Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[C:13]1(=[O:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.Cl>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:13]1([OH:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccccn1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(Cc2ccccn2)CCc2ccccc21
Temperature: -20 °C

Procedure:
A mixture of 29.5 ml (0.3 mol) of alpha-picoline with 140 ml of tetrahydrofuran was cooled to −20° C. and 187.5 ml of n-butyllithium (1.6M in hexane, 0.3 mol) were subsequently added while stirring. The mixture was allowed to warm to room temperature while stirring and a solution of 39.6 g (0.3 mol) of 1-indanone in 35 ml of tetrahydrofuran was then added over a period of 25 minutes while stirring. The mixture was then stirred for a further 1.5 hours and hydrolyzed with 600 ml of dilute hydrochloric acid, the organic phase was separated off and the aqueous phase was extracted once with diethyl ether. The aqueous phase was then neutralized with aqueous ammonia solution and extracted 3 times with 150 ml each time of chloroform. The organic phases were combined and the solvent was distilled off. The 1-(2-pyridinylmethyl)-1-indanol obtained in this way was dissolved using 500 ml of 10% strength by weight hydrochloric acid and heated for 3 hours on a waterbath. The reaction mixture was cooled, washed with ether and the aqueous phase was neutralized with aqueous ammonia solution. The neutralized aqueous phase was extracted 3 times with 150 ml each time of chloroform and the combined organic phases were dried over magnesium sulfate. After the magnesium sulfate had been filtered off, the solvent was distilled off to leave 52.7 g of a mixture of 2-(1H-inden-3-ylmethyl)pyridine and 2-[(E)-2,3-dihydro-1H-inden-1-ylidenemethyl]pyridine in a ratio of 10:9 in a total yield of 95%. NMR 1H (CDCl3): 8.61 (d, 1H); 7.61 (td, 1H); 7.55 (d, 1H); 7.51 (d, 1H); 7.36 (d, 1H); 7.32-7.22 (m, 3H); 7.16 (dd, 1H); 6.31 (m, 1H); 4.17 (br s, 2H); 3.43 (br s, 2H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:29]=1[CH3:36]>C(Cl)(Cl)(Cl)Cl.CCOCC>[F:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][C:29]=1[CH2:36][Br:8])[C:34]#[N:35]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: N#Cc1ccc(CBr)c(F)c1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
NBS (Aldrich, 3.02 g, 17 mmol) and benzoylperoxide (Aldrich, 0.37 g, 1.5 mmol) was added to a solution of 2-fluoro-4-cyanotoluene (compound 5-2, 2.08 g, 15 mmol) in CCl4. The reaction mixture was heated at 80° C. for 14 hours. After cooling down to ambient temperature, the mixture was diluted with ether (100 ml) and washed with aqueous Na2S3O3, and dried (MgSO4). Removal of solvent under vacuum led to a yellow oil which was purified by flash chromatography. The title compound 5-3 (1.4 g, 42%) was obtained, together with a by-product, 3-fluoro-4-(bromomethyl)benzonitrile (5-4) (1.0 g, 30%). For the title compound (5-3): 1H NMR (CDCl3): δ 4.46 (s, 2H), 7.35 (d, 1H, J=8.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.52 (t, 1H, J=8.0 Hz). For the by-product (5-4): 1H NMR (CDCl3): δ 6.90 (s, 1H), 7.35 (d, 1H, J=8.0 Hz), 7.55 (d, 1H, J=8.0 Hz), 7.96 (t, 1H, J=8.0 Hz).
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][N:15]3[CH3:18])=[CH:11][C:10]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=2[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.C([O-])=O.[NH4+]>[Pd].CCOC(C)=O>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][C:9]=2[NH:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:15]([CH3:18])[N:14]=[CH:13]3)=[C:21]([F:29])[CH:22]=1
Reactant: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cc3F)c(N=C(c3ccccc3)c3ccccc3)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1ncc2cc(Oc3ccc(N)cc3F)c(NC(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a 100 mL round bottom flask is added N-(diphenylmethylene)-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-amine (424 mg, 909 μmol) and EtOH (35 mL, 601 mmol). To the mixture is added ammonium formate (1000 mg, 15.9 mmol) followed by the addition of 10% Pd/C (300 mg, 141 μmol) and the reaction mixture is stirred at RT for 1 hour and heated at 45° C. for 15 min. The solvent is removed and the residue is dissolved in DCM (150 mL) and distilled water (100 mL). The organic layer is washed with distilled water (1 x 100 mL), and the combined aqueous layers are extracted with DCM (1 x 50 mL). The combined organic solution is dried with Na2SO4, filtered, and concentrated. The crude is purified on a silica gel column eluting with hexanes (A) and EtOAc (B), gradient from 90% (A)10% (B) to 40% (A):60% (B) over 90 min to give an off-white solid material as the title compound (204 mg, 51% yield). MS (m/z): 438.8 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1>>[Br:1][C:2]1[C:3]([O:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)(C)OC(=O)N1CC[C@@H](COc2nc(Cl)ncc2Br)C1

Procedure:
Using the procedure of Example 1 Step 1, 5-bromo-2,4-dichloropyrimidine was reacted with (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 4.10 (m, 2H), 3.62-3.17 (m, 5H), 2.72-2.69 (m, 1H), 2.10-2.05 (m, 2H), 1.80-1.75 (m, 1H), 1.44 (s, 9H); MS (ESI) m/z: Calc: 392.68 (M). Found. 337.9 (M+-(CH3)3C).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([Cl:22])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([Cl:22])[CH:5]=1
Reactant: [H][H]
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2C(=O)c3ccc(Cl)cc3C2=O)c(Cl)c1

Procedure:
The mixture of 2.3 g of N-(4-nitro-2-chlorophenyl)-4-chlorophthalimide, 220 ml of ethyl acetate and 1 g of Raney nickel is hydrogenated at room temperature and 3.1 atm. pressure until the hydrogen uptake ceases. It is filtered, evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-2-chlorophenyl)-4-chlorophthalimide melting at 198°-201°.
Reaction SMILES: Br[CH2:2][CH3:3].[O:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:2]([N:27]1[CH2:26][CH2:25][CH:24]([N:22]2[CH:23]=[C:19]([C:17]3[CH:18]=[C:13]([C:5]4[O:4][C:12]5[C:7]([N:6]=4)=[N:8][CH:9]=[CH:10][CH:11]=5)[C:14]([NH2:30])=[N:15][CH:16]=3)[CH:20]=[N:21]2)[CH2:29][CH2:28]1)[CH3:3]
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Bromoethane (0.019 ml) at 0° C. was added to a stirred mixture of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and potassium carbonate (68.8 mg) and DMF (1.5 mL) over a period of 5 minutes under argon. The resulting suspension was stirred at 25° C. for 20 hours. The solvent was evaporated. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 5-[1-(1-ethyl-4-piperidyl)pyrazol-4-yl]-3-oxazolo[4,5-b]pyridin-2-yl-pyridin-2-amine (60.0 mg) as a solid. NMR Spectrum: (DMSOd6) 1.03 (t, 3H), 1.91-2.10 (m, 6H), 2.38 (q, 2H), 2.94-3.01 (m, 2H), 4.09-4.18 (m, 1H), 7.48 (dd, 1H), 7.67 (bs, 2H), 7.92 (s, 1H), 8.23 (dd, 1H), 8.34 (s, 1H), 8.46 (d, 1H), 8.55 (dd, 1H), 8.58 (d, 1H); Mass spectrum: M+H+ 390.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C([O:25][C:26](=[O:35])[C@H:27]([NH2:34])[CH2:28][O:29]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:14])[CH3:15])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:34][C@H:27]([CH2:28][OH:29])[C:26]([OH:35])=[O:25])=[O:19])[N:3]=1
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Reactant: CC(C)(C)OC[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)N[C@H](CO)C(=O)O)nc(Cl)c2c1

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and (R)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=369.0 amu.
Reaction SMILES: [CH3:1][O:2]/[C:3](/[CH2:9][CH3:10])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].[Br:11]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:11][CH:9]([CH3:10])/[C:3](/[O:2][CH3:1])=[CH:4]\[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC/C(=C\C(=O)OC)OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C(/OC)C(C)Br
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 379.6 %

Procedure:
A 500-ml 4-necked pear-shaped flask equipped with a mechanical stirrer, a thermometer, a cooler, an argon inlet and an oil bath was charged under argon with 31.2 g of crude methyl (E)-3-methoxy-2-pentenoate (ca. 0.217 mol), 10.45 g of N-bromo succinimide (58.7 mmol), 0.47 g of 2,2′-azobis(2-methylpropionitrile) (2.86 mmol) and 100 ml of carbon tetrachloride. The resulting yellow suspension was heated for 10 min with an 80° C. oil bath to give an almost colorless suspension. Then three additional portions consisting each of 10.45 g of NBS, 0.47 g of AIBN and 35 ml of carbon tetrachloride, in total 31.35 g of N-bromo succinimide (0.176 mol), 1.41 g of 2,2′-azobis(2-methylpropionitrile) (8.59 mmol) and 105 ml of carbon tetrachloride were added in 5 min time intervals at the same temperature. 20 min after the last addition of reagents (total reaction time was 45 min) the oil bath was removed and the reaction mixture cooled under stirring with an ice bath for ca. 30 min. The suspension was filtered with suction and the filter cake washed with a total of 90 ml of carbon tetrachloride. The filtrate was rotary evaporated to dryness (50° C., 10 mbar) to give 49.7 g of crude methyl rac-(E)-4-bromo-3-methoxy-pent-2-enoate (theor. amount 48.4 g) as an orange oil. This material was used without purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[OH:13])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc([N+](=O)[O-])ccc1O
Yield: 83.1 %

Procedure:
Using 5-nitrosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:21])/[CH:18]=[CH:19]/[CH3:20].O>[OH-].[Na+].C(O)C.C1C=CC=CC=1>[C:17]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:21])/[CH:18]=[CH:19]/[CH3:20]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: C/C=C/C(=O)Oc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl crotonate was prepared by dissolving 22.2 grams of 2,6-di tert.butyl hydroquinone in a solution of 4 grams of sodium hydroxide in 100 milliliters of ethanol and adding drop wise to this solution a solution of 11.5 grams of crotonyl chloride in 50 milliliters of benzene. The addition was completed in 45 minutes. The reaction mixture was stirred for 4 hours at room temperature and then at 50° C. for 1 hour. After adding 100 milliliters of water to the reaction mixture, the layers were separated. The organic layer was evaporated to dryness and the residue dissolved in hexane. The hexane solution was washed three times with 10 percent sodium hydroxide solution, once with water, dried over sodium sulfate, and cooled to yield 10.5 grams of product which after recrystallization from hexane melted at 80° C. to 81.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1>C1COCC1.CCC(C)C.C1COCC1>[CH3:30][N:31]1[CH2:36][CH2:35][C:34]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]4)[N:9]=3)=[CH:6][CH:7]=2)([OH:37])[CH2:33][CH2:32]1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCC(C)C
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)CC1
Reaction time: 0.25 h

Procedure:
[4-(4-Bromophenyl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (116 mg; 0.3 mmol) in THF/isopentane (3 ml/0.6 ml) was cooled to −100° C. nBuLi (1.6M in hexane, 0.56 ml; 0.9 mmol) was added within 5 minutes and the reaction mixture stirred for 15 minutes at this temperature. N-methyl-4-piperidone (71 μl, 0.6 mmol) was added in THF (71 μl), the reaction mixture stirred for 10 minutes at −100° C., poured on water and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, evaporated to dryness and purified via chromatography on silicagel (EtOAc/MeOH/ammonia:90/9/1 to 80/18/2) to give the title compound as a white solid. Yield: 25 mg (17%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]([NH:27][C:28]([C:30]2[CH:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[O:29])[C:20](=[O:36])[N:19]2[CH2:37][C@H:38]([O:40][C:41]3[N:42]=[C:43]4[C:48](=[C:49]5[C:54]=3[CH:53]=[CH:52][CH:51]=[CH:50]5)[CH:47]=[CH:46][CH:45]=[CH:44]4)[CH2:39][C@H:18]2[C:17](=[O:55])[NH:16][C@:15]2([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:56][C@H:14]2[CH2:13]1.C(N(CC)CC)C>ClCCl>[CH3:35][C:33]1[O:32][N:31]=[C:30]([C:28]([NH:27][C@@H:21]2[C:20](=[O:36])[N:19]3[CH2:37][C@H:38]([O:40][C:41]4[N:42]=[C:43]5[C:48](=[C:49]6[C:54]=4[CH:53]=[CH:52][CH:51]=[CH:50]6)[CH:47]=[CH:46][CH:45]=[CH:44]5)[CH2:39][C@H:18]3[C:17](=[O:55])[NH:16][C@:15]3([C:57]([O:59][C:60]([CH3:62])([CH3:61])[CH3:63])=[O:58])[CH2:56][C@H:14]3[CH2:13][C:12](=[O:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:29])[CH:34]=1
Reactant: Cc1cc(C(=O)N[C@H]2CCCCCC(O)C[C@@H]3C[C@@]3(C(=O)OC(C)(C)C)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(=O)C[C@@H]3C[C@@]3(C(=O)OC(C)(C)C)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a solution of oxalyl chloride (0.017 ml, 0.198 mmol) in dichloromethane (0.6 ml) cooled to −60° C. was added DMSO (0.030 ml, 0.419 mmol) dropwise. The mixture was stirred for 15 min and added dropwise a solution of compound (2R,6S,13aS,14aR,16aS)-tert-butyl 12-hydroxy-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclo propa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 18h, 80 mg, 0.11 mmol) in dichloromethane (0.4 ml). The reaction mixture was stirred for 20 min at −60° C., and triethylamine (0.123 ml, 0.882 mmol) was added dropwise. The mixture was stirred at −60° C. for 5 min, and allowed to warm to room temperature with stirring for 10 min. The reaction mixture was quenched with water, stirred for 15 min, and diluted with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give a foamy material. The crude product was purified by flash chromatography on silica gel (5% methanol/dichloromethane) to provide the title compound (2R,6S,13aS,14aR,16aS)-tert-butyl 6-(5-methylisoxazole-3-carboxamido)-5, 12, 16-trioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (47 mg, 59% yield) .
Reaction SMILES: BrC1N=C(N)C(OC)=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[C:26]([O:30][C:31]([N:33]([C:41]1[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[C:43]([Br:49])[N:42]=1)C(OC(C)(C)C)=O)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C)C1C=CN=CC=1.CC#N>[C:26]([O:30][C:31](=[O:32])[NH:33][C:41]1[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[C:43]([Br:49])[N:42]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(Br)nc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: COc1ccc(Br)nc1N
Solvent: CC#N
Product: COc1ccc(Br)nc1NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-3-methoxypyridin-2-amine (10.2 g, 50.2 mmol), Boc2O (38.2 g, 0.18 mol) and 4-(dimethylamino)pyridine (1.2 g, 9.82 mmol) in MeCN (550 mL) was refluxed for 2 h. After cooling to rt and concentration in vacuo EtOAc (500 mL) was added and the organic phase washed with water (100 mL) and brine (50 mL). The organic phase was dried (MgSO4), filtered and the filtrate concentrated in vacuo. Purification by chromatography eluting with 4:1 DCM-heptane yielded a mixture of the title compound and di-tert-butyl(6-bromo-3-methoxypyridin-2-yl)imidodicarbonate (10.6 g) in an approximate ratio of 55:45.
Reaction SMILES: COC1C=CC(C([NH:9][C:10]2[C:15]([NH:16][C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH2:27][CH2:28][S:29][CH3:30])=[CH:14][N:13]=[CH:12][N:11]=2)=O)=C(OCCSC)C=1>P(Cl)(Cl)(Cl)=O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[NH:16][C:15]3[C:10](=[N:11][CH:12]=[N:13][CH:14]=3)[N:9]=2)=[C:19]([O:26][CH2:27][CH2:28][S:29][CH3:30])[CH:20]=1
Reactant: COc1ccc(C(=O)Nc2cncnc2NC(=O)c2ccc(OC)cc2OCCSC)c(OCCSC)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3ncncc3[nH]2)c(OCCSC)c1

Procedure:
An amount of 3.1 g of 4,5-bis-[4-methoxy-2-(2-methylmercapto-ethoxy)-benzoylamino]pyrimidine was refluxed in 25 ml of phosphorus oxychloride for two hours. After the phosphorus oxychloride was distilled off, the residue was taken up in water and filtered, and the product was precipitated by addition of sodium bicarbonate and recrystallized from ethanol. A further fraction was obtained by purification of the mother liquors over silicagel (eluate: methylene chloride/ethanol in a volume ratio of 19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>[Ni]>[NH2:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Product: COc1ccc(Cl)cc1N

Procedure:
0.037 mol (7 g) of 4-chloro-2-nitroanisole is dissolved in 100 ml of absolute alcohol and 3 g of nickel prepared by the RANEY process are added. The solution is hydrogenated at atmospheric pressure and at room temperature while stirring. The catalyst is separated and then washed with two portions of 20 ml of boiling ethanol. The alcoholic solution is concentrated under reduced pressure; the 2-amino-4-chloroanisole crystallizes.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH2:27][CH2:28][NH2:29]>C(Cl)Cl>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH2:27][CH2:28][NH:29][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11]
Reactant: NCCc1cc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(NCCc2cc3ccccc3[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
To a suspension of 1,2-difluoro-4-nitrobenzene (1.59 g, 10 mmol) and K2CO3 (6.90 g, 50 mmol) in DCM (40 mL) was added 2-(1H-indol-2-yl)ethanamine (1.96 g, 10 mmol) in one portion under N2 and the mixture was stirred at rt for 24 h. The mixture was then filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as a yellow solid (2.32 g, 78%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:48]=[CH:47][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[CH:20][C:19]=3[N:38](C)[C:39](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:49].O1CCOCC1>>[ClH:49].[CH3:39][N:38]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:47]=[CH:48][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(Oc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetylamino]-5-(4-phenoxyphenoxy)phenyl}-N-methylcarbamate (1.99 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 22 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and insoluble product was collected by filtration and washed with ethyl acetate to give the title compound (1.57 g).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][NH:9][CH2:10][CH:11]=2)=[CH:3][CH:2]=1.[CH2:13](I)I>C1C=CC=CC=1.[Cu]>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([C:7]23[CH2:13][CH:11]2[CH2:10][NH:9][CH2:8]3)=[CH:5][CH:6]=1
Reactant: ICI
Reactant: Cc1ccc(C2=CCNC2)cc1
Agent: [Cu]
Solvent: c1ccccc1
Product: Cc1ccc(C23CNCC2C3)cc1

Procedure:
A mixture of 3-(p-tolyl)-3-pyrroline, methylene iodide, and powdered copper in a molar ration of 1:2:4 is heated in benzene for about 50 hours. Filtration and evaporation of the solution gives 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][NH:9][C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:2][CH2:3]1)(=[O:31])=[O:32]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C(C=Cc1cccnc1)NCCN1CCNCC1
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCN1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1

Procedure:
Batch size: 8.0 g (22.6 mmol) N-(2-(piperazin-1-yl)-ethyl]-3-pyridin-3-yl-acrylamide.trihydrochloride (substance 317 as a trihydrochloride), 13 ml (92.7 mmol) TEA and 5.6 g (24.9 mmol) naphthalin-2-sulfonic acid chloride in 180 ml absolute dichloromethane.