Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrCC.Br[C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([CH3:15])[N:14]=2)[CH:11]=1.[CH2:16]=[O:17].Cl>O1CCCC1.II>[CH3:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([CH2:16][OH:17])=[CH:11][N:10]2[CH:12]=1
Reactant: C=O
Reactant: Cc1cn2cc(Br)ccc2n1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: Cc1cn2cc(CO)ccc2n1
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
In a nitrogen atmosphere, 78.56 g of magnesium was added to 2 l of tetrahydrofuran and 0.3 g of iodine and 18 ml of bromoethane were added to the obtained mixture to prepare a Grignard reagent. A solution of 170.5 g of 6-bromo-2-methylimidazo[1,2-a]pyridine and 162 ml of bromoethane in 500 ml of tetrahydrofuran was slowly dropped into the above reaction mixture. After the completion of the dropping, the obtained mixture was heated under reflux for 30 minutes and then cooled with ice. Formaldehyde gas generated by heating a container containing 242 g of paraformaldehyde to 200° C. was introduced into the reaction mixture by the use of a nitrogen stream. After 30 minutes, dilute hydrochloric acid was added to the resulting mixture and the obtained mixture was filtered to remove insolubles. The filtrate was alkalinized with concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1 to 10:1)] to give 120 g of the title compound as a pale-yellow solid (yield: 91.9%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH:9]1[CH2:10][CH2:11][C:12]2([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([OH:19])(=[O:18])[CH3:17]>CC#N>[C:16]([O:19][C@@H:9]1[CH2:10][CH2:11][C:12]([F:15])([F:14])[C@H:13]1[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: FC1(F)CCC2C1N2Cc1ccccc1
Reactant: CC(=O)O
Solvent: CC#N
Product: CC(=O)O[C@@H]1CCC(F)(F)[C@H]1NCc1ccccc1
Temperature: 80 °C

Procedure:
To a stirred solution of 6-benzyl-2,2-difluoro-6-azabicyclo[3.1.0]hexane (25 mg, 0.11 mmol) in CH3CN (1 mL), acetic acid (1 mL) was added at room temperature. The reaction mixture was heated to 80° C. for 16 h, cooled to room temperature and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 20% EtOAc/Hexanes afforded trans-2-(benzylamino)-3,3-difluorocyclopentyl acetate. MS ESI calc'd. for C14H17F2NO2 [M+H]+ 270. found 270.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].Cl>O1CCOCC1>[Br:1][C:2]1[N:3]=[N:4][C:5]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:10]([Cl:9])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Brc1ccc(Br)nn1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cccc(Nc2ccc(Br)nn2)c1
Yield: 25.1 %

Procedure:
3,6-Dibromopyridazine (1 g, 4.20 mmol) was added to a solution of 3-chloroaniline (0.536 g, 4.20 mmol) in 1,4-dioxane (10 mL) followed by 4M HCl in 1,4-dioxane (6 mL, 24 mmol). The mixture was refluxed for 3 h. The slurry obtained was filtered, and the crude product was purified by preparative HPLC to afford the title compound 21D (0.3 g, 23%) as a solid. 1H NMR (300 MHz, DMSO-d6): δ 9.67 (s, 1H), 8.09 (t, J=1.8 Hz, 1H), 7.7 (d, J=9.0 Hz, 1H), 7.5 (dd, J1=9.0 Hz, J2=0.9 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.12 (d, J=9.6 Hz, 1H), 7.05 (dd, J1=8.1 Hz, J2=0.9 Hz, 1H). ESI-MS m/z: 284 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47]1(/[CH:53]=[CH:54]/[C:55](Cl)=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:55](=[O:56])/[CH:54]=[CH:53]/[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added (2E)-3-phenylprop-2-enoyl chloride (0.062 g, 0.372 mmol) followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The residue was not purified (yield not calculated). ES-MS (m/z) 733 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:8]=3[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:10][CH:11]([CH2:12][CH2:13][CH3:14])[C:5]2=[N:4][N:3]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>>[F:25][C:22]1[CH:23]=[CH:24][C:7]2[N:6]3[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]4)=[N:3][N:4]=[C:5]3[CH:11]([CH2:12][CH2:13][CH3:14])[N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:21]=1
Reactant: CCN1CCNCC1
Reactant: CCCC1N=C(c2ccccn2)c2cc(F)ccc2-n2c(Br)nnc21
Product: CCCC1N=C(c2ccccn2)c2cc(F)ccc2-n2c1nnc2N1CCN(CC)CC1

Procedure:
In the manner given in Example 1, 1-bromo-8-fluoro-4-propyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-ethylpiperazine to give 8-fluoro-4-propyl-1-(4-ethylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH:11][C:12]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][N:13]=1>>[OH:11][C:12]1[CH:17]=[C:16]([CH2:18][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:15]=[CH:14][N:13]=1
Reactant: O=Cc1ccnc(O)c1
Reactant: Nc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1NCc1ccnc(O)c1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 2-hydroxy-4-pyridinecarboxaldehyde (Tyger). 13C-NMR (DMSO-d6) δ 169.8, 162.4, 153.6, 150.2, 135.0, 134.2, 131.6, 115.8, 114.7, 111.5, 110.5, 104.0, 44.7.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>C(O)C>[CH3:21][C:16]1[CH:17]=[C:18]([O:20][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:19]=[C:14]([CH3:13])[C:15]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(O)cc(C)c1-c1ccccc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC(O)CCc2cccnc2)cc(C)c1-c1ccccc1
Yield: 55 %

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (0.70 g), 2,6-dimethylbiphenyl-4-ol (0.79 g), ethanol (15 ml) and aqueous sodium hydroxide (1.9 M, 2.5 ml). After work up the residue was purified by column chromatography over silica with ethyl acetate to give the title compound as a solid (0.72 g).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[N+]([O-])([O-])=O.[Ag+:29]>>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ag+:29]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
Silver Behenate was prepared using procedure one and using 10 g of behenic acid and 4.8 g of silver nitrate to give a white powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C@@:3]([O:8][Si](C)(C)C)([CH3:7])[C:4](Cl)=[O:5].[F:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>CCOC(C)=O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:14])([F:13])[F:1])[CH2:24][CH2:23]2)=[O:21])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of (S)-3,3,3-trifluoro-2-trimethylsilyoxy-2-methylpropanoyl chloride (J. Med. Chem., 1999, 42, 2741-2746) (293 mg, 1.2 mmol) in EtOAc (5 ml) was added to a stirred mixture of 4-(4-fluorobenzoyl)piperidine (207 mg, 1.0 mmol) and triethylamine (0.21 ml, 1.5 mmol) in EtOAc (25 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was dissolved in methanol (10 ml), treated with 1 M hydrochloric acid (2 ml) and the mixture stirred at ambient temperature for 1 hour. The methanol was evaporated, the aqueous layer was extracted with EtOAc (2×25 ml), the EtOAc extracts were washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 10% EtOA/DCM as eluent to give a solid which was recrystallized from EtOAc/hexane to give the title compound as a solid (104 mg, 0.3 mmol). Mp: 78-79° C.; NMR: 1.7 (s, 3H), 1.8-2.0 (m, 4H), 3.2 (dd, 2H), 3.5 (m, 1H), 4.4 (dd, 2H), 5.25 (s, 1H), 7.15 (dd, 2H), 8.0 (dd, 2H); m/z 346.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1>C(O)C>[CH3:1][NH:2][C:3]([NH:15][CH2:14][CH2:13][NH:12][CH2:11][C:8]1[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=1)=[S:4]
Reactant: NCCNCc1ccncc1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NCCNCc1ccncc1

Procedure:
Methylisothiocyanate (1.46 g.) was added slowly to a solution of N-(4-picolyl)ethylenediamine (3.3 g.) in ethanol (25 ml.) The mixture was heated under reflux for 0.5 hours concentrated and extracted with isopropyl acetate to remove N-4-picolyl-N,N'-dimethylethane-1,2-bis thiourea (m.p. 173°-174°). The mother liquors were concentrated and the residue purified by column chromatography to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@:5]([CH3:39])([C:14]([NH:16][NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=2)=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14]2[S:50][C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[N:17][N:16]=2)[CH2:4][O:3]1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2nnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Yield: 70 %

Procedure:
A solution of (S)-tert-butyl 2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)-benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate (D8) (228 mg, 0.39 mmol) in toluene (5 mL) was treated with Lawesson's reagent (321 mg, 0.79 mmol). The reaction was chromatographed on a silica gel column eluted with ethyl acetate-hexane to afford the title compound (˜156 mg). MS (ESI): 572.17 (MH+), 1H NMR (400 MHz, CDCl3) δ 8.10 (d, 1H, J=8.8 Hz), 8.08 (d, 1H, J=6.8 Hz), 7.06 (d, 1H, J=8.0 Hz), 4.41 (d, 1H, J=8.0 Hz), 4.18 (d, 1H, J=9.6 Hz), 4.13-4.07 (m, 3H), 2.00 (s, 3H), 1.85 (m, 2H), 1.78 (s, 3H), 1.68 (m, 4H), 1.51 (s, 3H), 1.47 (m, 2H), 1.39-1.28 (m, 13H), 0.89 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:7]([C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[O:9])=[N:16][CH:17]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cn1)c1cc(F)ccc1[N+](=O)[O-]
Yield: 68.1 %

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol, 1.0 equiv), 2-amino-5-bromopyridine (12.2 g, 1.3 equiv), in 80 mL of pyridine was treated with phosphorous oxychloride (25.3 g, 3.0 equiv) for 30 min. The volatile was evaporated and the residue was redissolved into EtOAc, washed with 1N HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered, and evaporated. The volatile was evaporated, and the product was triturated with diethyl ether to give N-(5-bromo-2-pyridinyl)-(2-nitro)-5-fluorophenylcarboxamide (12.5 g, 68%). MS found for C12H7BrFN3O3 (M+H)+: 340, 342.
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1c(O)c2c(O)cccc2oc1=O
Reactant: CCOC(=O)CCBr
Product: CCCCCCCCOc1c(O)c2c(OCCC(=O)OCC)cccc2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-octyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-octyloxy-4-hydroxy-5-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]=[C:21]([CH2:24]OC(=O)C)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH2:24][C:21]1[CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:23][CH:22]=1)[C:1]([O:8][CH3:9])=[O:7]
Reactant: CC(=O)OCC1=CCN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)CC(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(CC1=CCN(C(=O)OC(C)(C)C)C1)C(=O)OC
Temperature: 25 °C
Yield: 77.6 %

Procedure:
5.28 g (40 mmol) dimethyl malonate were cautiously added to an ice-cooled suspension of 864 mg (36 mmol) sodium hydride in 80 ml THF. The resulting clear solution was added to a solution of 4.82 g (20 mmol) 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester and 462 mg (0.4 mmol) Pd(PPh3)4 in 40 ml THF and the mixture was heated to reflux for 20 h. The reaction mixture was cooled to room temperature, diluted with ether and quenched with sat. NH4Cl. The organic layer was washed with sat. NH4Cl and brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (ethyl acetate/petrol ether 4:1 to 2:1) and bulb-to-bulb distilled to yield 4.86 g (77%) of 2(1-tert.-butoxycarbonyl-2,5-dihydro-1H-pyrrol-3 -yl-methyl)-malonic acid dimetylester as a colorless oil, b.p. 130° C./0.2 mbar.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:13](O)[CH3:14]>S(Cl)(Cl)=O>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH3:14])=[O:5]
Reactant: Cc1cc(F)c(C(=O)O)cc1F
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(F)c(C)cc1F
Temperature: 70 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 2,5-difluoro-4-methylbenzoic acid (595 mg, 3.89 mmol) in ethanol (30 mL) was added a catalytic amount of thionyl chloride (2 drops). The reaction was stirred for 18 hours at 70° C., and cooled to room temperature. The solvent was removed in vacuo to afford the title compound as a clear oil (500 mg, 86%). No further purification undertaken.
Reaction SMILES: [OH-].[Na+].O.BrBr.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12](C(N)=O)=[CH:11]2.[N:21]1C=CC=CC=1>>[NH2:21][C:12]1[CH:13]=[N:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=2
Reactant: c1ccncc1
Reactant: COc1ccc2ncc(C(N)=O)cc2c1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2ncc(N)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
104 kg of a 32% sodium hydroxide solution are added to 341 kg of water. The solution is cooled to 0° C. and 22.0 kg of bromine are introduced over 1.5 hours while maintaining the temperature at 0° C. The solution is stirred at this temperature for 1 hour, and then 409 kg of pyridine are introduced over 3 hours at 0° C. 26.5 kg of 6-methoxy-quinoline-3-carboxamide are then added over 50 minutes at 0° C. The reaction medium is kept at this temperature for 2 hours and then gradually heated to 60° C. over 1 hour. After maintaining the temperature at 60° C. for 6 hours, the reaction mass is cooled to 20° C. and separated by settling out. The aqueous phase (172 kg) is washed with pyridine (60 liters). The organic phases are pooled (820 kg) and concentrated to dryness under reduced pressure (100-150 mbar) at a maximum of 84° C. The residue is then taken up with 425 l of water and 43 l of ethanol. The suspension obtained is refluxed for 1 hour and then cooled. The product begins to precipitate at a temperature of 65° C. The medium is then cooled to 0-5° C., and kept at this temperature for 2 hours. The precipitate is filtered off, washed with cold water, and then dried at 50-55° C. under reduced pressure. 16.5 kg (72.3%) of 3-amino-6-methoxyquinoline are obtained in the form of a brown solid (HPLC titer=99.1%), having a melting point of 108-110° C. A second crop of 3.7 kg (13.1%) is obtained from the mother liquors (HPLC titer=98%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11](Br)[C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2].CC1C=C(C)N=C(C)C=1>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Solvent: Cc1ccccc1C
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 140 °C

Procedure:
A mixture of 0.605 g. (0.0010 mole) of [1α,3β,7ξ,24R]-7-bromo-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.6 ml. of s-collidine and 18 ml. of xylene was heated at reflux (140° C.) for 0.5 hr and cooled. The mixture was diluted with 30 ml. of toluene This solution was washed with 10% aqueous sulfuric acid, and saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on 0.06-0.20 mm silica gel to yield [1α,3β,24R]-24-fluorocholesta-5,7-dien-1,3,25-triol 1,3-diacetate, [α]D23 -21° (c 0.5, CHCl3).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:36](=[O:35])[CH2:37][OH:38])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)CO)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CC([Mg]Cl)C.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:2]2[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCc1cccnc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OCc1cccnc1C1(O)CCN(Cc2ccccc2)CC1
Yield: 17.6 %

Procedure:
To a solution of 4.0 g (21 mmol) (2-bromo-pyridin-3-yl)-methanol in 105 ml dry tetrahydrofuran were added 22 ml (45 mmol) 2-propylmagnesium chloride solution (2.0 M in tetrahydrofuran). The reaction mixture was heated at reflux for 2 h. A solution of 3.8 g (21 mmol) 1-benzyl-4-piperidone in 22 ml tetrahydrofuran was added dropwise at a temperature of approximately 65° C. The reaction mixture was heated at reflux for 3 h and then quenched with water. The aqueous layer was basified to pH 9 with aqueous 1 M sodium hydroxide and extracted with three portions of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash-chromatography gave the title compound (1.1 g, 17%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([O:12][C:13](=O)[CH:14]([CH3:18])[C:15]([CH3:17])=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]2[C:3]=1[N:4]=[C:15]([CH3:17])[C:14]([CH3:18])=[C:13]2[OH:12]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: CCOC(=O)C(C)C(C)=O
Product: Cc1cc(Cl)c2nc(C)c(C)c(O)c2c1

Procedure:
Prepared according to procedure R using 2-chloro-4-methyl-aniline (2.0 mL, 16.3 mmol), ethyl-2-methyl-acetoacetate (4.6 mL, 32.5 mmol), and PPA (8.12 g, 81.2 mmol) to afford 8-chloro-2,3,6-trimethylquinolin-4-ol.