Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(N(C(C)C)C(C)C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: COCCl
Reactant: O=C1CCc2c(O)cccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc2c1CCC2=O
Reaction time: 8 h

Procedure:
To a solution of 4.12 g of 4-hydroxy-1-indanone and 7.3 ml of N-ethyldiisopropylamine in 30 m of dichloromethane, 2.3 ml of chloromethyl methyl ether was added dropwise while stirring under ice cooling. An ice bath was removed and the mixture was continuously stirred overnight. The reaction solution was diluted with diethyl ether, washed with water, an aqueous 10% citric acid solution and an aqueous 5% sodium hydroxide solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4.23 g of the desired compound as a pale orange crystal having a melting point of 51 to 54° C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>C1C=CC=CC=1.ClCCl>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([C:7]([F:6])([F:17])[F:18])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butylamine (2.0 eq) in 75 mL of benzene is added 3-trifluoromethylbenzoyl chloride (1.0 eq). The temperature is maintained below 15° C. during the addition and then the reaction mixture is allowed to warm to ambient temperature and stirred for 3 hours. The solvent is then stripped and the residue is dissolved in 75 mL of dichloromethane. This solution is washed with 5% hydrochloride acid (2×75 mL), water (2×75 mL), dried over MgSO4 and then the solvent is removed in vacuo to provide the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][O:11][CH:12]3[CH:17]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH3:37])=[CH:20][CH:19]=4)[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[CH2:49][CH2:50][CH2:51][O:52][CH3:53]>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH:17]2[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:13][CH:12]2[O:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][N:1]3[CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[CH:23][CH:22]=1
Reactant: COCCCCl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc3[nH]ccc23)cc1
Product: COCCCn1ccc2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21

Procedure:
Analogously to Example 10a, 0.148 g of benzyl 3-(1H-indol-4-ylmethoxy)-4-{4-[3-(2-methoxy-benzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10b2) and 0.110 ml of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=27.24 min (II).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([CH:9]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:9][N+:6]([O-:8])=[O:7])(=[O:4])=[O:3]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g of methanesulfonyl chloride in 150 ml of methylene chloride was added drop-by-drop over a 55 minute period to a stirred mixture of 20 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine and 40 ml of triethylamine in 150 ml of methylene chloride, at -30° C., in a nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at -30° C., and then washed with 2% hydrochloric acid. The aqueous phase was washed twice with methylene chloride. The resulting organic phases were combined, dried (Na2SO4), concentrated to about 50 ml, cooled to 0° C., and filtered. The crystalline solid was triturated with cold methylene chloride, to give N-(methylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (1A), as a crystalline solid, m.p.: 144-145° C. (with decomposition).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.Cl.[CH3:12][N:13]([CH3:32])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30].I.[NH2:34][C:35]1[C:36]([C:43]([NH:45][C:46](=[NH:49])SC)=[O:44])=[N:37][C:38]([Cl:42])=[C:39]([NH2:41])[N:40]=1>C(O)C>[CH3:32][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:46]([NH2:49])=[N:45][C:43]([C:36]1[C:35]([NH2:34])=[N:40][C:39]([NH2:41])=[C:38]([Cl:42])[N:37]=1)=[O:44]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CN(C)CCCNC(=O)CCCCCCCCCCCN
Agent: Cl
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCNC(=O)CCCCCCCCCCCNC(N)=NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
Diisopropylethylamine (0.23 mL, 1.31 mmol) was added to a suspension of 12-amino-dodecanoic acid (3-dimethylaminopropyl)amide dihydrochloride (5) (0.081 g, 0.22 mmol) in absolute ethanol (5 mL). The mixture became homogeneous. It was stirred at 70° C. (oil bath) for 5 min and then 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.093 g, 0.24 mmol) was added in one portion. The reaction mixture was stirred at this temperature for 3 hours and cooled to room temperature. The solvent was then removed by rotary evaporation, the residue dissolved in small volume of methanol, and this solution passed through an ion exchange resin column (Dowex 550A OH type). The resin was rinsed with methanol and the methanol solution was concentrated in vacuo. The resulting residue was purified by Biotage silica gel column chromatography, eluting with a gradient of 1% to 10% of 9:1 methanol/ammonium hydroxide in dichloromethane, to give 12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]dodecanoic acid (3-dimethylaminopropyl)amide 6 (0.070 g, 63%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 1.25 (m, 14H), 1.50 (m, 6H), 2.01 (t, 2H), 2.11 (s, 6H), 2.20 (t, 2H), 3.02 (m, 2H), 3.12 (t, 2H), 6.80 (br, 3H), 7.75 (m, 1H). m/z (ESI) 512 [C23H42ClN9O2+H]+. mp 82-84° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:19]
Reactant: CCOC(=O)CCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
4-Cyanophenol (5.0 g) is dissolved in DMF (40 ml), and thereto are added ethyl 5-bromopentanoate (11.4 g) and potassium carbonate (6.38 g), and the mixture is stirred at room temperature for 24 hours. The reaction mixture is poured into water, and the mixture is extracted three times with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated brine, and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, solvent; hexane/ethyl acetate=5:1 to 5:2). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (9.86 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([N:48]=[C:49]=[S:50])=[O:47]>C1(C)C=CC=CC=1.C(O)C>[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([N:48]=[C:49]=[S:50])=[O:47].[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([NH:48][C:49]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][N:20]=2)=[CH:30][CH:31]=1)=[S:50])=[O:47]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 58%).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[NH:87]1[C:91]([CH2:92][C:93]([OH:95])=O)=[N:90][N:89]=[N:88]1>>[NH:87]1[C:91]([CH2:92][C:93]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:95])=[N:90][N:89]=[N:88]1
Reactant: O=C(O)Cc1nnn[nH]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cc3nnn[nH]3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except (1H-tetrazol-5-yl)-acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 640.5 (M+H)+, 1.58 min (method 6). 1H NMR (500 MHz, METHANOL-d4) δ=7.95 (d, J=8.2 Hz, 2H), 7.48 (s, 1H), 7.25 (d, J=8.2 Hz, 2H), 5.33 (dd, J=1.5, 6.1 Hz, 1H), 4.82 (d, J=1.8 Hz, 1H), 4.68 (s, 1H), 4.12-4.00 (m, 2H), 2.79 (dt, J=5.0, 11.2 Hz, 1H), 2.72-2.62 (m, 1H), 2.45-2.35 (m, 1H), 2.19 (dd, J=6.4, 17.1 Hz, 1H), 2.07-1.92 (m, 2H), 1.84 (d, J=11.6 Hz, 1H), 1.77 (br. s., 1H), 1.76 (s, 3H), 1.73 (d, J=7.3 Hz, 1H), 1.66-1.56 (m, 3H), 1.56-1.49 (m, 4H), 1.48-1.27 (m, 6H), 1.23-1.15 (m, 1H), 1.12 (s, 3H), 1.08 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]#[CH:15]>CO>[CH2:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:14]#[CH:13]
Reactant: C#CCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCN1CCOCC1
Reaction time: 4 h
Yield: 69.6 %

Procedure:
Morpholine (100 ml, 1.148 mol) was dissolved in MeOH (1 L) and cooled in ice under nitrogen, then potassium carbonate (120 g, 0.63 mol) and propargyl bromide (124 mL, 1.148 mol) were added while stirring in ice. Stirring without cooling was continued for 4 h. The white suspension was filtered through paper and the solids were washed with MeOH (100 ml) and the MeOH was carefully evaporated. The white precipitate was suspended in DCM (400 ml), filtered through paper, and carefully evaporated. Finally the oil was distilled at 60° C./16 mbar. One obtained 100 g (70%) of a colorless oil.
Reaction SMILES: CCN(CC)CC.[OH:8][C@@H:9]([CH3:28])[C@@H:10]([NH:14][C:15]([O:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:16])[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:28][C@H:9]1[C@@H:10]([NH:14][C:15](=[O:16])[O:17][C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)[C:11](=[O:13])[O:8]1
Reactant: C[C@H](O)[C@@H](NC(=O)OC12CC3CC(CC(C3)C1)C2)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
In a two necked round bottom flask, Et3N (0.34 ml, 2.42 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(tricyclo[3.3.1.13,7]dec-1-yloxy)carbonyl]amino}butanoic acid (0.240 g, 0.81 mmol) in dry CH2Cl2 (12 mL) under argon. After cooling at 0° C., HBTU (0.459 g, 1.21 mmol) was added and the mixture stirred 3 h at 0° C., then 16 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude mixture was purified by typical silica gel column chromatography, eluting with Cy/AcOEt (90:10). The resulting white solid (0.093 g) was further triturated with cyclohexane to afford the pure title compound (0.065 g, 29%) as white solid. MS (ESI) m/z: 278.31 [M−H]−. Rf=0.19 (Cy/AcOEt 9:1, detection: ninhydrin). FTIR (cm−1): 3338, 2912, 2854, 1828, 1688, 1533, 1457, 1342, 1253, 1120, 1069, 1020, 970, 886, 820. 1H-NMR (CDCl3): δ 1.46 (d, 3H); 1.66 (m, 6H); 2.09 (m, 4H); 2.18 (m, 5H); 4.84 (m, 1H); 5.14 (d, 1H); 5.40 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:11]([N:10]1[C:5]2[C:4]([Cl:21])=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[CH:8]=[CH:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2ccn(Cc3ccccc3)c2c(=O)[nH]1
Product: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Temperature: 116 °C
Yield: 25.6 %

Procedure:
A mixture of 2-amino-5-benzyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (1.1 g, 7.4 mmol) and POCl3 (7 mL, 74 mmol) was heated at 116° C. for 3 h. Upon completion of the reaction, the reaction mixture was poured into ice and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography, eluting with CH2Cl2/Acetone (3:1), afforded the product as a white solid (490 mg, 40%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:16][N:14]1[CH:15]=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:26][C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)[CH:8]=2)[N:12]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4)c3s2)c1
Temperature: 190 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 224 (950 mg, 3.81 mmol), 4-nitrophenol (795 mg, 5.72 mmol), K2CO3 (1.05 g, 7.62 mmol) and Ph2O (5 mL) was stirred at 190° C. for 2 h in a sealed tube, cooled and treated with additional amount of 4-nitrophenol (795 mg, 5.72 mmol). The mixture was stirred for another hour at the same conditions, cooled to room temperature and diluted with DCM. The DCM solution was extracted with 2N HCl; the aqueous phase was collected, basified with concentrated ammonium hydroxide solution (pH˜11) and extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 225 (860 mg, 64% yield) as an orange solid. MS (m/z): 353.1 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[F:7][CH:8]1[CH:13]([O:14][C:15]2[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]([F:23])[CH:16]=2)[CH2:12][CH2:11][N:10]([CH2:24][CH:25]([N:29]2[CH:33]=[C:32]([C:34]3[C:35]4[CH:42]=[CH:41][N:40](COCC[Si](C)(C)C)[C:36]=4[N:37]=[CH:38][N:39]=3)[CH:31]=[N:30]2)[CH2:26][C:27]#[N:28])[CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:7][CH:8]1[CH:13]([O:14][C:15]2[CH:20]=[C:19]([CH2:21][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])[CH:18]=[C:17]([F:23])[CH:16]=2)[CH2:12][CH2:11][N:10]([CH2:24][CH:25]([N:29]2[CH:33]=[C:32]([C:34]3[C:35]4[CH:42]=[CH:41][NH:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH:31]=[N:30]2)[CH2:26][C:27]#[N:28])[CH2:9]1
Reactant: C[C@@H]1CCCN1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(Oc5cc(F)cc(C=O)c5)C(F)C4)c3)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CCCN1Cc1cc(F)cc(OC2CCN(CC(CC#N)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2F)c1
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a mixture of (2R)-2-methylpyrrolidine (2.3 μL, 0.023 mmol) and 4-[3-fluoro-4-(3-fluoro-5-formylphenoxy)piperidin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (13.5 mg, 0.0217 mmol) (diastereomer 2) in DCM (0.10 mL) was added resin of sodium triacetoxyborohydride (13 mg, 0.032 mmol). The resulting mixture was stirred overnight. The reaction solution was filtered, washed with additional DCM, and concentrated. The residue was purified with LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give the desired product (3.4 mg, 23%). LCMS (M+H)+: 691.4.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
69.1 g (0.5 mol) of para-hydroxybenzoic acid were first dissolved in 200 ml of water and 300 ml of isopropanol and this solution was adjusted to a pH of 10.5 at 20 to 25° C. using 87.4 g of NaOH solution (32% strength by weight aqueous solution, 0.7 mol). Metered into this solution then at a pH of 10.5, over the course of three hours, were 88.3 g (0.5 mol) of nonanoyl chloride. The pH was held at 10.5 using 40.5 g of NaOH solution (32% strength by weight aqueous solution, 0.324 mol), and the temperature was held at 20 to 25° C. The batch was stirred for one hour thereafter. Subsequently the reaction mixture was adjusted to a pH of 7 at 20 to 25° C. using 5.3 g of HCl solution (32% strength by weight aqueous solution) and adjusted to a pH of 1.5 to 3 at 65 to 70° C. using 60 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to room temperature (25° C.) and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 121.3 g (87.2% of theory). According to HPLC and NMR measurement, the product was free from nonanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CN(C)CCN.[C:14]([C:16]1[CH:39]=[CH:38][C:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=2[O:36][CH3:37])=[CH:18][CH:17]=1)#[N:15].O>ClCCl>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[O:32])=[CH:29][C:28]=2[O:36][CH3:37])=[CH:38][CH:39]=1)#[N:15]
Reactant: COc1cc(C(=O)O)ccc1OCCCCCOc1ccc(C#N)cc1
Reactant: CC(C)NC(C)C
Agent: CN(C)CCN
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid (3600 g, 10.13 mol) is suspended in dichloromethane (36 L) and to this is added thionyl chloride (1345 g, 11.30 mol) dropwise over 20 minutes followed by dimethylformamide (74.4 g, 10.0 mmol). The reaction mixture is stirred at room temperature for 21 hours; after 6 hours a complete solution is obtained. The solution is concentrated in vacuo (50° C, 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoyl chloride as a solid, which is then redissolved in dichloromethane (36 L) without further purification and cooled to 5° C. with an ice bath. Diisopropylamine (3077 g, 30.40 mmol) is added dropwise over a period of 1 hour. The reaction mixture is stirred at 20° C. for 3 hours and then, N,N-dimethylethylenediamine (80.3 g, 0.91 mmol) is added. The reaction is followed by TLC (2:1 ethyl acetate/hexanes, silica plates) until no more byproduct (bis-anhydride of 4-[5-(4-cyanophenoxy)pentoxy]3-methoxybenzoic acid) is detected. The reaction mixture is then stirred overnight at room temperature. Water (18 L) is added,stirred and the layers separated. The organic layer is washed with hydrochloric acid (1.0 N, 23 L), water (18 L), ammonium hydroxide (0.5 N, 2×23 L), water (18 L) and brine solution (18 L). The separated dichloromethane solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo (50° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)- benzamide as a solid. The solid is dissolved in 2 B ethanol (21.5 L) by warming and to the solution is added water (8.6 L). The product is allowed to crystallize overnight in an ice bath. The product is filtered, washed with EtOH/H2O (5:2, 2×2 L) and dried in vacuo (54° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)- benzamide, mp 90°-92° C. HPLC indicates a purity of >99.7%.