Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17]2[C:9](=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[N:8]([CH3:18])[C:7]=1[C:19]([O:21]C(C)(C)C)=[O:20])=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:17]2[C:9](=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[N:8]([CH3:18])[C:7]=1[C:19]([OH:21])=[O:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OC(C)(C)C)n(C)c2c1ccc1[nH]ncc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C(=O)O)n(C)c2c1ccc1[nH]ncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methyl-1,6-dihydro-1,6,7-triaza-as-indacene-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester C3 (0.68 mmol in DCM (10 mL), trifluoroacetic acid (1 mL) was added. The solution was stirred at rt for 2 h then the reaction mixture was evaporated to dryness affording the title compound in quantitative yield. ESI (+) MS: m/z 288 (MH+); MS (ES−) 286. 1H NMR: 1.35 (t, J=7.07, 3H), 4.18 (s, 3H), 4.33 (q, J=7.07, 2H), 7.47 (d, J=9.02, 1H), 7.91 (d, J=9.02, 1H), 8.51 (s, 1H), 13.46 (bs, 2H).
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:26]([O:28][CH2:29][C:30]1[N:31]([CH2:65][C:66]([OH:69])([CH3:68])[CH3:67])[C:32]2[C:41]3[CH:40]=[CH:39][C:38]([CH:42]=O)=[CH:37][C:36]=3[N:35]=[C:34]([NH:44][C:45]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:33]=2[N:64]=1)[CH3:27]>ClCCl>[CH2:26]([O:28][CH2:29][C:30]1[N:31]([CH2:65][C:66]([OH:69])([CH3:68])[CH3:67])[C:32]2[C:41]3[CH:40]=[CH:39][C:38](/[CH:42]=[CH:6]/[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:37][C:36]=3[N:35]=[C:34]([NH:44][C:45]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:33]=2[N:64]=1)[CH3:27]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C=O)ccc3c2n1CC(C)(C)O
Solvent: ClCCl
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(/C=C/C(=O)OCC)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
(Carbethoxymethylene)triphenylphosphorane (422 mg, 1.21 mmol) was added to a solution of 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carbaldehyde (472 mg, 808 μmol) in dichloromethane (8 mL) under argon. The reaction mixture was stirred for 20 h at room temperature and concentrated in vacuo. Crystallization from dichloromethane and diethyl ether afforded the title compound (0.399 g, 75%) as white solid, LC-MS (UV peak area, ESI) 89%, 655.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29](O)=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:4]=1.CCN=C=NCCCN(C)C.[CH3:51][C:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:27][CH:26]3[CH:12]([C:13](=[O:33])[N:14]([CH3:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH:21]4[C:23]([C:29]([NH:58][S:55]([C:52]5([CH3:51])[CH2:54][CH2:53]5)(=[O:57])=[O:56])=[O:30])([NH:24][C:25]3=[O:28])[CH2:22]4)[CH2:11]2)[CH:6]=[C:5]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:4]=1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
A solution of the acid 13e (250 mg, 0.46 mmol) and EDAC (150 mg, 0.6 mmol) in dry DCM (4 ml) was stirred overnight at room temperature. Methylcyclopropane sulphonamide (78 mg, 0.58 mmol) and DBU (182 mg, 1.2 mmol) were added and the mixture was stirred for additional 6 hours at room temperature. 5% Citric acid was added and the mixture was extracted with ethyl acetate. The organic phase was washed two times with 5% citric acid and water, dried with sodium sulphate and evaporated under reduced pressure. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the pure title compound, (130 mg, 44%), (M+H)+652.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:13])[C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1.CS(C)=O.Cl[CH2:19][CH:20]=[CH2:21]>O>[CH2:21]([O:13][C:6]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=[C:4]([CH3:3])[CH:5]=1)[CH:20]=[CH2:19]
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOc1cc(C)ccc1[N+](=O)[O-]

Procedure:
A solution of 26.1 g of sodium hydroxide in 50 ml of water was added drop-by-drop over 5 minutes to a stirred mixture of 100 g of 3-methyl-6-nitrophenol, 400 ml of dimethyl sulfoxide (DMSO) and 53.6 g of 3-chloropropene initially at room temperature. The temperature of the mixture rose to 43° C. The mixture was heated at 90°-110° C. for two hours, poured into water and filtered, to give 1-(2-propenyloxy)-3-methyl-6-nitrobenzene (1A), as a light yellow solid, m.p.: 30°-32° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][Si](C)(C)C)[CH:8]=2)[S:3]1.[OH-].[K+]>C(O)(C)C>[CH3:1][C:2]1([CH3:20])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[S:3]1
Reactant: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2S1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)S2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 527.6 mg (1.75 mmol) of 2,2,4,4-tetramethyl-6-trimethylsilyl-ethynylthiochroman (Compound 34) in 4 ml of isopropanol was added, under argon, 4 ml of 1N KOH solution. The reaction mixture was stirred at room temperature for 20 h and the isopropanol was then removed under vacuum. The residue was extracted with ether and the combined ether extracts were washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow oil. PMR (CDCl3): & 1.34 (6H, s), 1.37 (6H, s), 1.91 (2H, s), 2.99 (1H, s), 7.17 (1H, dd, J-8.1 Hz, 1.8 Hz), 7.26 (1H, d, J-1.8 Hz), 7.30 (1H, d, J-8.1 Hz). MS exact mass, m/e 230.1122 (calcd. for C15H18S, 230.1129)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.Cl.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:38][CH2:37][CH2:36][NH:35]2)[CH2:30][CH2:29]1)([CH3:27])[CH3:26]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[CH:15][C:2]([N:35]5[CH2:36][CH2:37][CH2:38][CH:34]5[CH:31]5[CH2:30][CH2:29][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:33][CH2:32]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCC(C2CCCN2)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(C2CCCN2c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 110 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
A mixture of 12-bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (300 mg, 0.800 mmol), 1-isopropyl-4-(pyrrolidin-2-yl)piperidine hydrochloride (163 mg, 0.800 mmol), Pd(PtBu3)2 (20 mg, 0.040 mmol), Na2OtBu (232 mg, 2.40 mol) in toluene (2 mL) in a seal tube was degassed with N2 for three times. The resulting mixture was stirred at 110° C. for 120 min. After the completion of the reaction, the solid was filtered off via Celite. The filtrate was concentrated and purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give racemic 175 (40 mg, 10% yield). The (R) and (S) enantiomers were separated by chiral-HPLC (OD-H column, 10% IPA in hexane isocratic) to give 7.0 mg one enantiomer and 10 mg the other enantiomer.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:10][NH:11][C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[Na]>C1(C)C=CC=CC=1.CO>[CH3:17][O:16][C:14]([CH:13]1[C:4](=[O:5])[C:6]2([CH2:7][CH2:8][CH2:9]2)[CH2:10][NH:11][C:12]1=[O:18])=[O:15]
Reactant: CCOC(=O)C1(CNC(=O)CC(=O)OC)CCC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1C(=O)NCC2(CCC2)C1=O

Procedure:
1-[(2-Methoxycarbonyl-acetylamino)-methyl]-cyclobutanecarboxylic acid ethyl ester (1.62 g, 6.3 mmol) dissolved in 15 ml toluene is added dropwise to a freshly prepared solution of sodium (0.15 g, 6.5 mmol) in methanol (20 ml). The reaction mixture is refluxed for 3 hours and then extracted 3 times with water. The aqueous phase is acidified using HClconc. and the now acidic solution is extracted with ethyl acetate. Drying and evaporation of the solvent delivered the crude product which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1[C:10]([CH:20]=[CH2:21])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(NN)(=O)=O)=CC=1.O.O.O.C([O-])(=O)C.[Na+]>COCCOC.O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([CH2:20][CH3:21])=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
The product from Example 44D (0.040 g, 0.102 mmoles) and p-toluenesulfonhydrazide (0.150 g, 1.02 mmoles) in ethylene glycol dimethyl ether (5 mL) at reflux were treated dropwise over a four hour period with a solution of sodium acetate trihydrate (0.232 g, 1.70 mmoles) in water. After the addition, the reaction mixture was allowed to cool to room temperature, poured into water and extracted with methylene chloride (3×). The extracts were combined, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN:0.1% TFA in H2O) on a YMC ODS Guardpak column. 1H NMR (300 MHz, CDCl3) δ7.32 (dd, J=8.0, 1.2 Hz, 1H), 7.35-7.15 (m, 11H), 7.09 (dd, J=8.0, 1.2 Hz, 1H), 6.14 (s, 1H), 4.09 (s, 4H), 2.85 (s, 3H), 2.74 (q, J=7.6 Hz, 2H), 1.00 (t, J=7.6 Hz, 3H); MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1([CH2:29][CH2:30][CH2:31]Cl)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:31][CH2:30][CH2:29][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCN1CCCCC1
Reactant: Oc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(-n2c(-c3ccc(OCCCN4CCCCC4)cc3)nc3ccccc32)cc1

Procedure:
The title compound was prepared by reacting the compound of Example 29 with 3-(piperdin-1-yl)propyl chloride in acetone and potassium carbonate as previously described. mp 86° C., NMR, MS 412.
Reaction SMILES: [C:1]1([CH:7]2[S:11][CH:10]([CH2:12]O)[CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OCC1CSC[S:17]1>>[C:1]1([CH:7]2[S:11][CH:10]([CH2:12][SH:17])[CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CSCS1
Reactant: OCC1CSC(c2ccccc2)S1
Product: SCC1CSC(c2ccccc2)S1

Procedure:
The same method was followed as in Example 1 except that 2-phenyl-4-hydroxymethyl-1,3-dithiolane produced in Example 2 was used in stead of 4-hydroxymethyl-1,3-dithiolane synthesized in Manufacturing Example 1 to obtain 2-phenyl-4-mercaptomethyl-1,3-dithiolane represented by the following formula (2-6).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=3)[NH:8][CH:7]=2)[CH2:29][CH2:28]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCBr)c2c1
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccccc4OC)CC3)c2c1

Procedure:
By reaction of methyl 3-(4-bromobutyl)indole-5-carboxylate with 1-(o-methoxyphenyl)piperazine "B" analogously to Example 1, methyl 3-[4-(4-o-methoxyphenylpiperazino)butyl]indole-5-carboxylate is obtained; hydrate, hydrochloride, m.p. 195°-196°.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:10]=[C:11]3[C:22]4[CH:21]=[CH:20][C:19](OC[C@@H](NC(=O)OC(C)(C)C)CC(C)C)=[CH:18][C:17]=4[O:16][CH:15]([CH3:38])[C:12]3=[CH:13][N:14]=2)=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:38][CH:15]1[C:12]2=[CH:13][N:14]=[C:9]([NH2:8])[CH:10]=[C:11]2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:16]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3c(cn2)C(C)Oc2cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc2-3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1Oc2ccccc2-c2cc(N)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a stirred solution of tert-butyl ((2S)-1-((2-(bis(4-methoxybenzyl)amino)-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (110 mg, 0.165 mmol) in dichloromethane (10 mL) was added TFA (0.254 mL, 3.29 mmol) and the reaction was stirred at room temperature overnight. The volatiles were evaporated and the crude material was purified by preparative HPLC (0.1% TFA in MeOH) to afford 8-4(S)-2-amino-4-methylpentyl)oxy)-5-methyl-5H-chromeno[3,4-c]pyridin-2-amine (25 mg, 0.069 mmol, 42% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 7.74 (m, 2H), 6.84 (s, 1H), 6.75 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 5.18 (m, 1H), 4.32 (m, 1H), 4.15 (m, 1H), 3.65 (m, 1H), 1.83 (m, 1H), 1.65 (m, 5H), 1.04 (m, 6H); LCMS (ESI) m/e 328.2 [(M+H)+, calcd for C19H26N3O2 328.2]; LC/MS retention time (Method D): tR=1.24 min; HPLC retention time (method A): tR=8.42 min.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])O.[Na+]>ClCCl>[F:7][CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CF
Reaction time: 6 h
Yield: 12.1 %

Procedure:
Diethylaminosulfur trifluoride (3.3 g, 20.5 mmols) was added to dichloromethane (30 mL) solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.2 g, 15.9 mmols) under cooling with ice, and stirred at the same temperature for 6 hours. The reaction liquid was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. Then the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. Concentrating the reaction liquid under reduced pressure, the residue was purified on silica gel column chromatography (C-300; ethyl acetate:hexane=1:20) to provide the title compound (390 mg, 12%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(I)cc1OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1ccc(I)cc1OCc1ccccc1

Procedure:
The procedure is the same as that described above, using 14 g of methyl 2-benzyloxy-4-iodobenzoate, 350 ml of toluene and 72 ml of DiBAlH. The product is purified by chromatography on a silica column, eluted with a heptane/ethyl acetate 9:1 mixture. After evaporation of the solvents, 12.2 g (99%) of the expected compound are recovered in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH2:11][C:12](=O)[CH:13]([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[NH2:18][C:19]1[C:23]([Br:24])=[CH:22][NH:21][N:20]=1>>[Br:24][C:23]1[CH:22]=[N:21][N:20]2[C:12]([CH:13]([F:15])[F:14])=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[N:18][C:19]=12
Reactant: Nc1n[nH]cc1Br
Reactant: CCOc1cccc(C(=O)CC(=O)C(F)F)c1
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(Br)c3n2)c1
Yield: 83.1 %

Procedure:
Prepared from 1-(3-ethoxy-phenyl)-4,4-difluoro-butane-1,3-dione (example C.19 step 2) (23.9 g, 99 mmol) and commercially available 3-amino-4-bromopyrazole (15.99 g, 99 mmol) as described in example C.1 step 2a to give the title compound (30.3 g, 83%) as a yellow solid. MS (ISP) 368.0 [(M+H)+], 370.0 [(M+2+H)+].
Reaction SMILES: C([CH2:3][C:4]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1)([CH3:8])[C:5]([OH:7])=[O:6])C.[NH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[SH:29]>CO>[CH3:8][C:4]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:29][C:20]3[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[CH:24][C:19]=3[N:18]=2)=[CH:14][CH:15]=1)([CH3:3])[C:5]([OH:7])=[O:6]
Reactant: CCCC(C)(Oc1ccc(C=O)cc1)C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1S
Solvent: CO
Product: CC(C)(Oc1ccc(-c2nc3cc(C(F)(F)F)ccc3s2)cc1)C(=O)O

Procedure:
A solution including Compound 97c (1.0 eq.) and 2-amino-4-trifluoromethylbenzenethiol (1.0 eq.) was stirred in a methanol solvent at room temperature. After methanol was removed, the precipitate was filtered, and washed with cold methanol to obtain a solid target product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])/[CH:9]=[CH:11]/[N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(Br)cc1
Yield: 61 %

Procedure:
A solution of 1-(4-bromophenyl)ethanone (2.0 g, 10 mmol) in DMF-DMA (25 mL) was stirred at 100° C. for 16 h. The solution was concentrated and purified by flash column chromatography (hexanes:EtOAc=4:1˜2:1) to give the title compound (1.57 g, 61%) as an orange-brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([O:16][CH:17]([CH3:19])[CH3:18])[CH:8]=2)=[N:3]1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([O:16][CH:17]([CH3:19])[CH3:18])[CH:8]=2)=[N:3]1
Reactant: CC(C)Oc1cc(-c2ccn(C)n2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1cc(-c2ccn(C)n2)ccc1N
Temperature: 80 °C
Yield: 14.4 %

Procedure:
In a microwave tube, 860 mg of 1-methyl-3-[4-nitro-3-(propan-2-yloxy)phenyl]-1H-pyrazole are introduced into 30 ml of methanol. 1.25 g of ammonium formate and 1.05 g of Pd/C (10%) are added. The reaction medium is microwave-heated at 80° C. for 3 times 7 minutes. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure and the residue is taken up with 30 ml of ethyl acetate and 3 ml of water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel, elution being carried out with a dichloromethane/methanol (95/5) mixture, so as to obtain 110 mg of 4-(1-methyl-1H-pyrazol-3-yl)-2-(propan-2-yloxy)aniline in the form of a purple oil.
Reaction SMILES: [NH2:1][CH:2]([CH3:6])[CH2:3][O:4][CH3:5].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:5][O:4][CH2:3][CH:2]([NH:1][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH3:6]
Reactant: COCC(C)N
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: COCC(C)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 2-amino-1-methoxypropane (5.0 g, 17.8 mmol) in tetrahydrofuran (25 mL) was slowly added 1,3-propane sultone (2.12 g, 17.0 mmol). The mixture was stirred at reflux for 4 h. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×25 mL), and dried in a vacuum oven (50° C.), to afford compound EI (3.1 g, 86%). 1H NMR (D2O, 500 MHz) δ ppm 3.53 (m, 1H), 3.41 (m, 2H), 3.27 (s, 3H), 3.11 (m, 2H), 2.89 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.18 (d, 3H, J=5.9 Hz). 13C NMR (D2O, 125 MHz) δ ppm 71.73, 58.80, 53.79, 48.08, 43.55, 21.52, 12.79. ES-MS 210 (M−1).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.[Br:24][CH2:25][CH2:26][CH2:27]O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:21][CH2:27][CH2:26][CH2:25][Br:24])=[O:20])=[CH:17][CH:16]=1
Reactant: OCCCBr
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)OCCCBr)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (3.4 g, 17.7 mmol) was slowly added to a solution of 4-methoxybenzoic acid (2.0 g, 13.1 mmol), 3-bromopropan-1-ol (1.1 mL, 12.6 mmol), and 4-(dimethylamino)pyridine (100 mg) in 80 mL of anhydrous dichloromethane. The mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl twice, followed by the addition of saturated NaHCO3 solution and brine. The organic layer was dried through MgSO4 and concentrated under reduced pressure. Chromatography (silica gel, 1:10 ethyl acetate/hexane) of the residue afforded 2.1 g (61%) of 3-Bromopropyl 4-methoxybenzoate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:30][C:31](=[O:43])[C:32]([NH:35]C(=O)OC(C)(C)C)([CH3:34])[CH3:33])[C:11]([N:13]1[CH2:29][CH2:28][CH2:27][C:15]2([C:18](=[O:19])[N:17]([CH3:20])[CH:16]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH2:35][C:32]([CH3:34])([CH3:33])[C:31]([NH:30][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([N:13]1[CH2:29][CH2:28][CH2:27][C:15]2([C:18](=[O:19])[N:17]([CH3:20])[CH:16]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14]1)=[O:12])=[O:43]
Reactant: CN1C(=O)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1C(=O)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)C2)C1c1ccccc1

Procedure:
A mixture comprising tert-butyl 1-((2R)-3-(benzyloxy)-1-(2-methyl-1-oxo-3-phenyl-2,6-diazaspiro[3.5]nonan-6-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (290.8 mg, 0.491 mmol) and TFA (0.378 ml, 4.91 mmol) in DCM (3 ml) was stirred at room temperature for 90 minutes. The solvent was removed in vacuo to afford a colourless oil. The oil was dissolved with methanol (3 ml) and passed through a 10 g SCX2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo to yield the title compound as diastereomeric mixture.