([C:8]([NH:10][C@@H:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[O:9])=[CH:3][C:2]=1[C:46]1[N:42]([CH3:41])[N:43]=[CH:44][C:45]=1[CH3:56]
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1cc(Br)c(Cl)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 75 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of 4-bromo-5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (260 mg, 0.46 mmol) in THF (5 mL) was added Na2CO3 (2N, 0.7 mL, 1.4 mmol), Pd(dppf)Cl2 (40 mg, 48 μmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (303 mg, 1.38 mmol). The reaction mixture was heated to 75° C. in a sealed tube under N2. After 8 h, the reaction mixture was concentrated under vacuum and purified on silica (10:1 CHCl3/MeOH) to afford the title compound (196 mg, 73.4%): LC-MS (ES) m/z=587 (M+H)+.