Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:72])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52](=[O:69])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([O:61][Si](C(C)(C)C)(C)C)=[O:60])[CH:47]([O:70][CH3:71])[CH2:46]2)[CH:8]([CH3:73])[CH:7]([O:74][Si](C(C)(C)C)(C)C)[CH2:6][C:5]1=[O:82])[CH:2]=[CH2:3].C(#N)C.F>C(OCC)(=O)C.O>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:72])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52](=[O:69])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([OH:61])=[O:60])[CH:47]([O:70][CH3:71])[CH2:46]2)[CH:8]([CH3:73])[CH:7]([OH:74])[CH2:6][C:5]1=[O:82])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCCCCCC(=O)O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCCCCCC(=O)O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a mixture of the 17-allyl-14-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-12-{2-[4-(7-(tert-butyl-dimethyl-silanyloxy-carbonyl)heptanoyl-oxy)-3-methoxy-cyclohexyl]-1-methyl-vinyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone prepared in Reference Production Example 1 (44 mg, 0.037 mmol) and acetonitrile (0.88 ml), 46-48% aqueous hydrogen fluoride (HF) (0.12 ml) was gently added, and this was followed by overnight stirring at room temperature. The reaction product was poured over an ethyl acetate-water mixed solution and extracted. The organic phase obtained was washed with water and saline, and dried over magnesium sulfate (MgSO4). After the MgSO4 was separated by filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified using a silica gel column (5% methanol (in chloroform)) to yield the desired 17-allyl-1,14-di-hydroxy-12-{2-[4-(7-carboxy-heptanoyl-oxy)-3-methoxy-cyclohexyl]-1-methyl-vinyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (14.2 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:33]=[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:23](=[O:24])[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][NH:20][CH:19]=2)=[O:17])=[CH:11][C:10]=1[F:32].C([O-])([O-])=O.[Cs+].[Cs+].[I-].[K+].[P:55]([O:67][CH2:68]Cl)([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>CN(C=O)C>[P:55]([O:67][CH2:68][N:20]1[CH:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:23](=[O:24])[C:18]([C:16](=[O:17])[NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([N:33]=[C:34]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:2]=3[Cl:1])=[C:10]([F:32])[CH:11]=2)=[CH:19]1)([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])([O:62][C:63]([CH3:64])([CH3:65])[CH3:66])=[O:56]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: O=C(Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(OCn1cc(C(=O)Nc2ccc(Oc3ccnc(N=C(c4ccccc4)c4ccccc4)c3Cl)c(F)c2)c(=O)c(-c2ccc(F)cc2)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 26 h
Yield: 72.5 %

Procedure:
To a solution of N-(4-(3-Chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (1.0 g, 1.58 mmol) in DMF (10 mL) at room temperature were added Cs2CO3 (1.3 g, 3.95 mmol), potassium iodide (525 mg, 3.16 mmol) and then di-tert-butyl chloromethyl phosphate (1.2 mL, 1.90 mmol: 2.0 M in DMF). The reaction mixture was stirred at room temperature for 26 h prior to being quenched by the addition of isopropyl acetate (10 mL) and cold water (50 mL). The organics were separated and washed with water (50 mL). The solvent was swapped into isopropanol (10 mL) by continuous distillation at 86° C. The solution was cooled to 20° C. and a solid precipitated. The solid was collected by filtration and dried under vacuum at 60° C. for 12 h to give the desired product (0.98 g, 72%) as an off-white solid. MS (ESI+) m/z 856 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][C:17]([OH:19])=O)=[O:13])[C:7]1=[O:34].CN(C)C=O.[CH3:44][O:45][CH2:46][CH2:47][NH2:48].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH3:44][O:45][CH2:46][CH2:47][NH:48][C:17]([CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:34])[N:6]([CH2:5][C:4]2[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:19]
Reactant: COCCN
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COCCNC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reaction time: 2 h

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-propionic acid (0.040 g, 0.000075 mol;) was dissolved in N,N-Dimethylformamide (3 mL, 0.04 mol;) and 2-Methoxyethylamine (30 uL, 0.0004 mol;) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.037 g, 0.000097 mol;) was added. The reaction was allowed to stir for 2 hours and LC-MS showed disappearance of starting material and appearance of product at 1.28 592.07. The reaction was purified by Gilson Preparative HPLC and the pure fractions were concentrated. ES (+) MS m/e=592.07; NMR (400 MHz, DMSO-d6) δ ppm 2.80 (m, 2H), 3.17 (m, 5H), 3.25 (t, 2H, J=7 Hz), 5.22 (m, 2H), 5.66 (m, 1H), 6.60 (t, 1H, J=8 Hz), 6.96 (d, 1H, J=3 Hz), 7.14-7.21 (m, 3H), 7.38-7.49 (m, 2H), 7.79 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.22 (d, 1H), 11.95 (s, 1H)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>[Fe].C(O)C>[F:18][C:10]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=1[NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(NCc2ccccc2)c(F)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Nc1ccc(NCc2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To 60 g (243.7 mmol) of the intermediate N-benzyl-2-fluoro-4-nitroaniline (3), 600 mL ethanol was added as a solvent. The resultant mixture was slowly heated to reflux and then 60 mL concentrated hydrochloric acid was added. After the reactant was completely dissolved, 55 g (974.6 mmol) of Fe powder was added in batches within 1 hour. Then, reflux was continued for five hours until the reaction almost completed. The mixture was cooled to room temperature and buffered to pH 8-9 with a saturated Na2CO3. Then, the mixture was filtrated, and the filtrate was evaporated to remove ethanol by rotatory evaporation. The residual water layer was extracted with ethyl acetate, and then the ethyl acetate layer was reversely extracted with 10% diluted hydrochloric acid solution. The ethyl acetate layer was discarded. The acid-water layer was adjusted to be basic with a NaOH solution and then extracted with ethyl acetate. Thus obtained ethyl acetate layer was rotary evaporated and 47 g of dark tan oily substance was obtained with a yield of 89.2%.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-])=O)=[CH:18][N:19]=1)[C:13]([NH:15][CH3:16])=[O:14])[CH2:3][CH2:2]2.[H][H]>CO.[Pd]>[NH2:20][C:17]1[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][C:10]([N:4]2[CH:5]3[CH2:6][CH2:7][N:1]([CH2:9][CH2:8]3)[CH2:2][CH2:3]2)=[N:19][CH:18]=1
Reactant: CNC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(N2CCN3CCC2CC3)ncc1N
Reaction time: 8 h

Procedure:
To a solution of 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-5-nitroisonicotinamide (Intermediate 28A) (50 mg, 0.16 mmol) in methanol (0.3 mL) under nitrogen was added palladium on carbon (25 mg). Reaction subjected to a hydrogen atmosphere and stirred overnight. The reaction mixture was filtered and concentrated to afford 5-amino-2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methylisonicotinamide.
Reaction SMILES: O.NN.O[N:5]1C2C=CC=CC=2N=[N:6]1.Cl.C(N=C=NCCCN(C)C)C.[C:26]([NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([C:43]([OH:45])=O)[CH2:39][CH2:38]1)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>O.CN(C)C=O>[NH:5]([C:43]([C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:36][C:26](=[O:27])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:38][CH2:39]1)=[O:45])[NH2:6]
Reactant: On1nnc2ccccc21
Reactant: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reaction time: 72 h

Procedure:
Hydrazine monohydrate (1.42 ml, 23.4 mmol), 1-hydroxybenzotriazole (2.44 g, 18.0 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.49 g, 23.4 mmol) were added to an N,N-dimethylformamide (75 ml) solution of trans-4-(carbobenzoxyamino)cyclohexanecarboxylic acid (5.00 g, 18.0 mmol) at room temperature and the resulting mixture was stirred for 3 days. Water (150 ml) was added to the reaction mixture and the precipitated solid was collected by filtration and dried under reduced pressure to give 4.52 g (86%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([CH3:27])[CH:23]=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: Cc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3cc(C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-5-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A41) the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>CN1CCCC1=O.O>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC(CO)CO
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(CO)CO)c2c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
A solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 2-aminopropane-1,3-diol (420.0 mg, 4.6 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was stirred at 160° C. for 16 hours. After being cooled to room temperature and diluted with water (50 mL), the resulting mixture was extracted with ethyl acetate (100 mL), washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 34.6 mg of the product as a white solid (yield was 15%). MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J=7.83, 1.01 Hz, 1 H), 7.86 (d, J=7.07 Hz, 1 H), 7.71-7.58 (m, 2 H), 7.51-7.40 (m, 2 H), 7.36-7.24 (m, 1 H), 6.16 (s, 1 H), 5.16 (s, 2 H), 4.79-4.59 (m, 1 H), 4.54 (brs, 1 H), 3.81 (s, 5 H), 3.69-3.50 (m, 2 H), 2.42 (s, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([O-:3])=[O:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:28](=[O:30])[CH3:29])[CH:8]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([O-:3])=[O:2]
Reactant: CCCCCCCCCCCC1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Reactant: CC(=O)OC(C)=O
Product: CCCCCCCCCCCC1N(C(C)=O)c2ccccc2-c2c([N+](=O)[O-])cnn21
Yield: 85 %

Procedure:
1-Nitro-5-undecyl-5,6-dihydropyrazolo[1,5-c]quinazoline is treated with acetic anhydride as described in Example 27 to give 1-nitro-5-undecyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 83°-85° C. Yield: 85%.
Reaction SMILES: B.[CH:2]1([C:6]([N:8]2[CH2:26][CH2:25][C@@:15]34[C:16]5[CH:17]=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][C:21]=5[CH2:22][C@@H:9]2[C@:10]3([OH:28])[CH2:11][CH2:12][C:13](=[O:27])[CH2:14]4)=O)[CH2:5][CH2:4][CH2:3]1.Cl>O1CCCC1>[CH:2]1([CH2:6][N:8]2[CH2:26][CH2:25][C@@:15]34[C:16]5[CH:17]=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][C:21]=5[CH2:22][C@@H:9]2[C@:10]3([OH:28])[CH2:11][CH2:12][C@H:13]([OH:27])[CH2:14]4)[CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2c(c1)[C@]13CCN(C(=O)C4CCC4)[C@H](C2)[C@]1(O)CCC(=O)C3
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@]13CCN(CC4CCC4)[C@H](C2)[C@]1(O)CC[C@H](O)C3
Reaction time: 2 h

Procedure:
A solution of 4.5 g of borane in 300 ml of tetrahydrofuran (THF) is cooled to -5° under a stream of nitrogen, and then a solution of 35 g of N-cyclobutylcarbonyl-3-methoxy-14-hydroxy-6-ketomorphinan in 200 ml of THF is added slowly over a 45 minute period, keeping the reaction temperature below 0° C. The reaction mixture is then refluxed for 3 hours, cooled, and 150 ml of ZN HCl is added slowly, which induces a vigorous evolution of gas. The solution is then evaporated to a volume of 150 ml in vacuo, diluted with 200 ml of water, and the pH adjusted to 9.0 by the careful addition of 14 N ammonium hydroxide. The precipitate is stirred for two hours and filtered to give crude N-cyclobutylmethyl-3-methoxy-6α,14β-di-hydroxymorphinan.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li][CH2:9][CH2:10][CH2:11]C.BrCCC.O>O1CCCC1>[CH2:9]([CH:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:1]1=[O:7])[CH2:10][CH3:11]
Reactant: [Li]CCCC
Reactant: O=C1CCCCN1
Solvent: C1CCOC1
Solvent: CCCBr
Solvent: O
Product: CCCC1CCCNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
A solution of 4.2 g (42.3 mmol) of δ-valerolactam (5) in 35 mL of tetrahydrofuran was cooled to -78° C. under argon atmosphere. To this cooled solution, 32 mL of n-BuLi (2.5 M solution in hexane, 80 mmol) was added dropwise over a period of 40 minutes. The reaction mixture was warmed to room temperature and was magnetically stirred for 2 hours. The reaction mixture was cooled to 0° C. and a solution of 3.87 mL (42.5 mmol) of 1-bromopropane in 20 mL of tetrahydrofuran was added dropwise. The reaction mixture was warmed up to room temperature and stirred magnetically for 16 hours. The reaction mixture was treated with 75 mL of water and concentrated to remove tetrahydrofuran. The residue was extracted with 3×200 mL of diethyl ether. The organic layers were combined, washed with brine, dried over MgSO4 and concentrated to yield a white solid which was recrystallized from petroleum ether to yield 3.2 g (22.6 mmol, 54%) of tetrahydro-3-propylpyridin-2(1H)-one (6). NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[C:4]([C:15]([O:17]C)=[O:16])=[N:3]1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[C:4]([C:15]([OH:17])=[O:16])=[N:3]1
Reactant: COC(=O)c1nn(C)c2cc(C(F)(F)F)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc(C(=O)O)c2ccc(C(F)(F)F)cc21
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a tetrahydrofuran (2 mL) of methyl 1-methyl-6-(trifluoromethyl)-1H-indazole-3-carboxylate (50 mg, 0.19 mmol) was added 2N sodium hydroxide (0.2 ml, 4.0 mmol) at room temperature. The mixture was refluxed at 90° C. with stirring for 3 hours. After being cooled to room temperature, 2N hydrochloric acid was added to the mixture until pH became 4.0. The organic layer was extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After the filtration to separate solvent and magnesium sulfate, the solvent was removed under reduced pressure to give 47 mg (quantitative yield) of the title as a white solid that was used in the next step without further purification;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][CH2:32][OH:33])=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCCO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Product: CCN(CCO)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with 2-ethylamino-ethanol
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]([F:18])([F:17])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1COCC1.[OH-].[Na+]>CO>[CH2:10]([O:9][C:7]([NH:6][CH2:5][C:4]([F:17])([F:18])[C:3]([OH:19])=[O:2])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(F)(F)CNC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCC(F)(F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
3-Benzyloxycarbonylamino-2,2-difluoropropionic acid methyl ester (3.3 g, 12.1 mmol), THF (50 ml), methanol (50 ml) and 1 N sodium hydroxide solution (50ml) were mixed and stirred for 16 hours at room temperature. After adjusting the pH to acidic reaction and removal of organic solvent by evaporation, the aqueous residue was extracted twice with ethyl acetate. The combined organic layers were washed twice with 5% brine, dried over magnesium sulphate and filtered through a short silica column before concentration in vacuo to afford 2.6 g (83%) of 3-benzyloxycarbonylamino-2,2-difluoropropionic acid as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH:5][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: Nc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Temperature: 0 °C
Yield: 64.6 %

Procedure:
3-fluoroaniline (40 g) was dissolved in MeOH and the solution was cooled to 0° C. Tert-butyl 4-oxo-1-piperidinecarboxylate (79 g, 1.1 eq), acetic acid (26.8 ml, 1.3 eq) and sodium cyanoborohydride (29 g, 1.3 eq, portionwise) were added successively to the solution. The reaction mixture was stirred at room temperature until completion. The reaction mixture was then cooled to 0° C. and an aqueous solution of NaOH (20%) was poured into the mixture (pH˜10). The precipitate was filtered off, washed with water, dried and recrystallised from iPrOH to give tert-butyl 4-(3-fluoroanilino)-1-piperidinecarboxylate 1 (68.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH2:14])=[CH:6][CH:5]=1)[CH3:2].C(O)(C)(C)C.N.[Li]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2cccc(N)c2c1
Agent: N
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCOC1=CCc2cccc(N)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
The product of Example 1D (1.8 g, 9.63 mmol) and tert-butanol (2.13 g, 28.8 mmol) were dissolved in tetrahydrofuran (20 mL) in a 3-neck 1000 mL round-bottom flask, and the solution was cooled to −78° C. Ammonia (˜35 mL) was condensed into the flask, then lithium metal was added (wire, 225 mg, 32.4 mmol) in portions over 10 min. The reaction mixture was stirred at −78° C. for 1 h, quenched with methanol (50 mL) and H2O (50 mL). The reaction was allowed to stir overnight at room temperature to allow NH3 to evaporate, then it was diluted with ethyl acetate (300 mL), washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel, eluting with 15%-25% ethyl acetate-hexanes, to afford the title compound as a brown oil (999 mg, 55%). 1H NMR (DMSO-d6) δ 6.82 (t, 1H, J=7.6 Hz), 6.44 (d, 1H, J=7.1 Hz), 6.35 (d, 1H, J=7.5 Hz), 4.80 (s, 2H), 4.78 (t, 1H, J=3.8 Hz), 3.78 (q, 2H, J=7.1 Hz), 3.36 (q, 2H, 4.8 Hz), 3.00 (t, 2H, J=4.9 Hz), 1.26 (t, 3H, J=7.1 Hz); MS (DCI+) m/z 190 (M+H).
Reaction SMILES: [CH3:1][S-:2].[Na+].CN(C)C=O.[CH3:9][O:10][C:11]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[C:26]([CH3:34])[C:12]=1[C:13]([C:15]1[C:16](Cl)=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])=[O:14].O>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[C:26]([CH3:34])[C:12]=1[C:13]([C:15]1[C:16]([S:2][CH3:1])=[N:17][CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])=[O:14]
Reactant: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2Cl)c(OC)c1OC
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2SC)c(OC)c1OC
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Sodium methanethiolate (0.32 g) was added to a dimethylformamide (15 ml) solution of 0.9 g of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-chloro-4-trifluoromethylpyridine (compound No. 11) at room temperature, followed by stirring for 1 hour. The mixture was poured into water (50 ml), and extraction with ethyl acetate was carried out. The ethyl acetate phase was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 0.54 g (yield 58%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-methylthio-4-trifluoromethylpyridine (compound No. 50; pale yellow oily substance), and its structure was confirmed by nuclear magnetic resonance spectrum.