Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[C:13]1([C:23](Cl)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:23]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[O:24])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCN(C2CCCCC2)C1
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cccc2ccccc12

Procedure:
To 9.69 gm. (0.06 mole) of 3-amino-1-cyclohexylpyrrolidine in 50 ml. of chloroform was added dropwise a solution of 8.4 gm. (0.046 mole) of 1-naphthalenecarbonyl chloride in 50 ml. of chloroform. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate containing 10% isopropyl ether and dilute hydrochloric acid. The separated acid layer was made basic with dilute sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over sodium sulfate, concentrated and the residue crystallized from ethyl acetate. The product weighed 3.8 gm. (25%) and melted at 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:12]([O:14][CH3:15])=O)[CH:10]=1)[NH:7][N:6]=[CH:5]2.ClC1C=C(C(OCC2(C3C=CC(F)=CC=3)CCN(C(OC(C)(C)C)=O)CC2)COC)C2C(=CN(COCC[Si](C)(C)C)N=2)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:12][O:14][CH3:15])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Agent: COCC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Product: COCC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12

Procedure:
Prepared according to the procedure used to prepare tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate using tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-methoxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as the starting material. 1H-NMR (CDCl3, 500 MHz) δ 10.01 (bs, 1H), 7.90 (s, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.25 (dd, J=8.9, 5.2 Hz, 2H), 7.04 (dd, J=8.6, 8.5 Hz, 2H), 6.99 (d, J=1.5 Hz, 1H), 4.46 (t, J=5.1 Hz, 1H), 3.60-3.85 (m, 2H), 3.56 (m, 2H), 3.44 (d, J=8.9 Hz, 1H), 3.32 (d, J=8.9 Hz, 1H), 3.27 (s, 3H), 3.05 (m, 1H), 2.98 (m, 1H), 2.23 (m, 1H), 2.05 (m, 1H), 1.86 (m, 1H), 1.76 (m, 1H), 1.43 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.6 (d, J=247 Hz), 155.0, 138.12, 138.09, 136.6, 133.7, 128.7 (d, J=7.7 Hz), 126.1, 125.3, 124.7, 123.6, 119.6, 115.6 (d, J=20), 81.6, 79.6, 79.4, 76.0, 59.5, 41.4, 40.0 (br), 32.4, 32.1, 28.5.
Reaction SMILES: [OH:1][C:2]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH2:20][CH:21]=[CH2:22])[CH2:3][O:4][C:5](=[O:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cr](Cl)([O-])(=O)=[O:43].[NH+]1C=CC=CC=1>C1COCC1.C(Cl)Cl.CCOCC>[Si:25]([O:24][CH2:23][C:2]1([CH2:3][O:4][C:5](=[O:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:1][C:22](=[O:43])[CH2:21][CH2:20]1)([C:38]([CH3:40])([CH3:39])[CH3:41])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: C=CCC(O)(COC(=O)CCCCCCCCCCCCC)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCC(=O)OCC1(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCC(=O)O1
Reaction time: 12 h
Yield: 70.8 %

Procedure:
A stirred solution of 2d (1.04 g, 1.8 mmol) in dry THF (35 mL) at -78° C. was treated dropwise with a THF solution of BH3 ·SMe2 (2M, 1.8 mL) while maintained under a blanket of argon. The reaction mixture was allowed to reach room temperature during the course of 3 h and was stirred further for 12 h. Evaporation of the solvent under reduced pressure gave a residue that was dissolved in dry CH2Cl2 (100 mL) and treated with pyridinium chlorochromate (PCC, 15 g, 69.5 mmol). The dark reaction mixture was stirred at room temperature for 3 days and was diluted with dry ether (500 mL) before being filtered through a short silica gel column. The solution obtained was dried (Na2SO4) and reduced to dryness. The residue was purified by flash column chromatography over silica gel using 10% EtOAc in hexane as eluant to give 3d (0.758 g, 71%) as a pale yellow oil; IR (neat) 1785.6, 1743.5 cm-1 ; 1H NMR (CDCl3) δ 0.87 (distorted t, 3 H, CH3), 1.05 (s, 9 H, C(CH3)3), 1.25 (m, 20 H, CH3 (CH2)10CH2CH2CO); 1.55 (m, 2 H, CH3 (CH2)10CH2CH2CO), 2.00-2.40 (m, 4 H, H-4, CH3 (CH2)10CH2CH2CO), 2.60 (m, 2 H, H-3), 3.70 (AB q, J=10.8 Hz, 2 H, CH2OSi), 4.20 (AB q, J=12.0 Hz, 2 H, CH2OCO), 7.30-7.70 (m, 10 H, Ph); 13C NMR δ 14.10, 19.17, 22.67, 24.78. 25.91, 26.72, 28.87, 29.08, 29.20, 29.33, 29.41, 29.57, 29.62, 31.90, 34.03, 65.64, 66.15, 85.77, 127.88, 130.01, 132.25, 132.50, 135.52, 135.59, 173.15, 176.28. Anal. Calcd for C36H54O5Si: C,72.68; H, 9.16. Found: C,72.76; H, 9.22.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:45])[C:29]=1[N:30]1[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]([NH:37]C(=O)OC(C)(C)C)[CH2:31]1)=[O:23])=O)(C)(C)C.N>Cl.CO.CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:45])[C:29]=1[N:30]1[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]([NH2:37])[CH2:31]1)=[O:23]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1C[C@@H](F)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: N
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1C[C@@H](N)C[C@H](F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
A mixture of tert-butyl (3S,5S)-1-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-5-fluoropiperidin-3-ylcarbamate (208 mg, 0.32 mmol) in HCl/MeOH (10 mL) was stirred at ambient temperature for 20 hours and concentrated reduced pressure to give a residue. The residue was diluted with MeOH (10 mL), neutralized with 28% ammonia solution, and concentrated to give a crude product. The crude product was purified by preparative HPLC to afford 189 (130 mg, 90%) as solid. 1H NMR (500 MHz, DMSO) δ (ppm): 8.82 (s, 1H), 7.56-7.51 (m, 3H), 7.41 (s, 1H), 7.30-7.26 (m, 2H), 4.80-4.65 (m, 1H), 3.64 (s, 3H), 3.06-2.98 (m, 2H), 2.89-2.84 (m, 1H), 2.70-2.66 (m, 1H), 2.23-2.18 (m, 1H), 1.72 (br s, 3H), 1.41-1.32 (m, 1H); MS (ESI) m/z: 452 [M+H+].
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:28][C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)(C)(C)C.[ClH:30].[OH-].[Na+]>CCO>[ClH:30].[NH2:7][C@@H:8]1[CH2:28][C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2c(n(Cc3ccccn3)c3ccc(C#N)cc23)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc2c(c1)c1c(n2Cc2ccccn2)C[C@@H](N)C1
Temperature: 47.5 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Equip a 3 L 3-necked round bottom flask with a heating mantle, air stirrer, temperature probe, nitrogen inlet, and addition funnel Charge the flask with (S)-(7-cyano-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid tert-butyl ester (85.0 g, 0.22 moles), and EtOH (850 mL). Add concentrated HCl (180 mL, 2.20 moles) in one portion. Heat the resulting solution to 45-50° C. and stir for 90 min, after which analyze by HPLC to indicate complete consumption of starting material. Transfer the mixture to a Buchi flask, dilute with deionized water (595 mL), and concentrate in vacuo to remove EtOH. Add EtOAc in two portions (2×170 mL) and re-strip to remove both the EtOAc and residual EtOH. Transfer the aqueous concentrate to a 5 L reaction flask, and cool to 10-15° C. While maintaining the temperature of the reaction at <30° C., adjust the pH of the solution to 11-12 by the drop-wise addition of 5 M NaOH (950 mL). Extract the resulting mixture with CH2Cl2 (1300 mL, 800 mL). Wash the combined CH2Cl2 extracts with deionized water (500 mL), dry over Na2SO4, and concentrate in vacuo to afford titled compound as a light green solid (65.0 g, 103%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[CH2:12]([CH2:14][NH2:15])[OH:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:15][CH2:14][CH2:12][OH:13])[CH:3]=[CH:2]1
Reactant: NCCO
Reactant: O=Cc1cccc2cc[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: OCCNCc1cccc2cc[nH]c12
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of indole-7-carboxaldehyde (10.0 g, 68.9 mmol) in 1,2-dichloroethane (300 mL) stirred under N2 at 20–24° C. was added ethanolamine (8.5 mL, 140.8 mmol), acetic acid (4.0 mL, 70.0 mmol) and NaBH(OAc)3 (16.8 g, 75.3 mmol). The resulting mixture was stirred at 20–24° C. overnight. The mixture was diluted with CH2Cl2 (200 mL), washed carefully with NaHCO3 (200 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×200 mL). The combined organic layer was washed with brine (100 mL) and dried over Na2SO4, filtered and concentrated in vacuo to give 12.4 g (95%) of the crude amine as a light yellow solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1 H), 7.41–7.39 (d, 1 H, J=7.81 Hz), 7.29 (s, 1 H), 7.0–6.99 (d, 1 H, J=6.84 Hz), 6.93–6.89 (t, 1 H, J=8.06 Hz), 6.41–6.4 (d, 1 H, J=2.44 Hz), 4.55–4.45 (bs, 1 H), 3.98 (s, 2 H), 3.49–3.47 (bt, 2 H, J=5.13 Hz), 2.61–2.58 (t, 2 H, J=5.86 Hz).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11])[CH:2]1[O:4][CH2:3]1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][CH2:3][CH:2]([OH:4])[CH2:1][N:5]1[CH2:9][CH2:8][O:7][CH:6]1[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C1OCCN1CC1CO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC(O)CN1CCOC1C(C)C
Reaction time: 2 h

Procedure:
Into a 500 ml., three-neck flask equipped with a mechanical stirrer, dropping funnel and condenser with a drying tube was charged 171 g. (1 mole) of 3-glycidyl-2-isopropyloxazolidine and 250 cc. of absolute methanol. While stirring at room temperature an equivalent amount of sodium methoxide (25% solution methanol) was added over a 30 minute period. The mixture was stirred an additional two hours after addition was completed. The solvent was then removed in vacuo to afford 3-(3-methoxy-2-hydroxypropyl)-2-isopropyl-1,3-oxazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]2[O:23][C:10]3[C:11](=[O:22])[N:12]([C@@H:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15](O)=[O:16])[CH2:13][C:9]=3[CH2:8][C:7]=2[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1.[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32][CH:31]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:15](=[O:16])[C@@H:14]([N:12]2[CH2:13][C:9]3[CH2:8][C:7]4[C:6]([O:25][CH3:26])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:24]=4[O:23][C:10]=3[C:11]2=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:32][CH:31]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC(C)C)N2CC3=C(Oc4c(OC)ccc(OC)c4C3)C2=O)nc1
Yield: 15 %

Procedure:
A solution of (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (Example 13, step 2c) (200 mg, 0.55 mmol), commercially available 6-aminonicotinic acid methyl ester (116 mg, 0.66 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (116 mg, 0.60 mmol), and N-hydroxybenzotriazole (HOBt) (82 mg, 0.60 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoylamino]-nicotinic acid methyl ester (41 mg, 30.8%), as a white solid. 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 8.88 (br. s., 1H), 8.28 (d, J=6.8 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.09 (d, J=5.9 Hz, 1H), 4.41 (s, 1H), 4.36 (br. s., 1H), 4.04 (d, J=18.6 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 6H), 3.55 (br. s., 2H), 1.76-1.94 (m, 1H), 1.61-1.74 (m, 1H), 1.46 (br. s., 1H), 0.93 (t, J=5.9 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([N+:11]([O-])=O)[CH:3]=1>CO.CC(O)=O.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([NH2:6])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(N)c([N+](=O)[O-])cc1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(N)c(N)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a stirred mixture of 4-bromo-5-methoxy-2-nitroaniline (5 g, 20 mmol) in MeOH (50 mL) and HOAc (20 mL) at 0° C. under argon was added zinc powder (5.3 g, 80 mmol) portionwise. The mixture was stirred for 2 h, then filtered, and the filtrate was cooled to 0° C. The pH of the filtrate was adjusted to pH˜9 by addition of solid Na2CO3. The mixture was then partitioned between EtOAc (250 mL) and water (200 mL). The EtOAc layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-bromo-5-methoxybenzene-1,2-diamine (3.8 g, 88%) as a dark purple solid. The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 6.66 (s, 1H), 6.34 (s, 1H), 4.08-4.83 (m, 4H), 3.63 (s, 3H). LCMS (ESI) m/z 217 and 219 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)[CH:4]=1)#[N:2].Cl.[NH2:22][C@@H:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:24][OH:25].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][C:27]([F:30])([F:29])[CH2:26][C@H:23]([NH:22][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:19])[CH2:24][OH:25]
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Reactant: N[C@H](CO)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccnc(-n2nc(C(=O)N[C@H](CO)CC(F)(F)F)c3c2[C@@H]2C[C@@H]2C3)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
To a solution of (1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (50 mg, 0.188 mmol), (S)-2-amino-4,4,4-trifluorobutan-1-ol hydrochloride (33.7 mg, 0.188 mmol), and triethylamine (0.052 mL, 0.376 mmol) in DMF (2 mL) was added HATU (71.4 mg, 0.188 mmol). The mixture was stirred at 23° C. for 30 min and purified by HPLC followed by preparative TLC to give the title product (6 mg) as a white solid. LCMS m/z=392.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.24-1.29 (m, 2H), 2.26-2.32 (m, 1H), 2.54-2.69 (m, 2H), 2.77-2.82 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.01 (dd, J=16.7, 6.4 Hz, 1H), 3.87 (d, J=4.0 Hz, 2H), 4.34-4.42 (m, 1H), 7.24 (d, J=8.1 Hz, 1H), 7.41 (dd, J=5.1, 1.1 Hz, 1H), 8.17 (s, 1H), 8.62 (d, J=5.1 Hz, 1H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]1([C:11]2[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)ccc1C
Yield: 84.8 %

Procedure:
A suspension of 1.19 g (9.46 mmol) of phenylboronic acid, 1.97 g (8.60 mmol) of methyl 5-bromo-2-methylbenzoate, 4 mg (0.017 mmol) of palladium (II) acetate, 2.97 g (21.5 mmol) of potassium carbonate, and 2.77 g (8.6 mmol) of tetrabutylammonium bromide in 20 ml of water was vigorously stirred under a stream of nitrogen, and stirred at 70° C. under an atmosphere of nitrogen for 1 hour. Water was added to the reaction mixture and it was extracted with tert-butyl methyl ether. The organic layer was dried and concentrated. The residue (1.9 g) was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=30:1) to obtain 1.65 g (7.29 mmol) of methyl 5-phenyl-2-methylbenzoate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:27](=[O:28])[CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)CCc1ccccc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)CCc3ccccc3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and 3-phenylpropionyl chloride the title compound was obtained as a light yellow solid (3%), MS: m/e=398 (M+H+).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[O:39])[CH:27]=2)[N:22]=1>C1COCC1.CCOC(C)=O.O>[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)([C:11]3[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=3)[OH:39])[CH:27]=2)[N:22]=1
Reactant: Cn1ccnc1
Reactant: COc1ccc(C(=O)c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)cc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
nBuLi (0.0665 mol) was added dropwise at −70° C. to a solution of 1-methyl-1H-imidazole (0.0665 mol) in THF (60 ml) under N2 flow. The mixture was stirred for 15 minutes. Chlorotriethyl-silane (0.0684 mol) was added dropwise. The mixture was stirred for 15 minutes. nBuli (0.059 mol) was added dropwise. The mixture was stirred for 15 minutes. A solution of intermediate 14 (0.038 mol) in THF (150 ml) was added at −70° C. The mixture was stirred at −70° C. for 1 hour and poured out into water. EtOAc was added. The mixture was extracted with EtOAc. The organic layer was washed with water, separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH4OH 96/4/0.2). The pure fractions were collected and the solvent was evaporated, yielding 11 g (59%) of 2-chloro-4-(3 -chlorophenyl)-α-(4-methoxyphenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (intermediate 15).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][C:15]=1[CH:26]([NH2:28])[CH3:27].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][C:15]=1[CH:26]([NH:28][C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[F:1])[CH3:27]
Reactant: CC(N)c1cc(N2CCOCC2)ccc1F
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccc1F)c1cc(N2CCOCC2)ccc1F
Reaction time: 16 h

Procedure:
A mixture of 2-fluoro-cinnamic acid (83 mg), 1-(2-fluoro-5-morpholin-4-yl-phenyl)ethylamine, Preparation 25(112 mg), DMAP (61 mg), EDC.HCl (190 mg), and Et3N (202 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. The crude product was purified by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) to give 150 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH2:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=O)[CH2:6][CH2:5][NH:4][CH2:3]1.O.NN.[OH-].[Na+]>C(O)COCCO>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[CH2:9][CH2:8][CH:7]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[CH3:1]
Reactant: COc1ccc2nccc(C(=O)CC3CCNCC3C)c2c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc2nccc(CCC3CCNCC3C)c2c1

Procedure:
The operation is as in Example 14, but starting from 3.7 g of 2-(3-methyl-4-piperidyl)-1-(6-methoxy-4-quinolyl)-ethanone (trans isomer, racemic), prepared as indicated in Example 4, 3.7 g of 98% hydrazine hydrate and 3.7 g of sodium hydroxide in 37 ml of diethylene glycol. 1.7 g are obtained of 6-methoxy-4-[2-(3-methyl-4-piperidyl)-ethyl]-quinoline (trans isomer), the acid fumarate of which prepared by the action of fumaric acid in ethanol, melts at 224° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]1[CH:32]=[C:31]([CH2:33][C:34](O)=[O:35])[O:30][N:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][C:31]3[O:30][N:29]=[C:28]([CH3:27])[CH:32]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: Cc1cc(CC(=O)O)on1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)on1

Procedure:
The title compound, off-white solid (84 mg, 74%), MS (ISP) m/z=450.3 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-(3-methyl-isoxazol-5-yl)-acetic acid.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27].CCN(C(C)C)C(C)C>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH:27][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: NCCc1cccs1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2cccs2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-thiophen-2-yl-ethylamine and DIEA to give 2-(2-thiophen-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 366 (MH+).