Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([N+:38]([O-])=[O:39])=[C:28]([N:30]([CH3:37])[C:31](=[O:36])[C:32]([O:34]C)=O)[CH:29]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[NH:21][C:22]([C:24]2[CH:29]=[C:28]3[C:27](=[CH:26][CH:25]=2)[N:38]([OH:39])[C:32](=[O:34])[C:31](=[O:36])[N:30]3[CH3:37])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:12])[F:11]
Reactant: COC(=O)C(=O)N(C)c1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cn1c(=O)c(=O)n(O)c2ccc(C(=O)N[C@@H](c3ccc(OC(F)(F)F)c(F)c3)c3ncccc3F)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-methyl 2-((5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)-2-nitrophenyl)(methyl)amino)-2-oxoacetate (0.500 g, 0.880 mmol) in MeOH (3 mL, Aldrich), was added palladium, 10 wt. % (dry basis) on activative carbon, wet, degussa type (0.047 g, 0.440 mmol, Aldrich). The resulting mixture was stirred at room temperature under hydrogen (balloon) for 4 h. The mixture was filtered through celite and the celite was washed with MeOH (2×10 mL). The combined filtrates were concentrated in vacuo. Dioxane (3.00 mL, Aldrich) and water (1 mL) were added, followed by potassium phosphate (0.560 g, 2.64 mmol, Strem Chemical). The mixture was heated at 90° C. for 18 h. The mixture was then cooled to room temperature and filtered. The solid was washed with water (2×30 mL) and dried in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.37 (d, J=7.8 Hz, 1H), 8.47 (d, J=4.5 Hz, 1H), 7.93 (br. s., 1H), 7.74-7.84 (m, 3H), 7.55-7.67 (m, 2H), 7.50 (dt, J=8.5, 4.3 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 3.52-3.66 (m, 3H). MS (ESI, positive ion) m/z: 523 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][OH:8].Br[C:10]1[CH:15]=[C:14]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:13]=[CH:12][N:11]=1>O1CCCC1>[CH2:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([O:8][CH2:7]/[CH:6]=[CH:5]/[CH2:4][NH2:3])[CH:15]=2)[CH2:18][CH2:19]1
Reactant: Brc1cc(CN2CCCCC2)ccn1
Reactant: NC/C=C\CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC/C=C/COc1cc(CN2CCCCC2)ccn1
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
0.78 g of 60% sodium hydride was suspended in 20 ml of anhydrous tetrahydrofuran, and 1.54 g (17.7 mM) of 4-amino-cis-2-buten-1-ol was slowly added. The mixture was refluxed with stirring for 20 minutes. Then, under ice cooling, a solution of 3.00 g (11.8 mM) of 2-bromo-4-(piperidinomethyl)pyridine in 10 ml of tetrahydrofuran was added slowly to the mixture, and the entire mixture was then refluxed for 48 hours with stirring. After the reaction, the insoluble matter was removed by filtration, and the solvent was evaporated from the filtrate. The residue was extracted with 100 ml of dichloromethane three times. The extracts were dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography using a 1:3 mixture of methanol and ethyl acetate as an eluent to give 1.49 g (yield 48%) of the compound as a pale brown oil.
Reaction SMILES: [Cl:1][CH:2]([NH:4][C:5](Cl)=[O:6])[CH3:3].[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].C(N=C=O)=C>>[Cl:1][CH:2]([N:4]=[C:5]=[O:6])[CH3:3].[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9]
Reactant: CC(Cl)NC(=O)Cl
Agent: C=CN=C=O
Agent: CCN=C=O
Product: CC(Cl)N=C=O
Temperature: 90 °C
Yield: 23.8 %

Procedure:
A mixture of 57 parts of 1-chloroethylcarbamyl chloride, 156 parts of ethyl isocyanate and 841 parts of hexamethylene diisocyante is heated to 90° C. in the course of 3 hours, whilst passing a stream of nitrogen at 22° C. through the mixture. A mixture of 11.8 parts (42.5% of theory) of vinyl isocyanate, of boiling point 38.5° C./1,013 mbar, 10.1 parts (23.8% of theory) of 1-chloroethyl isocyanate of boiling point 92° C./1,013 mbar and 149 parts of ethyl isocyanate is obtained in the distillation receiver.
Reaction SMILES: [N:1]1([C:7]2[CH:35]=[CH:34][C:10]([C:11]([NH:13][C:14]3[C:15]4[CH:26]=[C:25]([C:27]([O:29]C(C)(C)C)=[O:28])[S:24][C:16]=4[N:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:36]>O1CCOCC1>[ClH:36].[CH2:22]([O:21][C:19]([N:17]1[C:16]2[S:24][C:25]([C:27]([OH:29])=[O:28])=[CH:26][C:15]=2[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:35][CH:34]=2)=[N:18]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)OC(C)(C)C)sc21
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)O)sc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-tert-butyl 1-ethyl 3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[2,3-c]pyrazole-1,5-dicarboxylate (4.05 g) was added to a solution of hydrochloric acid in dioxane (88 mL, 4N solution). The resulting mixture was stirred at room temperature for 72 hours. Afterward, volatiles were removed by evaporation under reduced pressure and the residue triturated with diethyl ether, filtered, extensively washed with diethyl ether and dried under vacuum at 40° C. to give 3.4 g of the title compound, used in the next step without further purification.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]4[N:33]=[CH:34][CH:35]=[CH:36][C:24]=4[N:23]3[C:37]=2[C:38]2[CH:43]=[CH:42][C:41]([C:44]3([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:47][CH2:46][CH2:45]3)=[CH:40][CH:39]=2)=[CH:16][CH:15]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:8][S:9]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]4[N:33]=[CH:34][CH:35]=[CH:36][C:24]=4[N:23]3[C:37]=2[C:38]2[CH:43]=[CH:42][C:41]([C:44]3([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])[CH2:45][CH2:46][CH2:47]3)=[CH:40][CH:39]=2)=[CH:18][CH:19]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NS(C)(=O)=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Et3N (36.6 μL, 0.263 mmol) and methanesulfonyl chloride (7.46 μL, 0.0964 mmol) were added to a solution of tert-butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.0876 mmol) in DCM (1 mL) at 0° C., and stirred at room temperature. After reaction was completed, the mixture was diluted with sat. NaHCO3 and extracted with CHCl3 (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1, CHCl3/EtOAc=1:1) to afford desired product (30.9 mg, 54.4%) as pale yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.18-8.12 (m, 1H), 8.04-7.97 (m, 1H), 7.63-7.50 (m, 2H), 7.41-7.33 (m, 2H), 7.33-7.23 (m, 2H), 7.19-7.08 (m, 5H), 6.96 (d, J=7.8 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.60 (dd, J=7.8, 4.6 Hz, 1H), 6.44 (br s, 1H), 5.69-4.98 (m, 1H), 2.98 (s, 3H), 2.63-2.27 (m, 4H), 2.21-2.06 (m, 1H), 1.96-1.82 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9]2[CH:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1.FC(F)(F)C(O)=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[C:9]2[CH:31]=[CH:32][CH:33]=[CH:34][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(-c3ccco3)nc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(-c3ccco3)nc3ccccc32)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(fur-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37](O)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=2)[C:19]([CH3:40])=[C:18]3[CH3:41])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl.[NH2:43][NH2:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:43]([C:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:20]2[C:21]3[C:17](=[CH:16][C:15]([C:13]([NH:12][C@H:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=4)[CH3:11])=[O:14])=[CH:23][CH:22]=3)[C:18]([CH3:41])=[C:19]2[CH3:40])=[CH:30][CH:29]=1)=[O:38])[NH2:44]
Reactant: NN
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)NN)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the mixture of (S)-4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid (0.11 g, 0.201 mmol), hydrazine hydrochloride (0.028 g, 0.402 mmol) and HATU (0.092 g, 0.24 mmol) in DCM (2 mL) was added DIEA (0.14 mL, 0.8 mmol). The mixture was stirred at room temperature for 16 h. The solvent was removed and the residue was purified by silica gel to obtain the title compound. ESI-MS (m/z): 559 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Cl-].[CH2:8]([O:10][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][C:2]1[S:3][C:4]([C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:19])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCC(=O)O
Reactant: Clc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCC(=O)c1ccc(Cl)s1
Temperature: 0 °C

Procedure:
To a mixture of 2-chlorothiophene (36.0 g) and adipic acid monoethyl ester chloride (36.9 g) was added gradually aluminum chloride (50.8 g) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (1 L) and extracted with diethyl ether (200 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (200 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(5-chloro-2-thienyl)-6-oxohexanoate as an oil (52.5 g, quantitative).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([NH:28][CH:25]3[CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)NC3CC3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), cyclopropylamine (35 uL, 29 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 34 mg (43% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.45-0.51 (m, 2 H), 0.51-0.58 (m, 2 H), 1.49-1.65 (m, 4 H), 1.68 (s, 9 H), 2.10-2.22 (m, 1 H), 2.30-2.45 (m, 1 H), 3.31-3.41 (m, 2 H), 3.89-3.99 (m, 2 H), 4.54 (d, J=7.62 Hz, 2 H), 7.99 (dd, J=8.8, 1.8 Hz, 1 H), 8.07 (d, J=8.8 Hz, 1 H), 8.24 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=392.0; Anal. Calcd for C20H29N3O3S+1.30 TFA+0.40 EtOAc+0.5H2O (584.02): C, 49.77; H, 5.95; N, 7.20. Found: C, 49.78; H, 5.86; N, 7.20.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[CH3:5][C:4]([CH3:9])=[CH:3][CH2:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]#[N:11]
Reactant: N#CCc1ccccc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Product: CC(C)=CCC(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 119.8 %

Procedure:
384 g (4.8 mol) of 50% sodium hydroxide and 12 g of hexadecyl-trimethylammonium bromide are placed in a 2-liter flask provided with a thermometer, stirrer and reflux condenser and there is added dropwise while stirring within 0.25 hour a mixture of 469 g of benzyl cyanide (4 mol) and 502 g (4.8 mol) of prenyl chloride(1). During the addition the mixture warms and it is subsequently stirred for a further 3 hours at 60° C. After cooling, the mixture is poured on to 500 g of ice, extracted four times with ether and washed neutral with water. The phase separation can be facilitated by the addition of a small amount of alcohol. After drying over sodium sulphate, the ether is evaporated and the residue is fractionally distilled. There are obtained 444 g of 5-methyl-2-phenyl-4-hexene nitrile of boiling point 108°-109° C./3 mmHg; nD20 =1.5171-72; yield 60%.
Reaction SMILES: [Br:1][CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1)=[O:4].S(Cl)(Cl)(=O)=O.[CH3:21][C:22](=[CH:24][CH2:25][CH2:26]/[C:27](=[CH:29]/[CH2:30][OH:31])/[CH3:28])[CH3:23]>[Cl-].[Zn+2].[Cl-]>[Br:1][CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7]([O:31][CH2:30]/[CH:29]=[C:27](/[CH2:26][CH2:25][CH:24]=[C:22]([CH3:23])[CH3:21])\[CH3:28])[CH2:6]1)=[O:4]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: O=C(CBr)N1CCSc2ccccc2C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COC1CN(C(=O)CBr)Cc2ccccc2S1
Yield: 24.6 %

Procedure:
The above-mentioned 4-bromoacetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.5 g) and sulfuryl chloride (1.5 g) were reacted in the same manner as in Experimental Example 7 to give 4-bromoacetyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepmne (1.4 g). This compound (0.30 g), geraniol (0.30 g) and zinc chloride (0.26 g) were reacted in the same manner as in Experimental Example 9 to give 4-bromoacetyl-2-geranyloxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.21 g). Then, this compound (0.21 g), 4-benzyl piperidine (O.11 g) and potassium carbonate (0.13 g) were reacted in the same manner as in Experimental Example 6 to give 4-[1-(4-benzyl) piperidinyl]acetyl-2-geranyloxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.26 g).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C@@H:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:14]2)=[CH:9][CH:8]=1)C.CO.[Li+].[OH-]>O>[C:21]1([C@H:19]([NH:18][C@H:15]2[CH2:16][CH2:17][C@@H:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:12][CH:11]=3)[CH2:14]2)[CH3:20])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)COc1ccc([C@@H]2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OCC(=O)O)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
{4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid ethyl ester (0.214 g, 0.51 mmol) was added to a mixture of methanol (2.35 ml) and water (0.78 ml). To the milk-white mixture was added aqueous 2N LiOH (2.05 ml, 4.1 mmol). After stirring for about 10 minutes at room temperature the reaction mixture changed into a clear light yellow solution. The solution was stirred overnight at room temperature. After 20 hours the solution was concentrated slightly in vacuo and further 5 ml of water was added. The product was precipitated by adding 4N HCl (2.4 ml) under vigorous stirring. pH was adjusted to 5 with aqueous 2N LiOH. The precipitate was collected by filtration to give crude amorphous {4-[(1R,3S)-3-((R)-1-naphthalen-1-yl-ethylamino)-cyclopentyl]phenoxy}-acetic acid. Yield: 0.19 g (95%).
Reaction SMILES: [I:1][C:2]1[C:3]([CH2:11][OH:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCl.C(Cl)Cl>[I:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: OCc1cc2c(cc1I)OCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: ClCl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc2c(cc1I)OCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
(6-Iodobenzo[d][1,3]dioxol-5-yl)methanol (2.7 g, 9.7 mmol) in dry CH2 Cl2 was added dropwise to PCC(3.1 g, 14.6 mmol) in dry CH2Cl2 at 0° C. under N2 atmosphere. The mixture was stirred at room temperature for 20 h. After reaction, the crude product was purified by column chromatography on silica gel (petroleum ether) to obtain 6-iodobenzo[d][1,3]dioxole-5-carbaldehyde (2 g, 77%) as white solid. LCMS: 277 [M+1]+; 1H NMR (DMSO-d6) δ 6.20 (s, 2H), 7.28 (s, 1H), 7.61 (s, 1H), 9.79 (s, 1H).
Reaction SMILES: Cl.O.[OH:3][CH2:4][C@H:5]([NH:10][C:11]1[C:12]2[S:40][C:39]([O:41]C)=[N:38][C:13]=2[N:14]=[C:15]([S:17][S:18][C:19]2[N:20]=[C:21]([NH:30][C@H:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:32][OH:33])[C:22]3[S:27][C:26]([O:28]C)=[N:25][C:23]=3[N:24]=2)[N:16]=1)[CH2:6][CH:7]([CH3:9])[CH3:8]>O1CCOCC1>[OH:3][CH2:4][C@H:5]([NH:10][C:11]1[C:12]2[S:40][C:39](=[O:41])[NH:38][C:13]=2[N:14]=[C:15]([S:17][S:18][C:19]2[N:20]=[C:21]([NH:30][C@@H:31]([CH2:32][OH:33])[CH2:34][CH:35]([CH3:36])[CH3:37])[C:22]3[S:27][C:26](=[O:28])[NH:25][C:23]=3[N:24]=2)[N:16]=1)[CH2:6][CH:7]([CH3:8])[CH3:9]
Reactant: COc1nc2nc(SSc3nc(N[C@@H](CO)CC(C)C)c4sc(OC)nc4n3)nc(N[C@@H](CO)CC(C)C)c2s1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](CO)Nc1nc(SSc2nc(N[C@@H](CO)CC(C)C)c3sc(=O)[nH]c3n2)nc2[nH]c(=O)sc12
Temperature: 45 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A mixture of conc. hydrochloric acid (20 mL) and water (20 mL) was added to a solution of (2R)-2-{5-[7-((1R)-1-hydroxymethyl-3-methyl-butylamino)-2-methoxy-thiazolo[4,5-d]pyrimidin-5-yldisulfanyl]-2-methoxy-thiazolo[4,5-d]pyrimidin-7-ylamino}-4-methyl-pentan-1-ol (1.5 g, 2.4 mmol) in 1,4-dioxane (20 mL). The solution was then stirred at 45° C. for 18 h. The solvent was evaporated off and the residue was taken up in ethyl acetate. Any undissolved residue was collected by filtration. The filtrate was subjected to flash column chromatography (eluent ethyl acetate:methanol 95:5). The solid residue and the product collected from the chromatography were pooled together to give the title compound (600 mg, 42% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[N:11]=[CH:12][C:13]([C:29]#[N:30])=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:9]2=[CH:8][CH:7]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[OH:3][CH2:4][C:6]1[N:10]2[N:11]=[CH:12][C:13]([C:29]#[N:30])=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:9]2=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnn12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: N#Cc1cnn2c(CO)ccc2c1Nc1ccc(Oc2ccccc2)cc1
Reaction time: 6 h
Yield: 64 %

Procedure:
To a solution of 406 (39.8 mg, 0.1 mmol) in THF (2 ml) was added DIBAL-H (1.0 M in CH2Cl2, 0.2 ml, 0.2 mmol) at −78° C. The reaction mixture was stirred at this temperature for 6 h, then at 0° C. for 2 h, quenched with water (0.1 ml). The solid was filtered off, and the filtrate was concentrated. The residue was purified by preparative TLC to give the title compound (22.8 mg, 64%) as a brown solid (2.5% MeOH—CH2Cl2). LCMS Found: (M+H)+=357.
Reaction SMILES: [CH2:1](Br)[CH3:2].FC(F)(F)C(O)=O.[NH:11]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:11]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)[CH3:2]
Reactant: CCBr
Reactant: O=C(OCc1ccccc1)[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CC[C@H](C(=O)OCc2ccccc2)C1
Reaction time: 25 h

Procedure:
Ethyl bromide (0.21 mL) was added to a mixture of benzyl (S)-pyrrolidine-3-carboxylate trifluoroacetic acid salt (Intermediate 191, 0.897 g), potassium carbonate (0.971 g) and DMF (10 mL) at room temperature and the mixture was stirred for 25 hours. Further ethyl bromide (0.11 mL) was added and stirring was continued for 24 hours. Further ethyl bromide (0.05 mL) was added and stirring was continued for 22 hours. The resultant mixture was diluted with water and extracted with diethyl ether, washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give benzyl (S)-1-ethylpyrrolidine-3-carboxylate (0.563 g).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([K])[CH3:9].Cl>O>[C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CC[K]
Agent: Cl
Solvent: O
Product: CCOC(=O)CC(=O)O
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
Ethyl potassium malonate (25.0 g, 0.15 mol) was suspended in water (15.6 ml) and cooled in an ice bath. Concentrated HCl (12.5 ml) was added dropwise over 30 min, then the mixture was stirred for a further 10 min. The precipitate was filtered, then washed twice with ether. The filtrate was separated and the aqueous phase was extracted with ether. The combined ethereal solutions were dried (MgSO4) and evaporated to afford, as an oil, monoethyl hydrogen malonate (19.2 g, 99%) which was dried under vacuum overnight (or 50°/1 mm for 1 h) prior to use.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH:13]=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][N:25]([CH2:13][CH2:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2](=[O:1])[O:3][CH2:4][CH2:5]3)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=CCc1ccc2c(c1)CCOC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2)CCOC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1-Oxo-3,4-dihydro-1H-isochromen-6-yl)acetaldehyde (2.40 g, 12.6 mmol) was combined with 1-Boc-piperazine (3.53 g, 18.9 mmol) and sodium triacetoxyborohydride (13.4 g, 63.1 mmol) in DCM (90 mL). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added and the layers were separated. The organic layer was washed with brine, then dried over MgSO4. The crude product was purified first by MPLC (silica), eluting with 3% of a 10% NH4OH/methanol solution in DCM, then a second MPLC purification eluting with ethyl acetate, to afford the title compound.