Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([CH3:19])[C:17]=1[CH3:18])=[O:12].CC([O-])(C)C.[K+].Cl[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:10][C:11]([C:13]2[C:14](=[O:26])[N:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:16]([CH3:19])[C:17]=2[CH3:18])=[O:12])=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[O:8][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2cc(F)c(O)cc2Cl)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 120 °C
Reaction time: 15 h
Yield: 29.2 %

Procedure:
To a suspension of N-(2-chloro-5-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (751.6 mg, 2 mmol) and t-BuOK (224.4 mg, 2 mmol) in DMF (4 mL) and was added 4-chloropicolinamide (313.2 mg, 2 mmol). The reaction was warmed up to 120° C. and stirred for 15 hours. After the mixture cooling to rt, H2O (40 mL) was added and the resulted mixture was stirred at rt overnight. Filtered and the filter cake was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=50/1) to give the title compound as a light yellow solid (290 mg, 60.5%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH2:7][C:8]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=O.CSC>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH2:7][CH2:8][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(OC(=O)CNc2nccs2)cc1
Solvent: CSC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCNc2nccs2)cc1
Reaction time: 0.25 h

Procedure:
Amide 24-3 (1.0 g, 3.4 mmol) was dissolved in 7 mL toluene at 0°, and BH3.DMS (341 μL, 3.6 mmol) was added. After 15 min, the reaction was heated to reflux for 16 h, cooled to 0°, and quenched with 10% Na2CO3. The mixture was extracted with EtOAc, the organic phase was washed with water and brine, dried (MgSO4), concentrated, and purified by flash chromatography (silica, 70% EtOAc/hexane) providing 24-4 as a white solid. Rf 0.64 (silica, EtOAc).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:25][N:24]=1
Reactant: N#Cc1ccc(-c2cc(NC3CCCC3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1nc(NC2CCCC2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 95 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
In a 25 mL sealable tube was dissolved 4-[2-amino-6-(cyclopentylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (0.476 g, 1.16 mmol) in EtOH (10 mL). Hydrazine monohydrate (1.14 mL, 23.1 mmol) was added, the vial was sealed, and the reaction mixture was stirred for 16 hours at 95° C. The reaction was cooled to room temperature and concentrated. The resulting yellow solid was dissolved in EtOH (2 mL). Water (8 mL) was added, and the resulting mixture was sonicated for 10 minutes. The resulting white precipitate was filtered and dried to afford the title compound (177 mg, 47%) as a white solid. LC-MS (ES) m/z=310 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.38-1.61 (m, 4H), 1.61-1.78 (m, 2H), 1.92 (m, 2H), 4.22 (bs, 1H), 5.37 (s, 2H), 5.97 (bs, 2H), 6.26 (s, 1H), 6.87 (bs, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][NH:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:49]([N:48]([CH3:47])[C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)=[O:11])=[CH:20][CH:19]=2)=[O:23])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N(C)Cc4ccccc4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), methylbenzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:18])[NH:9][C@H:10]([CH2:16][OH:17])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:6])([CH3:5])[CH3:4].IC.[C:21]([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8](=[O:18])[NH:9][C@H:10]([CH2:16][O:17][CH3:21])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])O
Reactant: CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (51.3 mg, 1.284 mmol) in THF (10 mL) cooled at 0° C. under Argon atmosphere was slowly added ((S)-1-hydroxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (300 mg, 1.167 mmol). The mixture was stirred at 0° C. for 30 min and iodomethane (0.095 ml, 1.517 mmol) was added. The reaction mixture was allowed to reach RT and further stirred overnight. To complete the reaction, NaH (24 mg, 0.584 mmol) was again added at 0° C. followed 30 min later by the addition of iodomethane (36 μL, 0.584 mmol). The reaction mixture was stirred at RT for 6 h, then poured into a sat. aq. solution of NaHCO3 and extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash chromatography on silica gel (c-hexane to c-hexane/EtOAc 8:2) to give the desired material as a white powder. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 6.60 (m, 1H), 3.66 (m, 1H), 3.23 (s, 3H), 3.14 (m, 1H), 3.05 (m, 1H), 1.38 (s, 9H), 1.30 (m, 2H), 0.88 (s, 9H).
Reaction SMILES: O([CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.C1COCC1.[Na].[CH3:31][SH:32]>C(OCC)(=O)C>[CH3:31][S:32][CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSC=CC(=Nc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
Phenyl 3-phenoxy-N-phenylacrylimidate (0.30 g) was dissolved to THF (5 ml), sodium salt of methyl mercaptan (0.075 g) was added thereto and stirred for four hours at room temperature. Ethyl acetate (50 ml) was added to the reaction solution, and it was successively washed with water and aqueous saturated of sodium chloride solution, dried over magnesium sulfate (anhydrous), concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-methylthio-N-phenylacrylimidate (0.20 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCCC1>[F:35][C:20]([F:19])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]([Cl:1])=[O:4])[CH2:27][CH2:26]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cl)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A magnetically stirred mixture of triphosgene (365 mg, 1.23 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere was treated slowly with pyridine (485 mg, 6.15 mmol) via syringe. The resulting white suspension was then treated with a solution of 1-(3-Trifluoromethyl-benzyl) piperazine (1.0 g, 4.10 mmol) in tetrahydrofuran (10 mL) via addition funnel over 10 min. The reaction mixture was stirred at 25° C. overnight. At this time, the reaction was filtered to remove solids. The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60:40 hexanes/ethyl acetate afforded 4-(3-Trifluoromethyl-benzyl)-piperazine-1-carbonyl chloride (350 mg, 28%) as a clear oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[F:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]2[CH:43]=[CH:44][S:45][C:38]=12)[NH2:32]>C1COCC1>[F:28][C:29]1[CH:30]=[C:31]([NH:32][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:33]=[CH:34][C:35]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]2[CH:43]=[CH:44][S:45][C:38]=12
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(O)CCCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(CCCc1ccccc1)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-phenylbutanoic acid (49 mg, 0.3 mmol) in 1 mL THF at −78° C. under nitrogen was added N-methyl morpholine (66 μL, 0.6 mmol) followed by isobutyl chloroformate (34 μL, 0.26 mmol). After 15 minutes, a solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (Example 1, Step B) in 1 mL THF was added and the reaction mixture was warmed to reflux. After refluxing overnight, the reaction was cooled to room temperature and partitioned between CH2Cl2 (30 mL) and 10% citric acid (30 mL). The organics were isolated and washed 1×30 mL with 10% citric acid and 2×30 mL with saturated NaHCO3. The organics were dried (MgSO4), filtered, concentrated and loaded onto a Biotage 12S column with 2/3 EtOAc/hexanes and eluted. The fractions containing the product were pooled and concentrated to a white foam (63 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, 1H), 7.75 (d, 1H), 7.73 (m, 1H), 7.69 (br s, 1H), 7.55 (d, 1H), 7.29 (m, 2H), 7.20 (m, 5H), 6.50 (d, 1H), 2.72 (m, 2H), 2.38 (m, 2H), 2.09 (m, 2H). LRMS (ESI pos) m/e 407.0 (M+1).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:29]([NH2:32])[CH:30]=[CH2:31]>>[CH2:29]([NH:32][C:20]1[N:15]2[N:14]=[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=3)=[C:16]2[CH:17]=[CH:18][CH:19]=1)[CH:30]=[CH2:31]
Reactant: C=CCN
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Product: C=CCNc1cccc2c(-c3ccnc(NCCCC)n3)c(-c3ccc(F)cc3)nn12
Yield: 88.5 %

Procedure:
A solution of N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinamine (0.15 g, 0.38 mmol) in allylamine (5 mL, 67 mmol) was heated at 85° C. in a sealed tube for 88 hours. After cooling and concentrating the reaction mixture, flash chromatography (4:1 hexanes-ethyl acetate) afforded N-allyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (0.14 g, 88%) as a pale yellow foam. 1H NMR (CDCl3): δ 7.89 (broad, 1H), 7.78 (d, 1H), 7.62 (m, 2H), 7.36 (t, 1H), 7.16 (t, 2H), 6.31–6.26 (m, 2H), 6.09–5.92 (m, 2H), 5.39–5.24 (m, 2H), 4.06 (t, 2H), 3.50 (q, 2H), 1.72–1.41 (m, 4H), 0.98 (t, 3H); 19F NMR (CDCl3) δ −113.16; MS m/z 417 (M+1); Anal. Calcd for C24H25FN6: C, 69.21; H, 6.05; N, 20.18. Found: C, 69.27; H, 6.07; N, 20.03.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][C:7]1[N:12]=[C:11]([NH:13][C:14](=[S:16])[S-:15])[CH:10]=[CH:9][CH:8]=1.C([NH+](CC)CC)C.C(O)C>CN(C)C=O>[OH:5][C:3]1([CH3:4])[CH2:2][S:16][C:14](=[S:15])[N:13]1[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:6])[N:12]=1
Reactant: Cc1cccc(NC(=S)[S-])n1
Reactant: CC(=O)CCl
Agent: CC[NH+](CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cccc(N2C(=S)SCC2(C)O)n1
Temperature: 2 °C
Reaction time: 3 h

Procedure:
Chloroacetone (13.9 cc) is added to a solution of triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (50.0 g) in dimethylformamide (250 cc) at a temperature between 15 and 23° C. The reaction is continued for 3 hours at 20°-23° C. After filtration and evaporation of the dimethylformamide under reduced pressure (0.1 mm.Hg) at 45° C., the residual oil is dissolved in ethyl acetate (500 cc); the organic solution is washed with distilled water (100 cc), dried over sodium sulphate, treated with decolorising charcoal (2 g) and evaporated. The crystals obtained (38.0 g; m.p. 150°-153° C.) are dissolved in boiling ethanol (520 cc). After 2 hours cooling at 2° C., the resulting crystals are separated by filtration, washed twice with ice-cold ethanol (total 80 cc) and dried under reduced pressure (0.1 mm.Hg) at 45° C. 4-Hydroxy-4-methyl-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (24.9 g), melting at 156° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10](C(O)=O)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn2ccccc2c1C(=O)O
Product: Cc1nn2ccccc2c1Br
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (5.6 g, 24 mmol) in methanol (40 mL, 1000 mmol) was added aqueous sodium hydroxide solution (5.0 mL, 8 M) and the mixture heated to 4° C. for 60 h. The reaction was allowed to cool, hydrochloric acid (5.0 mL, 12 M) and water (150 mL) was added to give a colorless precipitate. The solid was filtered, washed with water and dried in a vacuum oven to give crude 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid, 2.63 g. A suspension of 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (2.0 g, 11 mmol), in Acetonitrile (120 mL) and water (60 mL) was degassed and [I,I-Bis(trifluoroacetoxy)iodo]benzene (2.90 g, 6.74 mmol) was added and the reaction heated under argon to 60 C for 15 min. Gave a clear solution. N-Bromosuccinimide (2.40 g, 13.5 mmol) was added and the solution was stirred at 60° C. for 30 minutes under an atmosphere of argon. The color turned dark. The reaction was heated for a further 30 min, allowed to cool, concentrated to remove acetonitrile and the aqueous extracted with EtOAc (3×50 ml). The organics were combined, washed with ascorbic acid solution, water, dried (MgSO4) and concentrated. The product was purified by column chromatography on silica gel eluting with DCM to 0.5% MeOH in DCM. The title compound was isolated as an off white solid, 0.56 g. LC/MS (FA) ES+ 210.9, 212.9.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2ccc(Oc3cc(F)cc(F)c3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3cc(F)cc(F)c3)ccc12
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 8e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 8e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-[4-hydroxy-1-methyl-6-(3,5-difluoro-phenoxy)-isoquinoline-3-carboxamido]acetic acid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CCOCC.C([O:12][C:13]([C@H:15]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=2)[N:16]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)C.Cl>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OCC)(=O)C>[CH2:29]([N:16]1[C@H:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=2)[CH2:18][CH2:19][C@@H:15]1[C:13]1([OH:12])[CH2:2][CH2:1]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2cc(F)c(F)c(F)c2)N1Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OC1([C@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N2Cc2ccccc2)CC1
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere and at room temperature, ethyl magnesium bromide (8.49 mL, tetrahydrofuran 1M solution) was added dropwise over 1 hour into an ether (10 mL) solution of (2R,5S)-1-benzyl-5-(3,4,5-trifluorophenyl)pyrrolidine-2-carboxylic acid ethyl ester (1.03 g) and titanium tetraisopropoxide (209 μL). The resultant was stirred at the same temperature for 15 hours. The reaction solution was ice-cold, and 1 N hydrochloric acid was added, stirring was continued for 30 minutes at the same temperature. Ethyl acetate was added, and the organic layer was partitioned, and after washing the organic layer with brine, the resultant was dried with magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography, and the title compound (602 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[CH:11](C(OC)=O)[CH2:10][N:9]2[CH3:21])=[CH:5][CH:4]=1.[ClH:24]>CC(C)=O>[ClH:24].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[CH2:11][CH2:10][N:9]2[CH3:21])=[CH:22][CH:23]=1
Reactant: COC(=O)C1CN(C)C(Cc2ccc(OC)cc2)C(C)(C)C1=O
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(CC2N(C)CCC(=O)C2(C)C)cc1
Yield: 87 %

Procedure:
A solution of the hydrochloride (80 g) of methyl 2-(p-methoxybenzyl)-4-oxo-1,3,3-trimethyl-5-piperidinecarboxylate in 450 ml of 1 N hydrochloric acid is refluxed for 12 hours. After cooling, some resinous material is removed by extraction with ether. Alkalinization of the aqueus solution with the aid of ammonia causes the separation of the piperidone which is extracted with ether. Concentration in vacuo of the extent gives a residue which is dissolved in ethanolic hydrogen chloride. Evaporation of the ethanol leaves a syrupy residue which is dissolved in acetone, whereafter the crystalline hydrochloride separates. Yield 87%. Melting point 168° - 170° C, with decomposition.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[CH2:13]([O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14].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>CN(C=O)C>[CH2:13]([O:15][C:16]([C:18]1([NH:27][C:10]([C:5]2[C:4]3[CH:3]=[CH:2][NH:1][C:9]=3[CH:8]=[CH:7][CH:6]=2)=[O:12])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3[nH]ccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a solution of 1H-indole-4-carboxylic acid (250 mg, 1.55 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-60% EtOAc in heptane) to give a pure product (55) as white solid (278 mg, 52%).
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24]([O:27][CH3:28])([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.[C:37](=[O:40])(O)[O-].[Na+]>C(O)CO>[NH2:29][C@@H:17]1[CH2:16][CH2:15][C@@H:14]([C:8]2[C:7]([F:6])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])[CH2:20][N:19]2[C:21]([C:24]([CH3:26])([O:27][CH2:28][CH2:37][OH:40])[CH3:25])=[CH:22][N:23]=[C:18]12
Reactant: COC(C)(C)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2NC(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: OCCO
Product: CC(C)(OCCO)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2N
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Methanesulfonic acid (78 μL, 1.19 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,6-difluorophenyl)-3-(1-methoxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (104 mg, 0.24 mmol) in ethylene glycol (4 mL). The reaction mixture was heated to 60° C. After 18 h, the mixture was allowed to cool to ambient temperature and saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×). The organic extracts were washed with saturated aqueous sodium bicarbonate, saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 366.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:12].[NH2:21][CH2:22][CH2:23][NH2:24]>C(O)(C)C>[NH2:21][CH2:22][CH2:23][NH:24][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cc2ccccc2)c1
Reactant: NCCN
Solvent: CC(C)O
Product: NCCNc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cc1ccccc1

Procedure:
16.0 g of benzyl 2-chloro-5-nitrophenyl sulphone and 12.0 g of 1,2-diaminoethane are refluxed in 100 ml of isopropanol for one hour. The reaction mixture is cooled down, and the solids are filtered off with suction, are washed with 50 ml of water and are dried. This gives 19.2 g of pale yellow [2-(2-aminoethyl)-amino-5-nitrophenyl]-benzyl sulphone.