Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1(F)CCN(C(C2NC3=NC=C(OC4CCN(C(C)C)CC4)C=C3C=2)=O)CC1.C[O:31][C:32]([C:34]1[N:53](C(OC(C)(C)C)=O)[C:37]2=[N:38][C:39]([Cl:52])=[C:40]([O:42][CH:43]3[CH2:48][CH2:47][N:46]([CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:44]3)[CH:41]=[C:36]2[CH:35]=1)=[O:33].Cl>O1CCOCC1>[ClH:52].[Cl:52][C:39]1[N:38]=[C:37]2[NH:53][C:34]([C:32]([OH:33])=[O:31])=[CH:35][C:36]2=[CH:41][C:40]=1[O:42][CH:43]1[CH2:44][CH2:45][N:46]([CH:49]([CH3:51])[CH3:50])[CH2:47][CH2:48]1
Reactant: COC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Cl)nc2n1C(=O)OC(C)(C)C
Agent: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3nc2Cl)CC1

Procedure:
The title compound was synthesized in analogy to example 13, intermediate b), from 6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and concentrated hydrochloric acid in dioxan after stirring at reflux temperature for 4 hours. The product was obtained as a light brown solid (>100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:20]#[C:21]Br.O>C1COCC1.C(OCC)(=O)C>[O:7]([CH2:6][CH2:5][C@H:2]1[CH2:3][O:4][C:21]([NH2:20])=[N:1]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@@H](CCOc2ccccc2)CO1
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a stirred mixture of (S)-2-amino-4-phenoxy-butan-1-ol (175 mg) and K2CO3 (200 mg) in THF (5 ml) under an argon atmosphere was added a solution of cyanogen bromide (123 mg) in THF (1 ml). The mixture was stirred for 18 hours, then water and ethyl acetate were added. The organic layer was washed with water, dried over MgSO4 and evaporated over Isolute® Flash-NH2 silica gel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=95:5) yielded the title compound as a white solid, (62 mg, 31%); MS (ISP): 207.1 ((M+H)+).
Reaction SMILES: [NH2:1][C:2]([C@@H:4]([NH:9][C:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:21][CH2:22][S:23]([CH3:25])=[O:24])[C:13]1=[O:26])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].ClC1C=CC=C(C(OO)=[O:35])C=1.C([O-])(O)=O.[Na+]>ClCCl>[NH2:1][C:2]([C@@H:4]([NH:9][C:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:21][CH2:22][S:23]([CH3:25])(=[O:35])=[O:24])[C:13]1=[O:26])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CS(=O)CCn1c(=O)n(C(=O)N[C@H](C(N)=O)C(C)(C)C)c2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)n1c(=O)n(CCS(C)(=O)=O)c2ccccc21)C(N)=O
Reaction time: 8 h

Procedure:
A mixture of N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(methylsulfinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (Example 33, 150 mg), m-chloroperbenzoic acid (70%, 170 mg) and NaHCO3 (150 mg) in dichloromethane (5 mL) was stirred overnight and quenched with sat. Na2S2O3 aq. (25 mL) The whole was extracted with ethyl acetate (25 mL×2). The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated in vacuo. The residue was purified by preparative TLC to yield the titled compound. (100 mg)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.N>C(Cl)Cl.CO>[C:14]([CH:11]1[CH:12]2[CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13]2)(=[O:16])[NH2:17]
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2C(=O)O
Reactant: c1ccc2[nH]nnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
The 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (252 mg, 1.11 mmol) prepared in Example 3, benzotriazole (180 mg, 1.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (255 mg, 1.33 mmol) were dissolved in 3.0 mL of methylene chloride and diisopropylethylamine (232 μL, 1.33 mmol) was added dropwise. After adding 2 M ammonia solution (2.49 mL, 4.98 mmol) dissolved in methanol dropwise at 0° C., the mixture was stirred at room temperature for 4 hours. The completion of the reaction was confirmed by TLC (CH2Cl2:MeOH=15:1). After the reaction was completed, the reaction mixture was diluted with methylene chloride and washed with saturated sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (CH2Cl2:MeOH=15:1) to obtain 177 mg (70.6%) of the target compound.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH2:8]([O:10][C:11](=[O:29])[CH2:12][N:13]([C:19]([S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:14][P:15](Cl)(Cl)=[O:16])[CH3:9].[CH:30]1[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:37]>C(OCC)C>[CH2:8]([O:10][C:11](=[O:29])[CH2:12][N:13]([C:19]([S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:14][P:15]([O:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:6]([CH3:7])[CH:30]=1)([O:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:37])[CH:30]=1)=[O:16])[CH3:9]
Reactant: Cc1cccc(O)c1
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Reactant: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(Oc1cccc(C)c1)Oc1cccc(C)c1)C(=O)SCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of triethylamine (7.25 g.; 0.072 mol.) in 100 ml. of diethyl ether was added dropwise to a solution of freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (13.8 g.; 0.036 mol.) and m-cresol (7.8 g.; 0.072 mol.) dissolved in 150 ml. of diethyl ether. The reaction mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with 5% sodium hydroxide, 10% hydrochloric acid, and brine. The ether layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was taken up in methylene chloride and again washed, dried and concentrated to yield ethyl-N-[(benzylthio)carbonyl]-N-[bis-(3-methylphenoxy)phosphinylmethyl]-glycinate as an oil (nD25 =1.5589) having the following analysis:
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].C(N(CC)CC)C.[C:14](Cl)(=[O:16])[CH3:15].Cl>CN(C)C1C=CN=CC=1.O.O1CCOCC1.O1CCOCC1>[C:14]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CNCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)CC(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Dimethylaminopyridine (3.66 g) was added to a solution of sarcosine (26.7 g) and triethylamine (50 ml) in (1:1) dioxane water (150 ml) cooled at 0° C. A solution of acetyl chloride (22.37 ml) in dioxane (20 ml) was added dropwise over a period of 30 min. The reaction solution was then stirred at room temperature for 1 hour and subsequently was acidified to pH 3 with cold 50% aqueous HCl. The mixture was extracted three times with ethyl acetate. The extracts were washed with a saturated NaCl solution, dried over Na2SO4 and concentrated. The residue was crystallized from ethyl acetate to give N-acetyl-sarcosine, m.p. 135°-137° C. Fab Mass spec. m/e 132 (M+H); Anal. for C5H9NO3, Calcd: C, 45.79; H, 6.91; N, 10.68; Found: C, 45.78; H, 7.03; N, 10.64.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(Cl)Cl.C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:28](=[O:29])[O:30][CH3:31])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)Cl
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.0 gm, 7.6 mmol) and triethylamine (1.0 gm, 10 mmol) in DCM (50 ml) was treated with methyl chloroformate (860 mg, 9.12 mmol) dropwise at room temperature. The mixture was stirred for 1 hr. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The purification was done by flash chromatography over a silica gel columns(28 gm of Sorbsil C-30, eluted with DCM and MeOH/DCM). The pure oil thus obtained weighed 2.34 gm. It was converted to a fumarate salt by treatment with fumaric acid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by adding drops of isopropyl ether, yield: 2.31 gm, m.p.=163°-165° C.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:23](=[O:24])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:21]2[S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:20]2[C:19]1=[O:36].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:24])[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:21]4[S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:20]4[C:19]3=[O:36])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Sc1cccc2nccn12
Reactant: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCCl)CCS2(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCSc1cccc3nccn13)CCS2(=O)=O
Reaction time: 0.17 h

Procedure:
To a suspension of 60 mg (1.5 mmol) of 60% oily sodium hydride in 10 ml of N,N-dimethylformamide, 225 mg (1.5 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 10 minutes. To this mixture, 480 mg (1.3 mmol) of 6-(4-chlorobutyl)-1,1-dioxo-8-phenyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione and 225 mg (1.5 mmol) of sodium iodide were added, followed by stirring at 80° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/ethanol=10/1) to yield 400 mg (65.7%, white foamy substance) of the desired product.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[NH:28][C:27]([O:29][C@@H:30]3[CH2:34][O:33][C@@H:32]4[C@:35]([CH2:39][CH:40]=[O:41])([OH:38])[CH2:36][O:37][C@H:31]34)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[OH2:42]>C(Cl)(Cl)(Cl)Cl.C(#N)C.O.[Ru](Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]2[NH:28][C:27]([O:29][C@@H:30]3[CH2:34][O:33][C@@H:32]4[C@:35]([CH2:39][C:40]([OH:42])=[O:41])([OH:38])[CH2:36][O:37][C@H:31]34)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: O=CC[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Reactant: O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(O)C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium periodate (41.5 mg, 0.194 mmol) and ruthenium (III) chloride hydrate (1.5 mg, 6.65 μmol) were added to a stirred solution of 2-[(3R,3aR,6R,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-6-hydroxy-3,3a,5,6a-tetrahydro-2H-furo[3,2-b]furan-6-yl]acetaldehyde (32.4 mg, 0.066 mmol) in carbon tetrachloride (0.2 ml), acetonitrile (0.2 ml), and water (0.26 ml). The reaction mixture was stirred at room temperature. After 6 hours, the reaction mixture was placed in the refrigerator overnight. In the morning, the reaction mixture was removed from the refrigerator and allowed to warm to room temperature. After 4 hours, the reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, dried over MgSO4, filtered, and evaporated under reduced pressure to give an off-white residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C26H22ClN3O6 507.12 observed m/e: 508.21 (M+H)+ (Rt 1.17/2 min); 1H NMR δ (ppm) (CD3OD): 7.97 (s, 1H), 7.74-7.77 (m, 4H), 7.70 (d, J=7.8 Hz, 2H), 7.48 (t, J=7.7 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 5.58 (qt, J=5.4 Hz, J=10.8 Hz, 1H), 4.99 (t, J=5.4 Hz, 1H), 4.41 (d, J=4.9 Hz, 1H), 4.15-4.21 (m, 2H), 3.83 (abqt, J=8.9 Hz, J=69.3 Hz, 2H), 2.58-2.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH2:6].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH:6][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: Cl
Product: O=[N+]([O-])c1ccc(CNCc2cc(Cl)cc(Cl)c2)cc1
Yield: 71 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 3,5-dichlorobenzylamine and 4-nitrobenzaldehyde gave the title compound as a yellow powder (71%). 1H NMR (CD3OD, 300 MHz) δ 8.37 (d, 2H, J=8.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 7.61 (br s, 3H), 4.48 (s, 2H), 4.38 (s, 2H). M−(LC/MS(ESI)): 309; M+(LC/MS(ESI)): 311 HPLC (Condition A), Rt: 2.78 min (HPLC purity: 93.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:31][C:32]2[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=2)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c(C(Nc2cc(C)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-1H-pyrazole-5-carboxylate (Step 52.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.74 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 553 [M+H]+ (LC-MS 2); Rf=0.55 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl.Cl[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[N:14]1[CH:15]=[CH:16][C:11]([S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccncc1
Reactant: Nc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2ccncc2)cc1
Temperature: 80 °C
Yield: 78 %

Procedure:
To a solution of 4-aminothiophenol (20.2 g, 156.5 mmol) in anhydrous DMF (200 mL) was added 4-chloropyridine hydrochloride (24.4 g, 161.0 mmol) followed by potassium carbonate (44 g, 318.4 mmol). The reaction mixture was heated at 80° C. overnight, then diluted with ethyl acetate (400 mL) and water (400 mL). The aqueous layer was back-extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with a saturated aqueous NaCl solution (200 mL), dried over anhy MgSO4, and concentrated under reduced pressure. The residue was filtered through a pad of silica with ethyl acetate and the resulting material was triturated with an ethyl ether/hexane solution to afford the desired product (24.7 g, 78%). TLC (50% ethyl acetate/50% hexane) Rf 0.25; 1H-NMR (DMSO-d6) δ 5.67 (bs, 2H), 6.65 (d, J=8.4 Hz, 2H), 6.88 (d, J=6.2 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 8.27 (d, J=6.2 Hz, 2H), MS[M+H]+=203.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[C:7]1([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([CH3:26])[C:15]=3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH2:27]>N1C=CC=CC=1>[C:7]1([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([C:26]([OH:2])=[O:27])[C:15]=3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O
Reactant: Cc1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Temperature: 40 °C
Reaction time: 12 h

Procedure:
2.1 g of potassium permanganate in 36 ml of water were added to a solution of 600 mg of 5-phenyl-3-methyl-1H-pyrazolo[4,3-c]isoquinoline in 36 ml of pyridine. The mixture was stirred at 40° C. for 12 h. The resulting suspension was filtered with suction through silica gel, after which the filtrate was concentrated under reduced pressure and the residue was purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 60.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(N(CC)C(C)C)(C)C>CN1CCN(C)C1=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][NH:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[O:29][CH3:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCN(C)C1=O
Product: COc1ccccc1CNC[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 93 °C
Reaction time: 7 h

Procedure:
A mixture of (2S)-2-(4-methylphenylsulfonyloxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (26.2 g), 2-methoxybenzylamine (44 ml) and N,N-diisopropylethylamine (17.6 ml) in 1,3-dimethyl-2-imidazolidinone (393 ml) was stirred at 93° C. for 7 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a syrup of (2S)-2-[(2-methoxybenzylamino)methyl]pyrrolidine-1-carboxylic acid benzyl ester (15.7 g).
Reaction SMILES: [CH3:1][S:2][C:3]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].Cl[CH2:21][CH2:22][O:23]C1CCCCO1>>[OH:23][CH2:22][CH2:21][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([S:2][CH3:1])([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]1=[O:12]
Reactant: CSC1(Cc2ccccc2)C(=O)Nc2ccccc21
Reactant: ClCCOC1CCCCO1
Product: CSC1(Cc2ccccc2)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-methylthio-3-phenylmethyl-1,3-dihydro-2H-indol-2-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described in Example 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1.[N+:18]([O-])([OH:20])=[O:19].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CN1CCC2(CC1)CC(=O)c1ccccc1O2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCC2(CC1)CC(=O)c1cc([N+](=O)[O-])ccc1O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Sulfuric acid (55 ml) was cooled to 0° C. and was stirred as 3,4-dihydro-1'-methyl-spiro[2H-1-benzopyran-2,4'-piperidin]-4-one (11.56 g, 0.05 mol) was added over 20 minutes. Some gum separated. A solution of 90% nitric acid (2.5 ml, 0.0525 mol) in sulfuric acid (5 ml) was added over 20 minutes. The mixture was stirred for 2 hours at 0° C. and then for 1 hour at room temperature. A solution resulted but nitration was not complete. 90% Nitric acid (0.3 ml, 0.007 mol) was added and stirring was continued for 1 1/2 hours at room temperature. The reaction solution was poured into a mixture of ice, ethyl acetate, and sodium bicarbonate (210 g). The basic mixture was filtered, the ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (150 ml). The combined ethyl acetate extracts were washed with saturated NaCl, dried, filtered and concentrated in vacuo to yield 10.6 g (77%) of product
Reaction SMILES: Cl.N[C:3]1([CH2:27][CH3:28])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C@H:23]([OH:26])[CH2:24][CH3:25])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[CH2:29]=O.[BH3-][C:32]#[N:33].[Na+]>CO>[CH3:29][N:33]([CH3:32])[C:3]1([CH2:27][CH3:28])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C@H:23]([OH:26])[CH2:24][CH3:25])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: CC[C@@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N)(CC)CC4)c3c21
Reactant: [BH3-]C#N
Reactant: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(CC)(N(C)C)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2R)-1-[(3R)-12-[(4-amino-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]butan-2-ol hydrochloride (90 mg, 0.21 mmol, 1.00 equiv) and HCHO (0.8 mL)(37%) in methanol (6 mL) was stirred at room temperature for 0.5 h. Then NaBH3CN (72.88 mg, 1.16 mmol, 5.49 equiv) was added. The resulting solution was allowed to react, with stirring, for an additional 2 h at room temperature. The reaction was then quenched by the addition of 20 mL of water and then extracted with 3×50 mL of chloroform/iso-propanol(3/1) and the organic layers combined and concentrated under vacuum. The crude product (98 mg) was purified by preparative HPLC under the following conditions (Waters): column: column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 50 mL NH4CO3 and CH3CN (5.0% CH3CN up to 44.0% in 12 min, up to 95.0% in 2 min, down to 5.0% in 2 min); Detector, 254/220 nm. This resulted in 34.6 mg (39%) of (2R)-1-[(3R)-12-[[4-(dimethylamino)-4-ethylcyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]butan-2-ol as an off-white solid. MS: 418 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.47 (1H, s), 5.33-5.42 (1H, m), 3.68 (1H, m), 3.42-3.45 (1H, m), 3.00-3.14 (1H, m), 2.92-2.98 (1H, m), 2.70-2.73 (1H, m),2.50-2.67 (1H, m), 2.31-2.45 (1H, m), 2.06-2.11 (3H, m), 1.41-1.82 (11H, m), 0.91-1.05 (6H, m).