Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C([Cl:93])N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(C)C(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[C:36]([Cl:93])[N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CO)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Cl)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CO)c2nc3c(Cl)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 70 %

Procedure:
Prepared in 70.0% yield from Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-(hydroxymethyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 722.3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:20]([O:27][C:28]1[CH:29]=[C:30]([CH:59]=[CH:60][C:61]=1[F:62])[C:31]([NH:33][NH:34][C:35](=[O:58])[C@H:36]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[C:50](Cl)[C:49]=1C)[C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH3:38])=O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[CH2:63]([Cl:65])Cl>>[Si:40]([O:39][C@H:37]([CH3:38])[C@@H:36]([NH:47][C:48]1[CH:49]=[CH:50][C:51]([C:54]#[N:55])=[C:63]([Cl:65])[C:53]=1[CH3:52])[C:35]1[O:58][C:31]([C:30]2[CH:59]=[CH:60][C:61]([F:62])=[C:28]([O:27][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH:29]=2)=[N:33][N:34]=1)([C:43]([CH3:46])([CH3:44])[CH3:45])([CH3:42])[CH3:41]
Reactant: ClCCl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)c(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Triphenylphosphine (1.0 g, 3.85 mmol) was dissolved in 25 mL of DCM followed by addition of 12 (977 mg, 3.85 mmol) and TEA (779 mg, 7.70 mmol) at 0° C. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-fluorobenzohydrazide (1.25 g, 1.93 mmol) in 35 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stir. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 100 mL saturated sodium thiosulfate and extracted with EtOAc. The crude mixture was chromatographed to give the product (1.10 g). 1H NMR (400 MHz, DMSO-d6, δ in ppm): 7.71 (m, 1H), 7.70 (d, J=9 Hz, 1H), 7.65 (m, 1H), 7.03 (d, J=9 Hz, 1H), 6.53 (d, J=9 Hz, 1H), 5.15 (d, J=9 Hz, 1H), 4.80 (m, 1H), 2.44 (s, 3H), 1.51 (d, J=6 Hz, 3H), 1.13 (s, 9H), 0.83 (s, 9H), 0.36 (s, 6H), 0.19 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[O:4]1.[NH2:18][CH2:19][CH2:20][OH:21]>>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([C@H:5]2[O:4][C@@H:3]([CH2:2][NH:18][CH2:19][CH2:20][OH:21])[CH2:7][CH2:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cccc([C@@H]2CC[C@H](CBr)O2)c1
Reactant: NCCO
Product: OCCNC[C@H]1CC[C@@H](c2cccc(C(F)(F)F)c2)O1

Procedure:
2-[({cis-5-[3-(Trifluoromethyl)phenyl]tetrahydrofuran-2-yl}methyl)amino]ethanol was prepared via reaction of cis-2-(bromomethyl)-5-[3-(trifluoromethyl)phenyl]tetrahydrofuran (see H. Ebel et al., PCT Int. Appl., 2010070032, Jun. 24, 2010) with 2-aminoethanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:17]3[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]4[CH:32]=N[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)=[CH:19][CH:18]=3)=[N:9][N:10]([CH2:12]C(F)(F)F)[CH:11]=2)=[CH:3][CH:2]=1.CN1C=C(C2C=CN=CC=2)C(C2C=CC(O)=CC=2)=N1.[Cl:54][C:55]1C2C(=CC=CC=2)N=C(CO)C=1>>[Cl:54][C:55]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:17]([C:8]3[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:11][N:10]([CH3:12])[N:9]=3)=[CH:34][CH:33]=2)[CH:32]=1
Reactant: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Reactant: OCc1cc(Cl)c2ccccc2n1
Agent: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cc(Cl)c4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-{4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline but substituting 4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol and (4-Chloro-quinolin-2-yl)-methanol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=4.6 Hz, 2H), 8.18 (d, J=8.7 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.73 (m, 2H), 7.60 (t, J=7.1 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J=9.1, Hz, 2H), 7.12 (d, J=6.2 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 5.30 (s, 2H), 3.90 (s, 3H); MS: (M+H m/z=427.1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][C:49](O)=[O:50])=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[O:50]=[C:49]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:48][CH2:47][NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.9 g, 15.4 mmol), pyrrolidine (3.2 g, 16.8 mmol) and diisopropylethylamine (5.4 mL, 42.2 mmol) was added to a suspension of 3-((tert-butoxycarbonyl)amino)propanoic acid (1.0 g, 14.0 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred at ambient temperature for 6 hours. TLC analysis showed no acid remaining so the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent was removed to afford a solid. The crude material was purified by silica gel chromatography using a 70:30 mixture of hexane and ethyl acetate as eluent to afford the title product as a solid (3.0 g, 88% yield). MS m/z: 243.26 [M+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1.B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:17](=[O:18])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 108 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4-Hydroxyphenylacetic acid (94.237 g, 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.201 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100° C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108° C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12% aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g, 87.0%).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:16]Cl.C(N(CC)CC)C.S(=O)(=O)(O)O>ClC(Cl)C>[CH3:1][N:2]([S:16][N:15]([CH2:14][CH2:13][O:12][CH3:11])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4]
Reactant: COCCN(CCC(=O)OC)SCl
Reactant: CNC(=O)ON=C(C)SC
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCN(CCC(=O)OC)SN(C)C(=O)ON=C(C)SC
Yield: 87.8 %

Procedure:
A 14.6 g (0.09 mole) quantity of S-methyl N-[(methylcarbamoyl)oxy]thioacetimidate was poured into 100 ml of a dichloroethane solution containing 22.75 g (0.1 mole) of N-methoxyethyl-N-methoxycarbonylethylaminosulfenyl-chloride. The mixture was agitated by a stirred and 18 g (0.18 mole) of triethylamine was added dropwise at less than 5° C. over a period of 30 minutes. Thereafter the mixture was agitated at the same temperature for 1 hour. A 5% aqueous solution of sulfuric acid was added to the mixture until a pH of 6 was achieved. The dichloroethane solution was washed with a 5% aqueous solution of sodium hydrogencarbonate and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated at reduced pressure, giving 31 g of a yellow brown oily product in a yield of 87.8%.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([OH:26])(=[O:25])[C@H:22]([CH3:24])[OH:23]>C(OCC)(=O)C>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:26])(=[O:25])[C@H:22]([CH3:24])[OH:23]
Reactant: C[C@H](O)C(=O)O
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: CCOC(C)=O
Product: C[C@H](O)C(=O)[O-]
Reaction time: 0.03 h

Procedure:
Sertraline base (the compound of Preparation AA, 200 mg) was dissolved in ethyl acetate (200 μL) in a 10 mL conical reaction vial. L-Lactic acid (solid, 68.5 mg) was separately dissolved in ethyl acetate(100 μL). The L-lactic acid solution was added to the sertraline base solution under constant stirring with a magnetic stirrer. A precipitate was observed within about 2 minutes after complete addition of the L-lactic acid solution to the sertraline base solution. The reaction mixture was allowed to granulate overnight (18 hour) at room temperature. The precipitate was filtered and the solid was rinsed with 1 mL of ethyl acetate. The solid was dried in a vacuum oven at 40° C. for 20 hours. The dried sold was characterized and identified as the L-lactate salt of sertraline. The yield was determined to be 72%. mp 153° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: O=C(Cc1ccc(O)cc1Br)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(Cc1ccc(O)cc1-c1ccccc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of benzyl (2-bromo-4-hydroxyphenyl)acetate (400 mg) in dimethoxyethane (4.00 mL) and water (1.20 mL) were added phenyl boronic acid (182 mg), sodium carbonate (396 mg), and 1,1′-bis(diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (50.9 mg), followed by stirring at 80° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (5-hydroxybiphenyl-2-yl)acetate (344 mg).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)C.[N:15]([O-])=O.[Na+]>O>[C:1]1([N:7]=[N+:8]=[N-:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=N[O-]
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Phenylhydrazine (6.7 g, 62 mmol) was added dropwise to a cold (0° C.) solution of concentrated hydrochloric acid (60 ml) over a period of 10 minutes. Diethyl ether (20 ml) was then added, followed by the dropwise addition of a solution of sodium nitrite (5 g, 72 mmol) in water (6 ml), keeping the temperature below 5° C. The reaction was then stirred at 0° C. for 1 hour and then extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (2×50 ml), saturated brine (50 ml), dried (MgSO4) and carefully evaporated in vacuo to give the crude title compound as a red oil (3.3 g, 45%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.O(CCCCO)C1C=CC=CC=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>>[O:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCCCCOc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: OCCCCOc1ccccc1
Agent: [K+]
Product: c1ccc(OCCCCOc2cncc(N3CCNCC3)n2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-(4-phenoxybutoxy)pyrazine (1.99 g, 7.14 mmol; obtained according to the procedure of example 50, step 1, starting from 4-phenoxy-1-butanol*), piperazine (1.84 g, 21.4 mmol) and K2CO3 (0.99 g, 7.14 mmol). The yield of the title compound was 1.52 g (65%) which was obtained as an oil. Purity100% (HPLC). MS m/z 329 (M+H)+. HRMS m/z calcd for C18H24N4O2 (M)+ 328.1899, found 328.1894.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](=S)=[S:18].[OH-].[K+].[K+].[Br-]>O.C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][C:5]2[N:15]=[C:17]([SH:18])[NH:16][C:4]=2[CH:3]=1
Reactant: CN1CCN(c2cc(N)c(N)cc2F)CC1
Reactant: S=C=S
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(c2cc3nc(S)[nH]c3cc2F)CC1
Yield: 93.9 %

Procedure:
6-Fluoro-5-(4-methylpiperazin-1-yl)-2-mercapto-1H-benzimidazole (15.0 g, 94%) was prepared by a similar procedure to that described in preparation 1 (step 5) using the diamine (14.0 g, 0.06 mol) (obtained in step 3 above), carbon disulfide (6.1 g, 0.08 mol), potassium hydroxide (4.49 g, 0.08 mol), ethanol (70 mL) and water (10 mL). mp 290° C. (decomp.); IR (KBr) 3088, 1481 cm-1 ; 1H NMR (DMSO-d6) δ 2.24 (s, 3H, CH3), 2.50 (t, J=4.3 Hz, 4H, N(CH2)2), 3.00 (t, J=4.4 Hz, 4H, N(CH2)2), 6.78 (d, J=7.3 Hz, 1H), 7.00 (d, J=11.9 Hz, 1H); Mass (m/z) 266 (M+.).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:36][C@@H:35]([OH:37])[C:32]4([CH2:34][CH2:33]4)[CH2:31]3)[N:26]=[C:25]([CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CC(O)=O.O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:36][CH:35]([OH:37])[C:32]4([CH2:34][CH2:33]4)[CH2:31]3)[N:26]=[C:25]([CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2C[C@@H](O)C3(CC3)C2)n1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CC(O)C3(CC3)C2)n1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
[(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-6-[(7S)-7-hydroxy-5-azaspiro[2.4]hept-5-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (91 mg, 0.202 mmol) was dissolved in a mixture of AcOH/H2O (10 mL, 4:1) and stirred at RT until LCMS indicated completion of the deprotection (overnight). The reaction mixture was concentrated to dryness under vacuum and was purified by RP-HPLC to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[5-fluoro-6-(7-hydroxy-5-azaspiro[2.4]hept-5-yl)-2-methyl-4-pyrimidinyl]hydrazino}-3-oxopropyl)hydroxyformamide (25 mg, 27%). LCMS: (M+H)+: 451.2.
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:10](=[N:26][N:27]([CH2:30][CH3:31])[C:28]=3[CH3:29])[C:11]([N:19](C([O-])=O)C([O-])=O)=[N:12][C:13]=2[C:14]=1C(C)(C)C)(C)(C)C.[O:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1.C(C1C=CC2C3C(=NN(CCC)C=3C)C(N(C([O-])=O)C([O-])=O)=NC=2C=1C(C)(C)C)(C)(C)C>>[NH2:19][C:11]1[C:10]2=[N:26][N:27]([CH2:30][CH3:31])[C:28]([CH2:29][C:35]3([OH:38])[CH2:36][CH2:37][O:32][CH2:33][CH2:34]3)=[C:9]2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:14][C:13]=2[N:12]=1
Reactant: CCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Reactant: O=C1CCOCC1
Agent: CCCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCOCC1

Procedure:
Di(tert-butyl)2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate was reacted with tetrahydro-4H-pyran-4-one according to the method of Example 2 using di(tert-butyl)2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate in lieu of di(tert-butyl)1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate. The crude product was recrystallized acetonitrile provide 0.349 g 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as off-white crystals, mp 253-255° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C>C1COCC1>[OH:1][CH:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.5 g) was dissolved in THF (7.5 ml) and cooled to −5° C. NaBH4 (0.212 g) was then added and the mixture was stirred for 1 h at room temperature (TLC monitoring). When the conversion was complete, acetic acid was added to the mixture and the methanol was then distilled off. The residue was taken up in water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 30% ethyl acetate/hexane). Yield: 1.2 g (80%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCOCC1>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:23])(=[O:24])[NH2:25])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 90 °C

Procedure:
Tert-butyl 4-aminopiperidine-1-carboxylate (8.63 g) was dissolved in 1,4-dioxane (250 mL), and 4-chloro-3-nitrobenzenesulfonamide (6.00 g) was added followed by triethylamine (10.60 mL). The solution was heated at 90° C. for 20 hours and then cooled. The solvent was removed under vacuum, and the material was purified by flash column chromatography on silica gel using 50% ethyl acetate in hexanes, increasing to 100% ethyl acetate and increasing further to 20% methanol in dichloromethane.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][NH:21][C:22]([O:24]CC)=O)=[O:19])=[CH:13][CH:12]=1)[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].Cl.O1CCOCC1>CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18](=[O:19])[NH:20][NH:21][C:22]2=[O:24])=[CH:15][CH:16]=1)[C:2]#[CH:3]
Reactant: C#CCOCCOCCOc1ccc(NC(=O)NNC(=O)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: C#CCOCCOCCOc1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
To ethyl 2-(4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)phenylcarbamoyl)-hydrazinecarboxylate (1.31 g, 3.59 mmol) in methanol (17.93 mL) was added K2CO3 (1.239 g, 8.96 mmol). The mixture was stirred at 55° C. for 30 minutes. After cooling to room temperature, 4N HCl in dioxane (3.59 mL, 14.34 mmol) was added. The precipitate was filtered, and the filtrate was concentrated in vacuo. The residue was then purified by silica gel chromatography (40-100% ethyl acetate/heptane) giving 4-(4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)phenyl)-1,2,4-triazolidine-3,5-dione (I-7d: 318 mg, 28%) as a white oily solid. LC-MS (M+1) 320.0, t=0.73 minute. 1H NMR (400 MHz, CDCl3) δ ppm 2.48 (t, J=2.15 Hz, 1 H) 3.68-3.83 (m, 4 H) 3.83-3.97 (m, 2 H) 4.11-4.32 (m, 4 H) 7.04 (d, J=8.84 Hz, 2 H) 7.36 (d, J=8.84 Hz, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]#[CH:18]>C(#N)C.C1(C)C=CC=CC=1>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[C:17]#[CH:16]
Reactant: OCc1ccc(O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C#CCOc1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of 4-hydroxyl-benzyl alcohol 13 (2.5 g, 20 mmol) in acetonitrile (50 mL), K2CO3 (3.96 g, 200 mol %) was added at room temperature (see Scheme 4). After stirring for 1 h, the mixture was treated dropwise with an 80 wt % solution of propargyl bromide in toluene (3.27 g, 110 mol %) and the reaction mixture was heated to 50° C. for 48 h, cooled, filtered and concentrated under vacuum. The residue was purified by flash chromatography using an eluent of 100% to 30% hexane in AcOEt. Evaporation of the collected fractions gave propargyl ether 14 as a yellow liquid (3.12 g, 95.5%): 1H NMR (CDCl3) δ (ppm): 7.28 (d, 2H, Ph-H), 6.96 (d, 2H, Ph-H), 4.69 (d, 2H, PhCH2), 4.57 (s, 2H, CCH2O), 2.54 (t, 1H, OH), 2.39 (s, 1H, CH); 13C NMR (CD3OD) δ (ppm): 157.4, 134.53, 128.97, 115.34, 78.97, 76.04, 65.10, 56.24. Anal. Calcd for C10H10O2: C, 74.07; H, 6.17. Found: C, 73.64; H, 6.03.