Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][C:13](=O)[C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.CO>O1CCCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCc2ccc(O)cc2C1)[C@@H](O)c1cccc(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)C[C@H](NC[C@@H](O)c1cccc(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of 3 g of N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamide, SR 58588, described in Example 8(b), in 40 ml of anhydrous tetrahydrofuran, heated with reflux under nitrogen stream, there is added 2.7 ml of a 10M solution of boranemethylsulfide in 20 ml of tetrahydrofuran, and the refluxing is maintained for 4 hours. To the solution cooled to room temperature, there is added 25 ml of methanol and the reaction mixture is left under stirring at first at room temperature for 30 minutes and then at reflux for 30 minutes. The solution is concentrated under reduced pressure and, after filtration, the product is crystallized twice from isopropanol. There is obtained 2.1 g (73%) of N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-(3-chlorophenyl)-2-hydroxyethanamine, SR 58590; m.p. 186°-188° C.; [alpha]=+76° (methanol, c=0.5%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)CCc2ccc(CCl)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.477 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.268 g of 7-chloromethyl-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.11 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[O:37]=[C:38]1[N:47]([CH2:48][CH2:49][CH3:50])[C:46](=[O:51])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:52]([C:54]3[N:58]4[CH:59]=[CH:60][CH:61]=[CH:62][C:57]4=[C:56]([C:63]4[CH:64]=[C:65]([CH:69]=[CH:70][CH:71]=4)[C:66](O)=[O:67])[N:55]=3)=[O:53])[CH:44]=2)[NH:39]1>CN(C=O)C>[C:1]([NH:4][NH:5][C:66](=[O:67])[C:65]1[CH:69]=[CH:70][CH:71]=[C:63]([C:56]2[N:55]=[C:54]([C:52]([C:43]3[CH:44]=[C:45]4[C:40](=[CH:41][CH:42]=3)[NH:39][C:38](=[O:37])[N:47]([CH2:48][CH2:49][CH3:50])[C:46]4=[O:51])=[O:53])[N:58]3[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=23)[CH:64]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NN
Reactant: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(C(=O)NNC(C)=O)c4)c4ccccn34)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
29.6 mg (0.4 mmol) of acetohydrazide, 98.4 mg (0.3 mmol) of TOTU and 0.104 ml (0.6 mmol) of N,N-diisopropylethylamine are added, under an inert atmosphere, at 0° C., to 93.7 mg (0.2 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 6 ml of DMF. The reaction medium is stirred for 1 hour at 0° C. and then for 6 hours at 50° C. and then concentrated under reduced pressure. The residue is taken up in 10 ml of methanol. The precipitate obtained is filtered off, washed with dyethyl ether and with pentane, and then dried under reduced pressure at 40° C. overnight. 45 mg of a yellow solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(OC(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 66.3 %

Procedure:
cis-2-(4-Chloro-benzenesulfonylamino)-cyclohexanecarboxylic acid amide (200 mg, 0.63 mmol), CsCO3 (250 mg, 0.76 mmol), and 1-bromomethyl-4-trifluoromethoxy-benzene (155 mg, 0.69 mmol) was stirred in acetonitrile (15 mL) at room temperature for 18 h. The reaction was then diluted with EtOAc (150 mL) and washed with H2O, brine, dried over Na2SO4 and concentrated to give a crude white wax. Further purification by flash chromatography (silica gel, 0.5%–1% MeOH/CHCl3) afforded the titled compound (205 mg) as a white solid in 67% yield: 1H NMR (DMSO-d6) δ 7.75 (d, 2 H, J=8.0 Hz), 7.59 (d, 2 H, J=8.0 Hz), 7.36 (m, 3 H), 7.21 (d, 2 H, J=8.0 Hz), 6.69 (s br, 1 H), 4.58 (AB2, 2 H, Δv=17, Jab=64 Hz), 3.89 (m, 1 H), 2.79 (s, 1 H), 2.44 (m, 1 H), 1.78 (m, 1 H), 1.66 (m, 2 H), 1.31 (m, 3 H), 0.98 (m, 1 H); MS m/e 491.03 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:29])[C@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26](Cl)=[O:27].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:15][C:16]1([CH3:29])[C@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:27]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: CC1(C)[C@H](C=C2CCSC2=O)[C@H]1C(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C2CCSC2=O)[C@H]1C(=O)OCc1cnc(Oc2ccccc2)s1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
2 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of (1R,3R)2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid chloride [described in French Pat. No. 70-21682 published under No. 2.097.244] prepared from 2.2 g of the corresponding acid in 30 ml of benzene and 0.81 ml of pyridine were added thereto at -10° C.The reaction mixture was stirred at 20° C. for 17 hours and was poured into aqueous dilute hydrochloric acid. The decanted aqueous phase was extracted with ether and the combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residuewas chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 2.9 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3R) 2,2-dimethyl-3[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18](=[O:21])[CH2:19]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH:26]1[CH:30]=[N:29][N:28]=[N:27]1.C(N(CC)CC)C>C(#N)C>[NH:26]1[C:30]([CH2:19][C:18]([C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:21])=[N:29][N:28]=[N:27]1
Reactant: c1nnn[nH]1
Reactant: CCCCCCCCCCCCCCOc1ccccc1C(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccccc1C(=O)Cc1nnn[nH]1

Procedure:
To a solution of 14.6 g of o-tetradecyloxyphenacylbromide in 75 ml of acetonitrile was added a solution of 2.8 g of tetrazole and 4.0 g of triethylamine in 75 ml of acetonitrile. The reaction mixture was stirred at reflux temperature for 2 hours then evaporated to dryness. The residue was dissolved in chloroform and the organic layer washed with water, dried over magnesiumsulfate, filtered and evaporated to give the crude compound. Recrystallisation from petrol (b.p. 60°-80° C.) gave the acetophenone derivative as a fine white powder. Yield: 12.7 g; m.p. 67° to 69° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[CH3:11])[NH2:7])([O-:3])=[O:2].C([Al](CC(C)C)CC(C)C)C(C)C.C[O:26][C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:11][C:10]1[CH:9]=[CH:8][C:6]([NH:7][C:27](=[O:26])[C:28]2[CH:29]=[CH:30][C:31]([CH2:34][N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[CH:32][CH:33]=2)=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To a solution of 10.95 g (72 mmol) of 3-nitro-4-methyl-aniline in 80 ml of toluene is added a solution of triisobutylaluminium (28% in hexane), 66.5 ml (61 mmol) over a period of 30 min at 0° C. followed by the addition of a solution of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (14.9 g, 60 mmol) in toluene (30 ml) during 1 hour at 0° C. under an atmosphere of argon. After stirring for 12 h at room temperature an other portion of triisobutylaluminium (66.5 ml (61 mmol) is added to the dark brown reaction mixture. The mixture is stirred for additional 6 h, then 2 additional small portions of triisobutylaluminium (each 18 ml, 18 mmol) are added and stirring is continued for several hours at room temperature. After acidic and basic workup with sulfuric acid and NaOH the combined organic toluene phases are evaporated in vacuo to give a brown crude product which was crystallized from t-butyl methyl ether to give the title compound as brownish yellow crystals: first crop (11.65 g), sec. crop (3.8 g) and a third crop (1.2 g). in summary 16.65 g (75.3%).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=2)([OH:3])=O.[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([NH:26][NH:27][C:1]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=2)=[O:3])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccccc1
Reactant: COc1cc(C)c2cc(C(=O)O)c(=O)oc2c1
Product: COc1cc(C)c2cc(C(=O)NNC(=O)c3ccccc3)c(=O)oc2c1

Procedure:
Compound 210 was prepared following the preparation of compound 26 except that 3-carboxy-5-methyl-7-methoxy-coumarin reacted with benzoyl hydrazine to give the title compound 210.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH:6]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[CH:9]=1)[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1>O>[CH2:2]([O:4][C:5](=[O:25])[CH:6]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:40]([C:35]2[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=2)(=[O:42])=[O:41])[CH:9]=1)[CH3:3]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)OCC
Reaction time: 8 h
Yield: 36.7 %

Procedure:
2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-prop ionic acid ethyl ester hydrochloride(110 mg, 0.294 mmol) and sodium carbonate (93.5 mg, 0.882 mmol) were dissolved in water (1.5 mL) and 3,5-dichlorobenzenesulfonylchloride (86.7 mg, 0.353 mmol) was added. This mixture was stirred overnight. The reaction was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound (59 mg, 37%). MS (CI) m/z 545.7 (M+1)
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[NH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.BrCBr.[H-].[Na+]>O1CCCC1>[Cl:6][C:5]1[N:4]=[C:2]([Cl:3])[N:1]=[C:8]([N:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][O:15][C:14]3[CH:25]=[CH:26][C:11]([N:10]([C:8]4[N:7]=[C:5]([Cl:6])[N:4]=[C:2]([Cl:3])[N:1]=4)[C:8]4[N:7]=[C:5]([Cl:6])[N:4]=[C:2]([Cl:3])[N:1]=4)=[CH:12][CH:13]=3)=[CH:19][CH:20]=2)[C:8]2[N:7]=[C:5]([Cl:6])[N:4]=[C:2]([Cl:3])[N:1]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(OCOc2ccc(N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: BrCBr
Product: Clc1nc(Cl)nc(N(c2ccc(OCOc3ccc(N(c4nc(Cl)nc(Cl)n4)c4nc(Cl)nc(Cl)n4)cc3)cc2)c2nc(Cl)nc(Cl)n2)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
Cyanuric chloride (11.473 grams, 62.2 mmol) in dry tetrahydrofuran (50 milliliters) was added to a solution of 1,1-bis(4-aminophenoxy)methane (3.58 grams, 15.55 mmol; prepared as described in Part B of Example VIII except that 1,1-dibromomethane was used instead of 1,5-dibromopentane) in dry tetrahydrofuran (175 milliliters) at −10° C. The mixture was stirred for 10 minutes and sodium hydride (3.75 grams, 93.3 mmol) was added dropwise. The mixture was then heated to 60° C. for 16 hours and subsequently filtered on CELITE. The volatiles were removed under reduced pressure and the crude solid was purified on silica gel using a mixture of AcOEt/hexane (3:7, v/v) as eluant to afford pure 1,1-bis[4-[N,N-bis[4,6-dichloro-1,3,5-triazin-2-yl]amino]phenoxy]methane (2.10 grams, 2.55 mmol, 16 percent yield) as a white solid. Chromatography with silica gel is believed to be responsible for the low yield.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[S:6])[CH2:2][C:3]([CH3:5])=O.[OH-].[K+].[CH3:16]I.O>C(O)C>[CH3:5][C:3]([CH3:16])=[CH:2][C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:6]
Reactant: CC(=O)CC(=S)Nc1ccccc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=CC(=S)Nc1ccccc1
Temperature: 20 °C

Procedure:
11.6 g of thioacetoacetanilide and then a solution of 3.4 g of potassium hydroxide in 35 ml of ethanol were added to 60 ml of ethanol and the mixture was stirred for an hour at 20° C. 8.5 g of methyl iodide were added thereto and the mixture was poured into 300 ml of water. The precipitate formed was recovered by vacuum filtration, and was dissolved in chloroform. The chloroform solution was dried and concentrated to dryness under reduced pressure to obtain 12g of 3-methylthio-crotonanilide melting at 175° C. After crystallization from acetone, the melting point was 178° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][C@H:23]([CH2:26][CH3:27])[CH2:24][OH:25]>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][C@H:23]([CH2:26][CH3:27])[CH2:24][OH:25])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CC[C@@H](N)CO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Crude 4-chloro-3-nitroquinoline (413.8 g, 1 eq.) was dissolved in dichloromethane (1.65 L). The solution was heated to reflux and then filtered through a layer of Celite® filter agent. The filtrate was cooled to 5° C. with stirring. Triethylamine (305.4 mL, 1.1 eq.) was added in a single portion. The reaction mixture was stirred for 15 minutes. (R)-(−)-2-Amino-1-butanol (205 mL, 1.1 eq.) was added dropwise while maintaining the temperature of the reaction mixture below 40° C. The reaction mixture was allowed to stir at ambient temperature for several days. The reaction mixture was cooled to −30° C. A yellow precipitate was isolated by filtration, washed with very cold dichloromethane and then sucked dry. The solid was slurried for 1 hour with cold 80/20 water/methanol (1 L), isolated by filtration, washed with cool water, washed with very cold methanol (2×300 mL), and then sucked dry on the filter overnight to provide 475 g of (2R)-2-[(3-nitroquinolin-4-yl)amino]butan-1-ol.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10].C(C(CCCC)C[O:35][N+:36]([O-])=[O:37])C>C(O)(C)(C)C>[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[C:19]([N+:36]([O-:37])=[O:35])[C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10]
Reactant: CCCCC(CC)CO[N+](=O)[O-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potasium tert-butoxide (7.6 g, 67.8 mM) and (20S)-20-hydroxymethylpregn-4-en-3-one (6.6 g, 20 mM) are combined in tert-butanol and heated at reflux temperature for 120 minutes. 2-ethylhexylnitrate (3.56 ml, 20 mM) is then added in one continuous portion. After 10 minutes, the reaction vessel is cooled to room temperature. The reaction is then quenched with acetic acid (9 ml) and stirred overnight. After diluting with dichloromethane (200 mL), the solids are removed, washed, and combined with the washing residue and subsequently purified as described in Example 1 to give crystallized (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>O1CCCC1.CN(C)C=O>[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[N:17][C:16]=1[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(-c2nc(Cc3cccc(CBr)c3)c(C)o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc(Cc2nc(-c3ccc(C)cc3)oc2C)c1)C(=O)OCC
Yield: 82.2 %

Procedure:
To 15 ml of dry tetrahydrofuran and 7 ml of dry N,N-dimethylformamide, 0.88 g of 60% sodium hydride was added. To the mixture was added dropwise 4.40 g of diethyl malonate with stirring under ice-cooling. After 15-minute-stirring, a solution of 3.93 g of 3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl bromide/5 ml of dry tetrahydrofuran was added and stirred for 1 hour under ice-cooling. The reaction solution was poured into ice-cold water, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=5:1) to provide 3.95 g of the objective compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[CH2:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:12]#[CH:13].CCN(CC)CC>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.CC#N>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]#[C:12][CH2:11][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: C#CCNS(C)(=O)=O
Reactant: COC(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of 5-bromo-thiophene-2-carboxylic acid methyl ester (1.66 g, 8.0 mmol), N-prop-2-ynyl-methanesulfonamide (1.09 g, 8.2 mmol), Et3N (1.7 mL, 12.1 mmol), and CH3CN (30 mL) was added Pd(PPh3)4 (462 mg, 0.4 mmol) followed by Cul (76 mg, 0.4 mmol). The reaction was heated at reflux for 24 h and was cooled to room temperature. The volatiles were removed in vacuo and the residue was purified via flash chromatography (20% EtOAc in hexanes to 33% EtOAc in hexanes) to yield 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester as a pale yellow solid (1.1 g). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H), 7.14 (d, 1H), 4.60 (m, 1H), 4.22 (d, 2H), 3.88 (s, 3H), 3.10 (s, 3H); MS 274 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([OH:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]2[CH:11]=[C:10]3[O:12][CH2:14][CH2:15][CH2:16][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cc(-c2ccccc2)n[nH]1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(-c2cc3n(n2)CCCO3)cc1

Procedure:
A mixture of 3-phenyl-1H-pyrazol-5-ol (8.80 g, 0.055 mol), 1-bromo-3-chloropropane (9.5 g, 1.1 eq, 0.06 mol) and potassium carbonate (30.3 g, 4 eq, 0.22 mol) in acetonitrile (120 mL) is heated for 5.5 h under reflux. Thereafter the volatiles are evaporated and the residue is treated with 50 mL ethyl acetate. The residual solid is washed 2× with ethyl acetate and the combined organic phases are evaporated. The obtained crude product is triturated with methyl tert butylether and 6.4 g (53%) of 2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine are obtained as solid.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[C:8]2[CH2:15]O.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.C(OCC)C>[Cl:19][CH2:15][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:11]=[N:10][CH:9]=1
Reactant: COc1ccc2cncc(CO)c2c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc2cncc(CCl)c2c1

Procedure:
The hydrochloride of the compound obtained in Step B (1.09 g; 0.005 mol) is suspended in 50 ml of chloroform. Thionyl chloride (2.80 ml; 0.04 mol) is added and then the reaction mixture is heated at reflux for 24 hours with stirring. After evaporation under reduced pressure, the residue obtained is taken up in ethyl ether. The precipitate formed is suction-filtered off and recrystallised from acetonitrile to yield the title compound in the form of a white solid.