Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Product: CN(C)C=CC(=O)c1cc(Cl)ccc1Cl

Procedure:
A mixture of 31.0 g of 2',5'-dichloroacetophenone and 25 ml of N,N-dimethylformamide dimethyl acetal was heated on a steam bath for 6 hours, then evaporated to dryness in vacuo. The residue was slurried with hexane, filtered, and gave 35.3 g of 2',5'-dichloro-3-dimethylaminoacrylophenone as orange crystals, mp 83°-85° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].CCN(C(C)C)C(C)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:20](=[O:22])[CH3:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 3-fluoro-4-methoxyaniline (1.15 g, 8.15 mmol) in dry CH2Cl2 (81 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer were added DIEA (5.4 mL, 32.7 mmol), DMAP (221 mg, 1.81 mmol) and acetic anhydride (4.4 mL, 46.5 mmol) and the mixture was stirred overnight at RT. The solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) gave N-(3-fluoro-4-methoxyphenyl)acetamide SMA 44032 as a brown solid (1.08 g, 72% yield).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:1][CH2:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:7][CH2:8]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate (0.50 g, 2.2 mmol) (Supplier: Chem-Impex) in methylene chloride (15 mL) was added triethylamine (1.29 mL, 9.27 mmol), 4-dimethylaminopyridine (53 mg, 0.44 mmol), and p-toluenesulfonyl chloride (0.89 g, 4.7 mmol). The resulting mixture was stirred at room temperature for 2 h before adding more p-toluenesulfonyl chloride (0.42 g, 2.2 mmol). The mixture was stirred overnight. Water and dichloromethane were added and the layers separated. The aqueous was extracted with dichloromethane. The combined organics were washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue was purified on Biotage Isolera (40 g Agela cartridge, eluted with 5-50% EtOAc/hexanes over 15 min) to give the desired product (0.72 g, 86%) as a white crystalline solid. LCMS calculated for C19H29NO5SNa (M+Na)+: m/z=406.2. Found: 406.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>[Pd](Cl)Cl.C(N(CC)CC)C>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 67.5 °C
Reaction time: 20 h

Procedure:
A stirred mixture of 3.05 g (14.31 mmol) of 4-tert-butylbromobenzene (Compound 22), 1.41 g (14.39 mmol) of trimethylsilylacetylene (Compound 18), 139 mg (0.13 mmol) of cuprous iodide, 293 mg (0.42 mmol) of bis(triphenyophosphine) palladium (II) chloride and 3 ml of triethylamine was flushed with nitrogen and then heated under nitrogen at 65-70 degrees C. for 20 hours. The reaction mixture was stirred at room temperature for a further 4 hours and the triethylamine then removed under vacuum. The residue was purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): δ0.26 (9H, s), 1.31 (9H, s), 7.32 (2H, d, J~8.2 Hz), 7.42 (2H, d, J~8.2 Hz).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([N:17]([CH3:25])[C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@@:28]1([CH3:35])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@@:28]1([CH3:35])[C:29]([NH:20][C@H:19]([C:18]([N:17]([C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:25])=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:30]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN1CCC[C@@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Yield: 89.6 %

Procedure:
According to the general procedure D, from #6 (4.3 g, 12 mmol, 1 eq.), #150 (2.15 g, 12 mmol, 1 eq.), dichloromethane (50 mL), HATU (5.46 g, 14 mmol, 1.2 eq.), and diisopropylethylamine (8.17 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 20 to 55% ethyl acetate in petroleum ether) to afford #202 (5.2 g, 89%) as a yellow oil.
Reaction SMILES: C([Sn](CCCC)(OCCCC)[O:6][Sn:7]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])CCC.[CH2:30](O)[CH2:31][CH2:32][CH3:33]>CCCCCC>[CH2:17]([Sn:7]([CH2:13][CH2:14][CH2:15][CH3:16])([O:6][CH2:30][CH2:31][CH2:32][CH3:33])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCCCC
Reactant: CCCCO
Solvent: CCCCCC
Product: CCCCO[Sn](CCCC)(CCCC)OCCCC
Temperature: 140 °C
Reaction time: 0.1 h
Yield: 54 %

Procedure:
A feed pump was used to start feeding the starting material 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane prepared in the same manner as in Example 12 from supply line 93 at 280 g/Hr and the reactant 1-butanol (manufactured by Wako Pure Chemical Industries Ltd., Japan, industrial product) from supply line 94 at 1,330 g/Hr. The holding time in the reactor was 6 minutes. A pump was used to supply hexane (manufactured by Wako Pure Chemical Industries Ltd., Japan, dehydration grade) at 300 g/Hr from the organic solvent supply line 96 to the reactor lower portion 102, wherein accumulated reaction solution was circulated at 6,000 g/Hr by the circulation line 97 and the reboiler 98 while heating at a temperature of about 140° C. The liquid temperature inside the reactor was 140° C., and the pressure of the back pressure valve 106 was adjusted to 0.12 MPa-G. Continuous supply was continued in this state for 10 hours, after which the system reached a steady state. Low boiling point components flowed from the reactor upper portion 101 and through the low boiling point component recovery line 103 for liquefaction at the condenser 104, and were thereby recovered from the liquid-phase recovery line 108 at 1,088 g/Hr. Furthermore, from the reactor lower portion 102, a dibutyltin alkoxide-containing component was recovered at 821 g/Hr from the extraction line 109. Analysis of the recovered liquid showed that using dibutyltin oxide as a reference, the liquid contained a dibutyltin alkoxide consisting of a yield of about 54.0% dibutyl-di(butyloxy)tin and 46.0% of 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane. Tributyltin butoxide had a yield of 0.013%. Meanwhile, the liquid recovered from the liquid-phase recovery line 108 was transparent and contained 2,500 ppm of moisture. The dehydration rate in the column reactor was 0.24 mol/Hr, which was greater than the value 0.00037 mol/Hr calculated from expression (16).
Reaction SMILES: C(C1CN([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33][CH3:34])=[O:32])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)N(C2C=CC=CC=2)C=1)=O.[Cl-].[CH2:43]([C:45]1[S:46][CH:47]=[C:48]([CH2:50][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:49]=1)[CH3:44].C(=O)([O-])[O-].[K+].[K+].[CH3:76][N:77]([CH3:80])C=O>O>[CH2:43]([C:45]1[S:46][CH:47]=[C:48](/[CH:50]=[CH:27]\[C:26]2[C:22]([O:14][CH2:15][C:16]3[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:28]5[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=5)[C:31]([O:33][CH3:34])=[O:32])[O:25][C:26]=4[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=3)=[N:23][N:77]([C:80]3[CH:38]=[CH:39][CH:16]=[CH:17][CH:18]=3)[CH:76]=2)[N:49]=1)[CH3:44]
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(CON4CC(C=O)=CN4c4ccccc4)cc3OC)c(C)o2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C(=O)OC)c4)oc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34 %

Procedure:
A mixture of methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-2-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (0.80 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.89 g), potassium carbonate (0.29 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give methyl 3-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as colorless crystals (0.32 g, yield 34%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 125-126° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[B:18]1([OH:28])[C:22]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=2[CH2:20][O:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:25]2[CH:24]=[CH:23][C:22]3[B:18]([OH:28])[O:19][CH2:20][C:21]=3[CH:26]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(=O)CCCOc1nc(Cl)c(Cl)cc1C#N
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)c(Cl)cc1C#N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 5,6-dichloro-2-(4-oxopentyloxy)nicotinonitrile (1.12 g, 4.12 mmol, 1.00 equiv) in DMSO (50 mL), benzo[c][1,2]oxaborole-1,5(3H)-diol (650 mg, 4.33 mmol, 1.05 equiv) and Cs2CO3 (1.60 g, 4.92 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at 40° C., then quenched by the addition of 100 mL of ice water. The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with 2×50 mL of water and 1×50 mL of brine, then dried over Na2SO4 and concentrated under vacuum. This resulted in 1.3 g (80%) of 5-chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-(4-oxopentyloxy)nicotinonitrile as a white solid. LC-MS (ES, m/z): 387 [M+H] 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.28 (1H, s), 8.60 (1H, s), 7.81 (1H, d, J=7.8 Hz), 7.33 (1H, s), 7.25 (1H, d, J=7.8 Hz), 5.02 (2H, s), 4.00 (2H, t), 2.35 (2H, t), 2.05 (3H, s), 1.8-1.6 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[C:20](N(OC)C)=[O:21]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: CON(C)C(=O)c1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C#CC(=O)c2cc(Cl)cc(Cl)c2)cc1
Temperature: 40 °C

Procedure:
To a solution of 4-methoxy-1-ethynyl benzene (0.57 g, 4.27 mmol) in 20 mL of anhydrous THF cooled to −78° C. under a N2 atmosphere was added nButLi (3.2 mL, 5.12 mmol). After 5 minutes a solution of 3,5-dichloro-N-methoxy-N-methylbenzamide (1.0 g, 4.27 mmol) in THF (10 mL) was added to the reaction. The reaction was slowly warmed to 40° C. over 30 minutes and then quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with EtOAc (3×). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 1:10 ethyl acetate-hexanes to give the title compound as a yellow solid. 1H NMR (CDCl3, 500 MHz): δ 8.09 (d, J=2.0 Hz, 2H), 7.7 (d, J=7.1 Hz, 2H), 7.64 (t, J=1.8 Hz, 1H), 7.0 (d, J=8.7 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: Cl[C:2]1([C:17]#[N:18])[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-:23].[NH4+].Cl>CN(C)C=O>[Cl:23][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:4]2[CH:3]=[C:2]([C:17]3[NH:18][N:21]=[N:20][N:19]=3)[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: N#CC1=C(Sc2ccccc2)CC(Cl)(C#N)C=C1
Reactant: [N-]=[N+]=[N-]
Reactant: [Cl-]
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2nnn[nH]2)cc1Sc1ccc(Cl)cc1

Procedure:
p-Chlorophenylthioterephthalonitrile (3.28 g), sodium azide (0.78 g), ammonium chloride (0.65g) and dimethylformamide (30 ml) were heated together on the steam bath for 16 hr. The mixture was cooled and poured into dilute hydrochloric acid. The oil which precipitated and solidified slowly was dissolved in sodium bicarbonate solution and the solution extracted with chloroform to remove unchanged starting material. Acidification of the aqueous solution precipitated 2-(p-Chlorphenylthio)-4-(5-tetrazolyl)benzonitrile, decomposes at 222° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:21](=[O:24])[CH2:22]Br)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[C:6]([CH3:25])=[CH:5]1)(=O)C.C([O-])([O-])=O.[K+].[K+].[C:32]([N:42]1[CH2:47][CH2:46]C[CH2:44][CH2:43]1)([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C[N:49](C=O)C>>[CH2:35]([O:34][C:32]([N:42]1[CH2:43][CH2:44][N:49]([CH2:22][C:21]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][C:10]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][CH:5]=[C:6]3[CH3:25])=[O:24])[CH2:46][CH2:47]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(=O)n1cc(C)c2cc(C(=O)CBr)c(OCc3ccccc3)cc21
Reactant: O=C(OCc1ccccc1)N1CCCCC1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c[nH]c2cc(OCc3ccccc3)c(C(=O)CN3CCN(C(=O)OCc4ccccc4)CC3)cc12
Yield: 17 %

Procedure:
Compound 1-(1-acetyl-6-benzyloxy-3-methyl-1H-indol-5-yl)-2-bromo-ethanone (0.039 g, 0.1 mmol), K2CO3 (0.019 g, 0.14 mmol) and Cbz-piperidine (0.026 ml, 0.1 mmol) was stirred in DMF (2 ml) at room temperature for 5 hours. The solvent was removed in vacuo and the residue redissolved in DCM and washed with water, brine, dried over MgSO4. Purification by column chromatography in hexane/EtOAc (3:2) afforded the product (0.008 g, 17%). LC/MS: RT=2.236 min. 498 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:10][N:11]3[C:16]([O:17]CC)=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:10][N:11]3[C:16]([OH:17])=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: CCOc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 60 °C

Procedure:
To a solution of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-ethoxypyrazolo[1,5-a]pyrimidine (11A-1; 250 mg, 0.653 mmol) in THF (6.5 ml) was added water (1.5 ml) and 1M tetrabutylammonium hydroxide in water (3.3 ml, 3.3 mmol). The reaction was heated at 60° C. overnight, cooled, diluted with ethyl acetate and water, and then adjusted to pH 4.5 with 1M aqueous HCl. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated to afford, after trituration from ethyl acetate, I-12A-1a as a tan solid (138 mg, 60%): +APcI MS (M+1) 354.1; 1H NMR (400 MHz, CD3OD) δ 7.79 (d, J=7.1 Hz, 1H), 7.49–7.43 (m, 1H), 7.42–7.35 (m, 3H), 7.30 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 5.93 (d, J=7.1 Hz, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[CH3:14][S:15][CH2:16][CH2:17][C:18](O)=[O:19]>ClCCl>[N:5]1([C:18](=[O:19])[CH2:17][CH2:16][S:15][CH3:14])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CSCCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CSCCC(=O)n1nnc2ccccc21
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
Sulfurous dichloride (4.95 g, 41.6 mmol) was added to a stirred solution of 1H-benzo[d][1,2,3]triazole (19.83 g, 166 mmol) in anhydrous dichloromethane (300 mL) at room temperature under argon. The mixture was stirred for 30 min and 3-(methylthio)propanoic acid (5.0 g, 41.6 mmol) was added in one portion and stirring was continued for 2 h. The resulting suspension was filtered off and the filtrated was washed with 2 M NaOH (3×50 mL), dried over MgSO4, and purified by column chromatography to give the title compound as clear oil (5.12 g). LCMS m/z=222.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.21 (s, 3H), 3.05 (t, J=7.07 Hz, 2H), 3.74 (t, J=7.07 Hz, 2H), 7.42-7.54 (m, 1H), 7.56-7.69 (m, 1H), 8.08 (d, J=8.34 Hz, 1H), 8.24 (d, J=8.08 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C@:11]([CH:14]1[CH2:16][CH2:15]1)([OH:13])[CH3:12])=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[CH:14]1([C@@:11]([OH:13])([CH3:12])[CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[C:34]([Cl:35])[CH:33]=3)[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]=2[C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:15]1
Reactant: C[C@@](O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: C[C@@](O)(CNC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N—((S)-2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 3,4-dichlorophenylboronic acid as starting materials, MS (ISP) 531.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[N:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:13]1([C:19]([O:1][C:2]2[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)c1cc(O)cc(C=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc(C=O)cc(OC(=O)N2CCOCC2)c1
Reaction time: 3 h
Yield: 22.1 %

Procedure:
To a stirring solution of 91.9 mg (0.634 mmol) of 3-hydroxy-5-isopropylbenzaldehyde in 5 mL of CH2Cl2 at r.t. was added 220 μL (1.92 mmol) of 4-morpholinecarbonyl chloride and 0.5 mL (3.59 mmol) of Et3N. After 3 h, sat. NaHCO3 (15 mL) was added, and the aqueous layer was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (20% EtOAc/hexanes) provided 38.8 mg of 3-formyl-5-isopropylphenyl morpholine-4-carboxylate as a yellow oil in 24% yield.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4]1)[CH3:2].Br>CCOCC.O.C(Cl)Cl>[CH2:1]([C@H:3]1[CH2:4][NH:5][CH2:6][C@H:7]1[C:8]1[N:12]2[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:21])=[O:22])[C:14]=3[N:15]=[CH:16][C:11]2=[N:10][CH:9]=1)[CH3:2]
Reactant: CC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1c1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CC[C@H]1CNC[C@H]1c1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of (cis)-benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate (0.838 g, 1.541 mmol, prepared using E from Example #36 Step D with TFA, N, R, S.1 with Example #3 Step E, and T with Lawesson's reagent) was added a solution of HBr (2.50 mL, 15.19 mmol, 33% in acetic acid). The reaction mixture was stirred at ambient temperature for about 1 h. The reaction was diluted with Et2O (50 mL) and water (20 mL). The layers were stirred for about 3 min and the organic layer was decanted then the procedure was repeated 5 times. The aqueous layer was cooled to about 0° C. was basified with saturated aqueous NaHCO3 solution (10 mL) to about pH 7. The aqueous layer was extracted with EtOAc (3×50 mL), combined, and dried over anhydrous Na2SO4, filtered and concd to give a brown solid. The solid was dissolved in DCM (50 mL) and washed with water (3×20 mL), dried over anhydrous Na2SO4, filtered and coned to afford 8-((cis)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.453, 61%) as a brown residue: LC/MS (Table 1, Method a) Rt=1.73 min; MS m/z: 410 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[P:14]([O:19]C)([O:17][CH3:18])[O:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:16][O:15][P:14]([CH2:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O:17][CH3:18])=[O:19]
Reactant: Cc1nc2ccccc2cc1CBr
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cc2ccccc2nc1C)OC
Yield: 105.6 %

Procedure:
A mixture of the obtained 3-bromomethyl-2-methylquinoline (0.25 g, 1.0 mmol) and trimethyl phosphite (0.4 ml, 3.2 mmol) was refluxed in toluene (10 ml) for 16 hours. The reaction mixture was then concentrated in vacuo and the residue was flash chromatographed on silica gel. Elution with ethyl acetate afforded 0.28 g of 3-(dimethylphosphonomethyl)-2-methylquinoline.
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[O:8][CH2:9][CH:10]2[O:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)(C)C>[O:20]1[CH2:21][CH2:22][N:17]([CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH2:18][CH2:19]1
Reactant: C1COCCN1
Reactant: c1ccc(-n2cccc2)c(OCC2CO2)c1
Solvent: CC(C)O
Product: OC(COc1ccccc1-n1cccc1)CN1CCOCC1

Procedure:
A solution of 15 g of 1-[o-(pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane and 7 g of morpholine in 150 ml of isopropanol is heated for 2 hours to the boil under reflux. After evaporation in vacuo, an oil remains, which crystallises and after recrystallisation from butanone gives 1-morpholino-3-[o-(pyrrol-1-yl)-phenoxy]-2-propanol of melting point 81°-82° C. It forms a neutral fumarate of melting point 136°-137° C (from butanone).