Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([NH:26][C:27]([O:29][C@@H:30]2[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[O:28])[C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>C1COCC1>[C:1]1([CH:7]([NH:26][C:27]([O:29][C@@H:30]2[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[O:28])[C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(COc2cccc(C(NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a stirred solution of methyl 4-((3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (2.27 g, 4.50 mmol) in THF (23 mL), was added an aqueous solution of lithium hydroxide (2.0 M, 9.0 ml, 18.0 mmol). The mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to 6 by the addition of 4M aqueous hydrochloric acid. The mixture was then extracted with 10% methanolic ethyl acetate (×2), and the combined organic extracts evaporated at reduced pressure. The residue was then dissolved in ethanol and re-evaporated at reduced pressure to afford the title compound (1.85 g, 84%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:17]=[C:16]4[N:18]([CH2:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[N:28]=[CH:27][CH:26]=[CH:25]6)[N:19]=[N:20][C:15]4=[CH:14][CH:13]=3)=[CH:8][C:7]=2[F:32])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:17]=[C:16]4[N:18]([CH2:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[N+:28]([O-:42])=[CH:27][CH:26]=[CH:25]6)[N:19]=[N:20][C:15]4=[CH:14][CH:13]=3)=[CH:8][C:7]=2[F:32])=[O:33])[CH2:2][CH2:3]1
Reactant: O=C(NC1CC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NC1CC1)c1ccc(-c2ccc3nnn(Cc4ccc5c(ccc[n+]5[O-])c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.2 %

Procedure:
To a solution of example 46 (0.080 g, 0.182 mmol) in dichloromethane (1 ml), m-chloroperbenzoic acid (0.044 g, 0.255 mmol) was added and stirred at RT for 12 h. The reaction mixture was quenched with sodium sulphite solution, washed with saturated potassium carbonate solution and concentrated. The crude product was chromatographed using methanol:dichloromethane to afford the title compound as a pale yellow solid (0.025 g, 30%). M.P.: 89-92° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.75 (d, J=9.0 Hz, 1H), 8.51 (m, 2H), 8.28 (t, J=8.1 Hz, 1H), 7.98-7.86 (m, 5H), 7.71 (d, J=8.5 Hz, 1H), 7.32 (dd, J=8.5, 6.1 Hz, 1H), 6.89 (d, J=11.8 Hz, 1H), 6.15 (s, 2H), 2.99 (m, 1H), 0.94 (m, 2H), 0.69 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:55])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:46]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:55])([O:47][Si:48]([CH2:51][CH3:52])([CH2:53][CH3:54])[CH2:49][CH3:50])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C/CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 88.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (E)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (116 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (73.4 mg, 89%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[CH:28][N:27](COCC[Si](C)(C)C)[N:26]=4)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:27]1[CH:28]=[N:29][C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]3[CH:17]=[N:16][N:13]4[CH:14]=[CH:15][C:10]([N:5]5[C@@H:4]([CH2:1][CH2:2][CH3:3])[CH2:8][O:7][C:6]5=[O:9])=[N:11][C:12]=34)=[CH:24][CH:23]=2)=[N:26]1
Reactant: CCC[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Reaction time: 18 h
Yield: 61.6 %

Procedure:
A mixture of (S)-4-propyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.039 g, 0.075 mmol) in DCM (0.4 mL) was treated with trifluoroacetic acid (0.4 mL) at ambient temperature. The mixture was stirred for 18 hours. The solvent was concentrated and the residue was partitioned between EtOAc and aqueous saturated NaHCO3. The aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried, concentrated and purified by column chromatography (1-5% 20% 7N ammonia in MeOH/dichloromethane) to give (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-propyloxazolidin-2-one (0.018 g, 62%) as a beige solid. LCMS (APCI+) m/z 390 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:31][CH2:30][N:29]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=3)[CH2:28][CH:27]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CC=C(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at 90° C. to yield 4-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid;
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[F-].[Cs+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:17][C@H:18]1[O:20][CH2:19]1)(=O)=O.O>CN(C=O)C>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:17][C@H:18]2[O:20][CH2:19]2)=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
p-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF and cesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature and (S)-Glycidyl nosylate (1.71 g, 6.6 mmol) was added. The system was stirred for an additional 24 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent system to give (S)-Glycidyl p-nitrophenyl ether (99.6% ee, based on chiral HPLC with Chiralcel OD, m.p 78-9° C.) as a yellowish solid (1.21 g, 93% yield). The NMR values are the same as the literature values for the racemic mixture: 1H-NMR (CDCl3) δ 2.78 (dd, 1H), 2.95 (t 1H), 3.39 (m 1H), 4.0 (dd, 1H), 4.38 (dd, 1H), 6.99 (dd, 2H), 8.2 (dd, 2H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.S(=O)(=O)(O)O.[CH:18](OC)(OC)OC>CO>[C:1]([O:12][CH3:18])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(O)c(O)c(O)c1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a solution in which gallic acid (5.0 g, 29.39 mmol) was dissolved in methanol (25 mL), concentrated sulfuric acid (0.5 mL) and trimethyl orthoformate (3.21 mL, 88.17 mmol) were added consecutively at room temperature. The reaction mixture was heated under reflux for 10 hours, cooled to room temperature, and methanol was removed by vacuum distillation. To the residue obtained as above, distilled water (10 mL) was added, and the precipitated solid was filtered to give methyl gallate (5.15 g, 95%). 1H NMR (500 MHz, DMSO-D6) δ 9.29 (s, 2H), 8.96 (s, 1H), 6.92 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[CH2:10][CH:9]1O)=O)(C)(C)C.Cl.[OH-].[Na+]>O1CCCC1>[NH:8]1[C:16]2=[CH:15][N:14]=[CH:13][CH:12]=[C:11]2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1c2cnccc2CC1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1cc2cc[nH]c2cn1
Temperature: 50 °C

Procedure:
The azaindoline (step b, 1.1 g, 5.0 mmol) was dissolved in tetrahydrofuran (20 ml) and treated with 5.5M hydrochloric acid (5 ml). The mixture was heated at 50° C. for 4.5 hours cooled to 0° C. and basified with 5M sodium hydroxide (7.0 ml). The mixture was extracted with ethyl acetate (2×20 ml) and the combined ethyl acetate fractions were washed with saturated brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a pale yellow crystalline solid; yield: 0.57 g (97%). mp. 132°-134° C.[Lit. mp 131°-132° C.].
Reaction SMILES: [CH2:1]([O:13][CH2:14][C@H:15]([CH2:17][OH:18])[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:19]1([C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)Cl)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O1CCCC1.C(#N)C>C(N(CC)CC)C>[CH2:1]([O:13][CH2:14][C@H:15]([CH2:17][O:18][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCOC[C@@H](O)CO
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
19.83 grams of (S)-1-dodecyl-glycerol and 21.0 grams of triphenylchloromethane were added to a mixture of 250 ml dry tetrahydrofuran (THF) and 60 ml dry acetonitrile. 22 ml of dry triethylamine was added and the reaction mixture was refluxed for 17 hours under nitrogen. The reaction mixture was then cooled to room temperature, and 5 ml triethylamine and 10 grams of ice were added. The mixture was transferred to a separatory funnel and extracted with 100 ml MTBE. The organic phase was washed consecutively with 150 ml water, 150 ml of dilute (1.5%) H2SO4, 150 ml water, 150 ml of concentrated aqueous sodium bicarbonate, and again with 150 ml water. The solution was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The residue, 40.63 grams of a brown oil, was dissolved in 200 ml ethyl acetate and cooled to −20° C. for a couple of days. The mixture was centrifuged at a temperature of −10° C. and the mother liquid was poured off. The solid melted at room temperature and was purified by chromatography on a silica gel column (195 grams). 18.57 grams of pure (R)-1-dodecyl-3-trityl-glycerol was eluted by mixtures of chloroform and hexane followed by a mixture of 9:1 (v/v) chloroform:ethyl acetate. The yield was 48.5%.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][CH:26]=[CH:25]2)=[CH:20][CH:19]=1)=[O:17].[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32]>C1COCC1>[F:29][C:30]([F:37])([F:36])[C:31](=[O:32])[CH2:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH:25]=[CH:26][N:27]=[CH:28]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-n2ccnc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a THF (5 mL) solution of 1,1,1,3,3,3-hexamethyldisilazane (0.178 g, 1.1 mmol) was added n-butyl lithum (1.6 M solution in hexane, 0.72 mL, 1.2mmol) at 0° C. under nitrogen, and the mixture was stirred for 30 minutes, and cooled to −78° C. 4-(1-Imidazolyl)acetophenone (prepared according the method of M. A. Khan et, al., J. Chem. Soc. C., 1970, 85., 0.186 g, 1.0 mmol) was added to the mixture, and residue was stirred for 1 hour. Ethyl trifluoroacetate (0.17 g, 1.2 mmol) was added tothe reaction mixture, the residure was warm to room temperature. The reaction mixture was poured into ice water and the whole was extracted with ethyl acetate (30 mL×2). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting solid was washed with small amount of ethyl acetate to give the title compound (0.163 g).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:19]([OH:21])=O)[CH3:3].C1N=C[N:24](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].C(OCC)(=O)C>C1COCC1>[CH3:1][CH:2]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:19]([NH2:24])=[O:21])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1ccc2ccc(C(=O)O)c(OC(C)C)c2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2ccc(C(N)=O)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a room temperature solution of 1,7-bis-(1-methylethoxy)-2-naphthalenecarboxylic acid (200 mg, 0.69 mmol) in 10 mL of THF is added N,N-carbonyldiimidazole (135 mg, 0.83 mmol). The solution is heated at reflux for 1 hour and cooled to room temperature. Aqueous NH4OH (4 mL) is added and the reaction mixture is stirred at room temperature for 30 minutes, then poured into ethyl acetate, and washed with aqueous NaHCO3 and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is recrystallized from methanol and water to provide 1,7-bis-(1-methylethoxy)-2-naphthalenecarboxamide in 40% yield; mp 145°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=3)[O:11][C:9]=2[N:10]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:60]([O:64][C:65](=[O:71])[C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)([CH3:63])([CH3:62])[CH3:61].Cl>CN(C)C=O.O>[C:60]([O:64][C:65]([C@@H:66]1[CH2:70][CH2:69][CH2:68][N:67]1[C:22](=[O:23])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:11][C:9]3[N:10]=[C:5]([O:4][C:3]4[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=4[F:1])[N:6]=[CH:7][C:8]=3[N:13]=2)=[CH:15][CH:16]=1)=[O:71])([CH3:63])([CH3:61])[CH3:62]
Reactant: O=C(O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Reaction time: 16 h
Yield: 39.5 %

Procedure:
140 mg of {(E)-3-{4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenyl}-acrylic acid were dissolved in 2 ml of N,N-dimethylformamide, and 98 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 19 mg of 1-hydroxy-7-azabenzotriazole and 397 μl of N,N-diisopropylethylamine were added, followed by the addition of 49 mg of L-proline tert-butyl ester after 5 min. After 16 h at room temperature, 10 ml of water were added, and the mixture was brought to pH 3 by addition of 2 M aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers were washed with a saturated sodium hydrogencarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC. 60 mg of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(NCC)C.[ClH:29]>CO>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@H:9]([NH:15][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[C@H](NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCNCC
Product: C[C@H](N[C@@H]1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1

Procedure:
(1R)-6-Bromo-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-bromo-N-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, Chiral Technologies, 10% methanol, (2% diethyl amine/10% chloroform) 1500 psi, 50° C., 2 mL/min, retention time: 19.8 min.) The oil obtained was converted to the HCl salt to give a white solid. 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 10.08 (s, 1H), 9.64 (s, 1H), 7.86 (d, J=6.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.55-7.45 (m, 3H), 7.42 (d, J=8.6 Hz, 1H), 7.29 (dd, J=6.8 Hz, J=1.8 Hz, 1H), 4.75 (m, J=6.4 Hz, 1H), 4.57 (t, J=4.4 Hz, 1H), 3.47-3.37 (m, 2H), 2.70-2.64 (m, 2H), 2.13-2.07 (m, 2H) 1.71 (d, J=6.8 Hz, 3H); MS m/z 367, 369 (M−1); Anal. Calcd. For C20H22BrN2Cl: C, 59.20; H, 5.46; N, 6.90. Found: C, 59.32; H, 5.58; N, 6.97.
Reaction SMILES: [C:1]([NH2:5])(=[S:4])[CH2:2][CH3:3].Cl[CH:7]([CH:13]=O)[C:8]([O:10]CC)=[O:9]>C(O)C>[CH2:2]([C:1]1[S:4][C:7]([C:8]([OH:10])=[O:9])=[CH:13][N:5]=1)[CH3:3]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CCC(N)=S
Solvent: CCO
Product: CCc1ncc(C(=O)O)s1
Reaction time: 8 h

Procedure:
a solution of 26 gm of thiopropionamide in 100 cc of ethanol is mixed with a solution of 36.5 gm of ethyl 2-chloro-3-oxo-propionate in 50 cc of ethanol. The reaction mixture is left in contact overnight, then the alcohol is evaporated off. The residue is dissolved in ether, the ethereal phase is washed with an aqueous 20% sodium carbonate solution, then with water. The oil obtained is distilled and the fraction coming off at 80° C. to 90° C. under a pressure of 0.5 mm is recovered. This fraction is saponified with an alcoholic solution of potassium hydroxide, then acidified and recrystallized from toluene. 2-Ethyl-5-thiazolecarboxylic acid is obtained in the form of colorless crystals, soluble in ethanol and sodium hydroxide, insoluble in water, melting at 157° C.
Reaction SMILES: [Na].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[C:12](#[N:16])[C:13]([CH3:15])=[CH2:14].C>CCCCCC.C(O)C>[NH2:16][C:12]1[CH:13]([CH3:15])[CH2:14][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[N:11]=1
Reactant: NNc1cccc(F)c1
Reactant: C=C(C)C#N
Agent: Cl
Agent: [Na]
Solvent: CCCCCC
Solvent: CCO
Product: CC1CN(c2cccc(F)c2)N=C1N

Procedure:
A 1.38 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 8.1 g. of m-fluorophenylhydrazine hydrochloride is added followed by 3.9 g. of methacrylonitrile. The reaction mixture is refluxed for 5 hours, then is evaporated to dryness in vacuo. Water is added to give a dark semi-solid precipitate. The aqueous is decanted then more water is added and the solid is collected by filtration. The solid is dissolved in dichloromethane and the solution is passed through a short column of a hydrous magnesium silicate. The effluent is evaporated to give an oil. The oil is dissolved in hexane, treated with activated charcoal and filtered and evaporated to give a solid. The solid is recrystallized from hexane to give 0.65 g. of the desired product as light orange prisms, m.p. 78°-80° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:19]=2[CH3:20])=[O:14])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1.[CH3:28][S:29]([O-:31])=[O:30].[Na+].CS(C)=O.CNCCNC>CCOC(C)=O.[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O>[CH3:28][S:29]([C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:19]=2[CH3:20])=[O:14])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(Br)c1
Reactant: CS(=O)[O-]
Agent: [Cu+2]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(S(C)(=O)=O)c1
Temperature: 100 °C
Yield: 30.5 %

Procedure:
1-(4-Chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(5-bromo-pyridin-3-yl)-butyl]-amide (100 mg, 0.22 mmol), copper(II) triflate (81 mg, 0.22 mmol), sodium methylsulfinate (80 mg, 0.67 mmol) are added to a reaction vial with a septum top which is then evacuated and filled with nitrogen for 3 cycles. DMSO (1 mL) and N,N′-dimethylethylenediamine (71 μL, 0.67 mmol) are added and the reaction is heated at 100° C. for 30 hours. The resultant mixture is cooled to room temperature, diluted with EtOAc (50 mL), and washed with saturated aqueous ammonium chloride (2×25 mL), saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is purified by preparative reverse phase HPLC (eluted with 10 to 95% CH3CN/H2O and 0.1% TFA as additive) to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(5-methanesulfonyl-pyridin-3-yl)-butyl]-amide as a colorless foam (30 mg, 30%).