Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:6]1[O:7][CH2:8][CH2:9][S:10][CH:11]=1)[C:3]([O-:5])=[O:4].[OH-].[Na+]>CO>[NH2:1][CH:2]([C:6]1[O:7][CH2:8][CH2:9][S:10][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)[O-])C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(C(=O)O)C1=CSCCO1
Reaction time: 3 h
Yield: 52.1 %

Procedure:
Ethyl DL-α-amino-(5,6-dihydro-1,4-oxathiin-2-yl)-acetate (37 g.) is dissolved in methanol (350 cc.) and N sodium hydroxide solution (182 cc.) is then added. The reagents are left in contact for 3 hours at a temperature of about 4° C., and the solution is then concentrated under reduced pressure (20 mm.Hg) to about 1/3 of the initial volume. It is then acidified to pH 4.5, at a temperature of about 5° C, by adding 4 N hydrochloric acid. A product crystallises. The mixture is stirred for 15 minutes and the precipitate is then filtered off; DL-α-amino-(5,6-dihydro-1,4-oxathiin-2-yl)-acetic acid (19.4 g.) is thus obtained in the form of white crystals melting at about 270° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CCO.[Pd]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:11]=[C:2]([NH2:1])[C:3]=1[NH2:18]
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of methyl 3-amino-5-morpholino-2-nitrobenzoate (72; 2.1 g, 7.5 mmol) in EtOH (100 ml) was hydrogenated over 5% Pd/C (200 mg) at room temperature. After 3 h, the reaction mixture was filtered and concentrated under reduced pressure to afford 2,3-diamino-5-morpholin-4-yl-benzoic acid methyl ester 73 (1.3 g, 69.5%) as a brown yellow solid.
Reaction SMILES: [C:1](O)(=O)/C=C/C(O)=O.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C@H:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][CH2:25][C@@H:26]2[O:40][C:30]3=[C:31]4[C:36](=[CH:37][CH:38]=[C:29]3[O:28][CH2:27]2)[N:35]=[C:34]([CH3:39])[CH:33]=[CH:32]4)[CH2:20]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C@H:19]1[CH2:23][CH2:22][C@@H:21]([N:24]([CH3:1])[CH2:25][C@@H:26]2[O:40][C:30]3=[C:31]4[C:36](=[CH:37][CH:38]=[C:29]3[O:28][CH2:27]2)[N:35]=[C:34]([CH3:39])[CH:33]=[CH:32]4)[CH2:20]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN[C@@H]1CC[C@H](c2c[nH]c4ccc(F)cc24)C1)O3
Reactant: O=C(O)/C=C/C(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN(C)[C@@H]1CC[C@H](c2c[nH]c4ccc(F)cc24)C1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a mixture of N-[(1R*,3S*)-3-(5-fluoro-1H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine fumarate (200 mg, 0.365 mmol) and formaldehyde (37%, 50 μL, 0.67 mmol) in 2:1 tetrahydrofuran/methanol (3 mL) was added sodium triacetoxyborohydride (155 mg, 0.73 mmol). The reaction was allowed to stir at ambient temperature overnight, then was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (2×20 cm silica gel, 3% methanol/methylene chloride) afforded 115 mg (70%) of the title compound as a semi-solid, which was converted to its fumarate salt as a white powder: mp 198-199° C. (dec); MS (ES) m/z 446 [M+H]+.[α]D5.3°(c 1.0, DMSO)
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=C3CCCC3=2)[C:14](=[O:24])[C:13]1=[O:25]>>[CH:7]1[CH:6]=[C:5]2[CH:4]=[CH:3][C:2]3[C:13](=[O:25])[C:14](=[O:24])[NH:11][C:1]=3[C:10]2=[CH:9][CH:8]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: O=C1Nc2c(ccc3c2CCC3)C1=O
Product: O=C1Nc2c(ccc3ccccc23)C1=O
Yield: 54 %

Procedure:
The benz[g]isatin was prepared in two steps from 5,6,7,8-tetrahydro-1-naphthylamine using the methods described for 1,6,7,8-tetrahydrocyclopenta[g]indole-2,3-dione (G. W. Rewcastle et. al., J. Med. Chem., 1991, 34, 217). The product (54% yield from N-[1-(5,6,7,8-tetrahydronaphthalenyl)]-2-(hydroximino)acetamide) was obtained as an orange solid: mp. 234–235° C. (lit. [U.S. Pat. No. 1,856,210, 1929] 232° C.); NMR δH (400 MHz, DMSO-d6) 1.73 (4H, m), 2.49 (2H, m), 2.73 (2H, m), 6.78 (1H, d, J 7.7 Hz), 7.21 (1H, d, J 7.7 Hz) and 10.92 (1H, s).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.[Cl-].[Na+].O>[S:30]([O:1][CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:27]1[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1 g) in dichloromethane (50 mL) was added triethylamine (1.604 mL) and 4-methylbenzene-1-sulfonyl chloride (1.097 g). The mixture was stirred at ambient temperature under nitrogen for 72 hours. The reaction was diluted with methylene chloride (50 mL) and brine (100 mL). The brine layer was extracted with methylene chloride (75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified on a silica gel column eluting with a 15-65% ethyl acetate in hexane gradient to give the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(Cl)Cl>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C(=O)O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C(=O)Cl)C(F)(F)F
Reaction time: 14 h

Procedure:
DMF (3 drops) was added to a solution of 3,3,3-trifluoro-2,2-dimethyl-propionic acid [889940-13-0] (179 mmol) in CH2Cl2 (160 mL) at rt. Slowly added a solution of oxalyl chloride (197 mmol) in CH2Cl2 (20 mL). After stirring for 14 h, the reaction mixture was carefully evaporated (500 mbar, 33° C.) to afford the title compound (volatile!) as a yellow solution.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.[C:17]([O:22][CH3:23])(=[O:21])/[CH:18]=[CH:19]/[CH3:20]>C(O)(C)(C)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:20][CH:19]=[CH:18][C:17]([O:22][CH3:23])=[O:21])[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(C=O)c1
Reactant: C/C=C/C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C=CC=Cc1cccc(OC)c1
Temperature: 65 °C

Procedure:
A mixture of potassium tert-butoxide (52 g) and tert-butanol (170 ml) was treated dropwise with a mixture of 3-methoxybenzaldehyde (30 g) and methyl crotonate (35 ml). The temperature of the reaction mixture rose to 80° C. during the addition and was then maintained for a further 3 hours at 65° C. The reaction mixture was cooled to room temperature, poured into ice/water and washed with diethyl ether. The aqueous phase was acidified with concentrated HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and evaporated under reduced pressure to yield an orange oil. Yield 53.2 g. Used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:43])C(=O)C1>C(Cl)Cl>[NH2:22][C:21]1[C:16]2[C:15]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:27][CH:28]=3)=[C:14]([Br:43])[N:13]([C@@H:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (2) (330 mg, 0.70 mmol) in DCM (10.0 mL) was added NBS (124 mg, 0.70 mmol). After the mixture was stirred at r.t. for 30 min, the reaction solution was partitioned between DCM (20.0 mL) and water (20.0 mL). The layers were separated and the organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the product (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (375 mg, 98% yield) as a brown solid. LC-MS (ESI): m/z (M/M+2) 550.1/552.1.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C@H:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:6]([NH:21][C:22](=[O:37])[C@H:23]([CH3:36])[NH:24][C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[C:5]1=[O:38])[CH:2]=C.I([O-])(=O)(=O)=[O:40].[Na+]>C1COCC1.O.S(=O)(O)[O-].[Na+].O=[Os](=O)(=O)=O>[F:34][C:29]1[CH:28]=[C:27]([CH2:26][C:25]([NH:24][C@H:23]([C:22]([NH:21][C@@H:6]2[C:5](=[O:38])[N:4]([CH2:1][CH:2]=[O:40])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C@@H:7]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:37])[CH3:36])=[O:35])[CH:32]=[C:31]([F:33])[CH:30]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)[C@@H](c2ccccc2)Oc2ccccc21
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(CC=O)c2ccccc2O[C@@H]1c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 63c (582 mg) in THF (10 mL) was treated with a solution sodium periodate (530 mg) in water (10 mL) followed by a 4% solution of OsO4(1 mL). The reaction mixture was stirred for 16 h, diluted with sodium bisulfite solution (20 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were washed with NaCl solution, dried over magnesium sulfate and concentrated under reduced pressure. The product thus obtained was dissolved in THF (50 mL) and treated with a solution sodium periodate (530 mg) in water (50 mL). After stirring for 16 h the reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (2×100 mL). The organic layers were concentrated under reduced pressure and the product was purified by chromatography to obtain the title compound in 1:1 mixture with the (2S,3R) diastereomer (417 mg). 1H NMR (300 MHz, CDCl3) δ 1.05 (m, 3H), 3.47 (two peaks, 2H), 6.74 (m, 2H), 7.25-7.60 (m, 12H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCCC1=O.[Br:22][C:23]1[N:28]=[C:27]([C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=1.CN1CCCC1=O>O>[Br:22][C:23]1[N:28]=[C:27]([C:29]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:30])[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1cccc(Br)n1
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccccc1Nc1ccccc1)c1cccc(Br)n1
Yield: 49 %

Procedure:
Dissolving 4.4 g (24 mmol) of N-phenyl-1,2-phenylenediamine into 30 milliliter of N-methylpyrrolidone, 10 milliliter of 6-bromo picolinoyl chloride/N-methylpyrrolidone was dropped under cooling with ice. The resultant solution was further stirred at room temperature for 4 hours. After completion of the reaction, the reacted solution was poured into 400 milliliter of water and the resultant solution was further stirred. The resultant solids were separated by filtration, washed with water and methanol, dried under reduced pressure, thereby obtaining 4.5 g of 6-bromo-2′-(N-phenylamino)-picoline anilide (yield: 49%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=2[F:25])[N:18]=[C:17]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=2)[C:16]=1[CH3:34].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]([NH:13][C:15]3[C:24]4[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=4[F:25])[N:18]=[C:17]([C:27]4[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=4)[C:16]=3[CH3:34])[CH:10]=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: Nc1cncc(C2=CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(C4=CCOCC4)c3)c2C)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine (38.8 mg, 0.22 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (52.8 mg, 0.17 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (14.4 mg, 0.03 mmol), tris(dibenzylideneacetone)dipalladium (0) (7.2 mg, 7.9 μmol), and sodium tert-butoxide (45.1 mg, 0.47 mmol) in dry toluene (1.5 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-30% EtOAc in hexanes) to afford an orange film as N-(5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (1H, m), 8.28 (1H, d, J=2.0 Hz), 8.17 (1H, d, J=2.5 Hz), 7.66 (2H, m), 7.20 (1H, ddd, J=5.0, 1.7, 0.8 Hz), 7.14 (1H, d, J=11.9 Hz), 7.10 (2H, m), 6.20 (1H, tt, J=3.0, 1.5 Hz), 4.32 (2H, q, J=2.7 Hz), 3.93 (2H, t, J=5.4 Hz), 2.55 (5H, m), 2.14 (3H, s). Mass Spectrum (pos.) m/e: 445.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f23) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: O=C(Cl)c1cc(Cl)cc(Cl)c1

Procedure:
A solution of 13.4 g. (0.07 mol.) of 3,5-dichlorobenzoic acid and 10.7 g. (0.09 mol.) of thionyl chloride in 60 ml. of methylene chloride was refluxed on a steam bath for two hours. Concentration under reduced pressure and distillation of the residue gave 3,5-dichlorobenzoyl chloride.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O.N1C2C=CC=CC=2N=N1>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1coc(-c2ccc(CO)cc2)n1
Reactant: O=S(Cl)Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1coc(-c2ccc(CCl)cc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
A solution of ethyl 2-[4-(hydroxymethyl)phenyl]-1,3-oxazole-4-carboxylate (0.467 g, 1.89 mmol) in CH2Cl2 was treated with a solution of thionyl chloride (0.281 g, 2.36 mmol) and benzotriazole (0.281 g, 2.36 mmol) in CH2Cl2, and stirred 6 hours at room temperature. The reaction was diluted with CHCl3, filtered over Celite and concentrated under vacuum. The resultant residue was purified by flash chromatography (silica, MeOH:CH2Cl2 5%) to give the title product in 82% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 266 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:8].Br[C:18]1[CH:19]=[CH:20][C:21]2[S:25][CH:24]=[CH:23][C:22]=2[CH:26]=1.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Na+].O.COCCOC>[S:25]1[C:21]2[CH:20]=[CH:19][C:18]([CH:9]([C:7]#[N:8])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:26][C:22]=2[CH:23]=[CH:24]1
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: Brc1ccc2sccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)C(C#N)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
To 1,2-dimethoxyethane (25 mL) suspension of 0.16 g of dichlorobis(triphenylphosphine)palladium(II) were added 0.12 g of triphenylphosphine, 0.01 g of sodium borohydride, 5.53 g of potassium tert-butoxide and 3.48 g of tert-butyl cyanoacetate, which was then stirred at room temperature for 10 minutes. Thereto was added 5.00 g of 5-bromobenzothiophene, which was then refluxed for 2 hours. After to the reaction mixture was added 15 mL of water, the pH was adjusted to 1 with 2 mL of hydrochloric acid. The precipitate was collected by filtration to provide 5.69 g of tert-butyl 2-(1-benzothiophen-5-yl)-2-cyanoacetate as pale yellow solid form.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][CH:9]=[CH:8][C:7]=1[C:26]1[CH:31]=[C:30]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH3:41])[N:34]=2)[C:29](=[O:49])[N:28]([CH3:50])[CH:27]=1)(=O)C.O.[Li+].[OH-]>CC(O)C.O1CCCC1>[OH:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][CH:9]=[CH:8][C:7]=1[C:26]1[CH:31]=[C:30]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][CH2:39][N:40]([CH3:41])[C:42](=[O:43])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])[N:34]=2)[C:29](=[O:49])[N:28]([CH3:50])[CH:27]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccn(CCN(C)C(=O)OC(C)(C)C)n3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CN(CCn1ccc(Nc2cc(-c3cccc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)n1)C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of 206g (750 mg, 1.1 mmol) in propan-2-ol (15 mL), tetrahydrofuran (15 mL), and water (5 mL) was added LiOH (2.6 g, 110 mmol). The mixture was stirred at 30° C. for 2 h. It was then evaporated and the residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 in 1:3 water/CH3CN to give 206h as a brown solid (500 mg, 71%). MS: (M+H)+ 642
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8](N(OC)C)=[O:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C[Li].[CH3:16]COCC.C(O)(=O)C>C1COCC1>[C:8]([C:4]12[CH2:7][N:1]([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)(=[O:9])[CH3:16]
Reactant: CCOCC
Reactant: CON(C)C(=O)C12CCN(CC1)C2
Agent: [Li]C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)C12CCN(CC1)C2
Temperature: -40 °C
Yield: 68.5 %

Procedure:
1-Azabicyclo[2.2.1]hept-4-yl-N-methoxy-N-methyl carboxamide (D21) (10 g, 0.054 mole) was dissolved in dry THF (250 ml) under nitrogen cooled to -40° C. and treated with methyl lithium in ether (55 ml, 1 molar, 0.055 moles). The solution was allowed to warm to room temperature over a period of 1 h. Acetic acid (3.3 ml, leq) was added and the solution concentrated in vacuo to a gum. The residue was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum which was distilled in vacuo to afford 4-acetyl-1-azabicyclo[2.2.1]heptane (D22) (5.15 g, 0.037 mole, 68%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]([C:22]([NH:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([N+:35]([O-:37])=[O:36])[CH:26]=1)=[S:23])[NH2:21]>Cl.CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17](=[N:21][NH:20][C:22]([NH:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([N+:35]([O-:37])=[O:36])[CH:26]=3)=[S:23])[CH3:19])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(NC(=S)NN)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=S)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
Dimethylformamide (1.3 mL) and conc. hydrochloric acid (1 drop) were added to 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (71 mg, 0.26 mmol) synthesized in Reference Synthetic Example 33 and methyl 4-hydrazinocarbonothioylamino-2-nitrobenzoate (70 mg, 0.26 mmol) synthesized in Reference Synthetic Example 56, and the mixture was stirred at room temperature for 2 days. The precipitated solid was filtered to obtain 110 mg of the desired product as a pale yellow solid (yield 81%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=O.O>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH:21]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a mixture of sodium hydride (0.84 g: 55% dispersion in mineral oil) and tetrahydrofuran (40 ml) was dropwise added a solution of ethyl diethylphosphonoacetate (4.33 g) in tetrahydrofuran (20 ml) with ice-cooling of 6° to 12° C. over a 12 minutes period. After stirring at room temperature for 30 minutes, to the mixture thus obtained was dropwise added a solution of 3,5-dichlorobenzaldehyde (3.07 g) in tetrahydrofuran (20 ml) with ice-cooling of 8° to 11° C. over a 10 minutes period. After stirring at room temperature for 4 hours, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extract was washed with water, dried and concentrated. The residue was purified by flash column chromatography through silica gel (100 g). Fractions eluted with a 99:1 mixture of hexane and ethyl acetate were collected and worked up to afford the title compound (3.33 g), melting at 71°-73° C.