Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(CN2CCCC2)cc1
Solvent: ClCCl
Product: ClCc1ccc(CN2CCCC2)cc1

Procedure:
A solution of the product of Step C in DCM (200 mL) was treated with thionyl chloride (20 mL) at 40° C. for 16 hours. Solvent was removed in vacuo to give the titled compound (15 g), which was used without purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[S:24]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25]1.Cl.Cl.C(OCC)C>C(Cl)(Cl)Cl>[ClH:22].[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:33][C:30]5[N:29]=[CH:28][C:27]6[O:26][CH2:25][S:24][C:32]=6[CH:31]=5)[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)C[C@H]1O
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=c1ccc2ncc(Cl)c3c2n1CC3CN1CC[C@H](NCc2cc3c(cn2)OCS3)[C@H](O)C1

Procedure:
The free base of the title compound was synthesised from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 61) according to the general method of Example 24(b). The free base of the title compound was converted to the hydrochloride by dissolving in chloroform and adding 1 equivalent of 1M HCl/diethyl ether, then evaporating to dryness. MS as that of free base.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:10]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28](C#N)=[C:27]([N:31]=[CH:32][N:33]([CH3:35])C)[NH:26][N:25]=2)=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO>[C:10]([O:14][C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:28]3[C:27](=[N:31][CH:32]=[N:33][C:35]=3[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([Cl:2])[CH:4]=3)[NH:26][N:25]=2)=[CH:22][CH:23]=1)=[O:16])([CH3:11])([CH3:13])[CH3:12]
Reactant: Nc1cccc(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)c1C#N
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reaction time: 19 h

Procedure:
With the exclusion of air, 172 mg (1.05 mmol) of 3-chloro-aniline hydrochloride (see Step 14.4) are added to 248 mg (0.70 mmol) of N'-[3-(4-tert-butoxycarbonylamino-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine in 2 ml of methanol and the reaction mixture is boiled for 19 hours. The reaction mixture is then concentrated by evaporation and chromatographed (SiO2, methylene chloride/ethanol [20:1]). Stirring with diethyl ether/hexane yields 3-(4-tert-butoxycarbonylamino-phenyl)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 165-168° C. (decomposition); FAB-MS: (M)+= 436; HPLC: TRet (Grad20-100)=15.4.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([NH:40][C:41](=[O:43])[CH3:42])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([NH:40][C:41](=[O:43])[CH3:42])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
N-{6-[1-Hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}acetamide (11.5 g) and pyridine hydrochloride (390 mg) were dissolved in methanol (8 ml) and the mixture was stirred at 60° C. for 2 h. After allowing to cool, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate. The solvent was evaporated and the residue was collected by filtration and washed with ethanol. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (eluate, dichloromethane:methanol =30:1→10:1) and recrystallized from ethyl acetate to give the title compound (5.52 g) as a pale-red powder.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[C:21]([OH:29])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][CH2:4][C@@H:2]2[CH2:3][O:1]2)[CH:20]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Cl)cc1OC[C@@H]1CO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To a mixture of (2S)-oxiran-2ylmethyl3-nitrobenzenesulfonate (3.37 g, 13.25 mmol), N-(4-chloro-2-hydroxyphenyl)acetamide (2.46 g, 17.23 mmol) and Cs2CO3 (6.48 g, 19.88 mmol) was added DMF (20 mL) at 0° C. and the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (hexane:ethyl acetate 3:2) to give the subtitled compound (2.36 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]1=[O:21])[O:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:31](=[O:33])[CH3:32])=[CH:10][CH:9]=2)[CH2:5][O:6]1
Reactant: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 3-(5-Amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (56.5 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.5 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring at room temperature for 3 h, the mixture was concentrated in vacuo and the solid triturated with MeOH. Filtering the mixture and rinsing with MeOH and hexanes/EtOAc (7:3) afforded the title compound (55.9 mg, 87%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:32]([N:39]([CH:44]([CH3:46])[CH3:45])[C:40](=[O:43])[CH2:41]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.P([O-])([O-])([O-])=O>[CH2:32]([N:39]([CH:44]([CH3:46])[CH3:45])[C:40](=[O:43])[CH2:41][N:13]1[C:12](=[O:21])[CH2:11][C:10]2[N:16]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]1=2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CBr
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(A) (30.0 g, 108 mmol) in DMF (200 mL) at 0° C. was added NaHMDS (1.0M in THF, 13.6 g, 118 mmol) and N-benzyl-2-bromo-N-isopropyl-acetamide (Preparation 1(C) (35.2, 130 mmol) in DMF (25 mL). The reaction was stirred at room temperature for 24 hours and was diluted with a pH 6.8 phosphate buffer. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with brine (3×), dried (Na2SO4), filtered and concentrated. Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 12% acetone in CH2Cl2) provided 13.9 g of N-benzyl-N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide. 1H NMR (CDCl3) δ 7.64-7.55 (m, 2H), 7.44-7.08 (m, 11H), 6.89 (m, 1H), 4.96-4.08 (m, 6H), 3.57 (m, 1H), 1.17 (m, 6H).
Reaction SMILES: C(O)C.C([O:6][C:7]([C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:11][C:10]=1[CH3:21])=[O:8])C.[OH-].[Na+]>C(O)(=O)C>[CH3:21][C:10]1[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:13][C:9]=1[C:7]([OH:8])=[O:6]
Reactant: CCOC(=O)c1sc(Nc2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc(Nc2ccccc2)sc1C(=O)O
Temperature: 80 °C
Reaction time: 15 h
Yield: 47.9 %

Procedure:
To 70 ml of ethanol, 10.7 g (70 mmol) of phenylthiourea and 11.6 g (70 mmol) of ethyl 2-chloro-3-oxobutanate were dissolved, followed by heating under refluxing for 8 hours. The reaction liquid was concentrated and dissolved in ethyl acetate and the organic layer was washed with an aqueous solution of sodium carbonate, water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. Solid obtained was washed with diisopropyl ether to obtain 16.8 g (yield: 91%) of ethyl 4-methyl-2-(N-phenylamino)thiazole-5-carboxylate. (2) To 50 ml of ethanol, 12.8 g (49 mmol) of ethyl-4-methyl-2-(N-phenylamino)thiazole-5-carboxylate was dissolved, followed by adding 24 g (150 mmol) of 25% sodium hydroxide aqueous solution, and stirring at 80° C. for 15 hours. The reaction liquid was poured into ice water, and acetic acid was added to make acidic. Crystal precipitated was filtered, washed with water and a mixed solvent of hexane/ethyl acetate and dried to obtain 5.50 g (yield: 48%) of 4-methyl-2-(N-phenylamino)thiazole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(NCc2ccccc2)ccn1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=c1c(Br)c(NCc2ccccc2)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one (0.50 g, 1.62 mmol) in anhydrous CH2Cl2 (10 mL) was added N-bromosuccinimide (NBS, 0.30 g, 1.7 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 3 h. The reaction mixture was purified by flash chromatography (silica gel) using EtOAc in hexanes (1:1 v/v). The appropriate fractions were combined and concentrated.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1ccc2ccc(N)cc21
Temperature: 70 °C
Yield: 40.2 %

Procedure:
1-methyl-6-nitro-1H-indole (90 mg, 0.51 mmol), ammonium chloride (55 mg, 1.02 mmol) and iron powder (143 mg, 2.55 mmol) were suspended in ethanol/water (2 mL/1 mL) and heated at 70° C. for 2 h. After cooling, the solution was filtrated through a pad of Celite®, which was washed with ethanol. Ethyl acetate was added to the filtrate and the organic layer was washed with water twice. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 30 mg (37%) of the title compound
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:21](=[O:26])[CH2:20]2)[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CC(CC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A suspension of 4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}piperidine-2,6-dione (Example 14, 0.500 g, 1.35 mmol), methyl bromoacetate (0.247 g, 1.62 mmol), and potassium carbonate (0.56 g, 4.05 mmol) in DMF (6 mL) was stirred at 60° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=50:50 to 0:100) to provide methyl (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetate (0.474 g, 79%) as a white amorphous.
Reaction SMILES: [CH2:1]([N:4]([C:42]1[C:47]([C:48]([O:50]CC)=[O:49])=[CH:46][CH:45]=[C:44]([C:53]([F:56])([F:55])[F:54])[N:43]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[CH2:1]([N:4]([C:42]1[C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=[C:44]([C:53]([F:54])([F:55])[F:56])[N:43]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nc(C(F)(F)F)ccc1C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nc(C(F)(F)F)ccc1C(=O)O

Procedure:
Ethyl 6-trifluoromethylpyridin-2-one-3-carboxylate, prepared by the method described in Helv. Chim. Acta. 71, 596 (1988), is chlorinated with phosphorus oxychloride to give the 2-chloro compound. Treatment of ethyl 2-chloro-6-trifluoromethylpyridine-3-carboxylate with N-triphenylmethyl-5-[2-(4'-propylaminomethyl-biphenyl)]tetrazole, prepared as described in Example 72B, in tetrahydrofuran containing triethylamine affords the tertiary amine. Treatment of ethyl 2-{N-propyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-6-trifluoromethyl-pyridine-3-carboxylate with p-toluenesulfonic acid monohydrate in methanol to detritylate followed by sodium hydroxide in methanol hydrolysis gives the title compound.
Reaction SMILES: [CH2:1]1[O:20][C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14]CC(O)=O)[C:10](=[O:19])[CH2:9]2)([O:5][CH2:6][CH3:7])[O:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:27]1CCCC1>>[CH2:1]1[O:20][C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:27])[C:10](=[O:19])[CH2:9]2)([O:5][CH2:6][CH3:7])[O:3][CH2:2]1
Reactant: CCOC1(N2CCC(CCC(=O)O)C(=O)C2)OCCO1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCOC1(N2CCC(CO)C(=O)C2)OCCO1
Temperature: 0 °C
Yield: 84 %

Procedure:
To an ice cooled solution of ethyl 4-carboxyethyl-3-oxopiperidine-1-carboxylate ethylene ketal (38 g, 0.132 mol, U.S. Pat. No. 4,278,676) in tetrahydrofurane (100 ml) is added lithium aluminium hydride pellets (2.51 g, 0.066 mol). The ice bath is removed and the reaction mixture is allowed to reach reflux temperature and is then kept at reflux temperature for 3 hours. The mixture is quenched with dilute hydrochloric acid and is diluted with dichloromethane. The mixture is washed twice with saturated brine, dried over magnesium sulphate and evaporated in vacuo to give 27.3 g (0.111 mol, 84%) of oily title product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4](OS(C)(=O)=O)[CH2:3]1.[N-:13]=[N+:14]=[N-:15].[Na+].O>CN(C=O)C>[N:13]([CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCCC(OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCC(N=[N+]=[N-])C1
Temperature: 80 °C

Procedure:
To a stirred solution of methanesulfonic acid 1-methyl-piperidin-3-yl ester (A) (3 g, 0.17 mmol) in DMF (35 cm3) was added sodium azide (11 g, 0.17 mol). The reaction was then heated to 80° C. for 16 h, and allowed to cool before water (80 cm3) was added and the organic material was extracted into ethyl acetate (80 cm3). The aqueous layer was then extracted with a further portion ethyl acetate (60 cm3) and the combined organic collections and washed with saturated aqueous sodium chloride solution (100 cm3). The organic mixture was and dried over sodium sulfate and then evaporated under reduced pressure to afford the title compound as a crude oil, which was used as crude in next reaction.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([CH3:39])[CH2:21][CH2:22]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCNCC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(c2nc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c(-c3nc4ccccc4s3)c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Into a solution of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-(piperidin-4-yl)-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate (100 mg, 0.20 mmol, 1.00 equiv) and formaldehyde (30% in water, 22 mg, 0.73 mmol, 3.74 equiv) in dichloromethane (5 ml) was added sodium triacetoxyborohydride (62.3 mg, 0.29 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature, quenched with water (5 mL), and extracted with ethyl acetate (2×5 mL). The combined organic phases were washed with brine (10 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under vacuum, 100 mg of the title compound was obtained as a solid, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 525.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[C:5]([Cl:30])=[CH:4][N:3]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O.C(O)(=O)C>ClCCl>[Cl:30][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)=[CH:7][C:2]([NH:1][CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(N)ncc4Cl)ccnc3[nH]2)CC1
Reactant: O=Cc1cccc(F)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(NCc5cccc(F)c5)ncc4Cl)ccnc3[nH]2)CC1
Reaction time: 8 h

Procedure:
To a solution of Example 307A (74 mg, 0.17 mmol) and 3-fluorobenzaldehyde (107 mg, 0.86 mmol) in dichloromethane was added acetic acid (0.05 mL, 0.86 mmol) and MP-CNBH3 (2.49 mmol/g) (278 mg, 0.69 mmol). The mixture was stirred overnight and the insoluble material was filtered off. The filtrated was concentrated. The residue was purified by flash chromatograph eluting with a gradient of 10%-50% ethyl acetate in hexanes to provide the title compound. LCMS: 537 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][N:14]=2)[CH:3]=1.[N:25]1([CH2:31][CH2:32][OH:33])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CCCCO>[OH:33][CH2:32][CH2:31][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[S:11][C:12]([S:15][C:16]4[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=4)=[CH:13][N:14]=3)[CH:3]=2)[CH2:27][CH2:26]1
Reactant: OCCN1CCNCC1
Reactant: Cc1nc(Cl)cc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 115 °C
Yield: 69 %

Procedure:
To a stirring solution of 4-(2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazol-5-ylthio)picolinic acid (104 mg, 0.274 mmol) and 2-(piperazin-1-yl)ethanol (195 mg, 1.50 mmol) in n-BuOH (2 mL) was added i-Pr2NEt (0.20 mL, 1.15 mmol). The reaction was then heated to 115° C. in a sealed reaction vessel overnight. The reaction was cooled to room temperature and the solid collected by filtration, the filter cake was washed with n-BuOH then air dried to give the title material (89.5 mg, 69%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.59 (1H, s), 8.27 (1H, d, J=5.05 Hz), 7.71 (1H, s), 7.53 (1H, d, J=2.02 Hz), 7.07 (1H, dd, J=5.05, 2.02 Hz), 6.03 (1H, s), 4.45 (1H, t, J=4.67 Hz), 3.49 (6H, s), 2.41 (2H, t, J=6.32 Hz), 2.33 (3H, s). LC/MS (M+H)+: 474. HPLC ret. time (Condition I): 1.097 min.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:22])[CH:15]=1.CC(O)=O>C(Cl)Cl.[Zn]>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:21]([CH2:20][C:16]2[CH:15]=[C:14]([S:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:35])=[O:4])[CH:19]=[CH:18][CH:17]=2)=[O:22])=[CH:26][CH:27]=1
Reactant: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)O)c1)OCc1ccc(C(F)(F)F)cc1
Yield: 69.9 %

Procedure:
2-[3-(4-Trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester (105 mg, 0.177 mmol) was dissolved in DCM (8 mL) and zinc (232 mg, 3.55 mmol) was added. After stirring for 5 minutes HOAc, 97% (1 mL, 18 mmol) was added dropwise. The resulting slurry was stirred for 1.5 h before zinc was filtered off and washed with DCM. The organic phase was washed with water, dried through a phase separator and concentrated. The crude was submitted to flash chromatography using heptane and EtOAc (70/30-60/40) as eluent to give the titled compound (57 mg, 70%) as an oil; 1H NMR (400 MHz, CDCl3): δ 3.64 (s, 2H), 4.56 (s, 2H), 5.18 (s, 2H), 7.09-7.14 (m, 1H), 7.16-7.21 (m, 2H), 7.22-7.34 (m, 3H), 7.36-7.43 (m, 3H), 7.60 (d, 2H), 8.00 (d, 1H); Mass spectrum: M−H+ 459.