Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:4][C:3]=2[O:2]1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=2)[CH2:51][Cl:52])[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:68].Cl>>[ClH:52].[ClH:68].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=5)[CH:19]=4)[CH2:13][CH2:12]3)[CH2:51][C:50]3[CH:53]=[CH:54][CH:55]=[C:48]([C:40]4[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:38]([O:37][CH3:36])[CH:39]=4)[CH:49]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2cccc(CN(c3ccc4c(c3)OCO4)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[C:14]([O:24][CH3:25])[CH:13]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=O)=O>CN(C)C=O>[CH3:25][O:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10][C:9]2[S:8][C:7]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=3)=[N:6][C:5]=2[CH2:4][CH2:3][CH2:2][S:44][CH3:43])[CH:17]=[CH:16][C:15]=1[C:18]1[NH:22][C:21](=[O:23])[O:20][N:19]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCO)ccc1-c1noc(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCSC)ccc1-c1noc(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 100 mg of 3-{4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one in 1 mL of dimethylformamide at 0° C. were added 0.077 mL of triethylamine and 0.015 mL of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 30 minutes and then concentrated under reduced pressure. The product was dissolved in 3 mL of dimethylformamide. To the resulting solution were added 5.5 mg of sodium methanethiolate and 13 mg of potassium iodide. The reaction mixture was heated for 10 minutes to 90° C. under microwave irradiation in a sealed tube. It was then concentrated under reduced pressure, taken into dichloromethane, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 20 mg of 3-{2-methoxy-4-[4-(3-methylsulfanyl-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[O:16][S:17](=[O:38])(=[O:37])[NH:18][C:19](=[O:36])[CH2:20][C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH:33]([CH3:35])[CH3:34])([CH3:3])[CH3:2].[H][H]>[Ni].O1CCCC1.C(OCC)(=O)C>[NH2:10][C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:16][S:17](=[O:38])(=[O:37])[NH:18][C:19](=[O:36])[CH2:20][C:21]2[C:22]([CH:33]([CH3:34])[CH3:35])=[CH:23][C:24]([CH:30]([CH3:31])[CH3:32])=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])=[C:6]([CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: [H][H]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)c(C(C)C)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(N)cc2C(C)C)c(C(C)C)c1
Reaction time: 21 h
Yield: 89.5 %

Procedure:
22.0 g of [(2,4,6-Triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-4-nitro-phenyl ester and 6 g of Raney nickel were mixed in 110 mL tetrahydrofuran under 50 psi of hydrogen. After 21 hours, the reaction was filtered and concentrated to give an orange oil which was dissolved in ethyl acetate, filtered through a pad of silica, and concentrated to give an oily solid. Recrystallization from 53 diethyl ether/hexanes gave 18.60 g (89%) of the title compound as a cream colored solid; mp 153-155° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=O)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:27]([NH2:29])[CH3:28].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:24]=[N:29]/[O:27][CH3:28])[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(C=O)c2s1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(/C=N/OC)c2s1
Temperature: 105 °C
Yield: 70.4 %

Procedure:
1-(5-(Benzyloxy)-7-formylbenzo[d]thiazol-2-yl)-3-ethylurea (425 mg, 1.20 mmol), methoxylamine hydrochloride (105.2 mg, 1.26 mmol) and N,N′-diisopropylethylamine (0.77 g, 1.05 ml) were stirred in DMF degassed with N2. The reaction was purged with N2, sealed and heated to 105° C. for 18 h. LCMS after indicated complete consumption of starting material. The solvents were removed under reduced pressure and the resulting residue absorbed onto silica and purified by flash column chromatography eluting with 0 to 100% EtOAc in petroleum-ether to afford the product as a white solid 325 mg (70%) which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][C@:10]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][NH:27][O:28][CH3:29]>>[CH3:29][O:28][N:27]([CH3:26])[C:13]([C@H:12]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][C@@:10]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[CH2:11]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1C[C@@]2(C[C@H]1C(=O)O)C(=O)Nc1ccccc12
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)[C@@H]1C[C@]2(CN1C(=O)OC(C)(C)C)C(=O)Nc1ccccc12

Procedure:
(3S,5′S)-tert-butyl 5′-(methoxy(methyl)carbamoyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was prepared by the procedures described in Example 10, Step 5, substituting (R)-2-(1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yl)acetic acid with (3S,5′S)-1′-(tert-butoxycarbonyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxylic acid, and substituting NH4Cl with N,O-dimethylhydroxylamine hydrochloride. LCMS (APCI+) m/z 376 [M+H]+; Rt=2.88 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[Br:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([N:65]1[CH2:64][CH2:63][N:62]([C:45](=[O:44])[CH2:46][NH:47][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[O:49])[CH2:67][CH2:66]1)=[O:15]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc([N+](=O)[O-])ccc2Br)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 39.4 %

Procedure:
DIPEA (230 mg, 0.33 mL, 1.8 mmol) was added to a stirred solution of 2-bromo-5-nitro-benzoic acid (114 mg, 0.46 mmol) in DMF (2 mL). HOBT (93 mg, 0.69 mmol) and EDCI (220 mg, 1.15 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (150 mg, 0.46 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using basic alumina and 10% MeOH in CHCl3 as eluent) to afford 100 mg (39.5% yield) of biphenyl-4-carboxylic acid {2-[4-(2-bromo-5-nitro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 96.4%. 1H NMR (CDCl3): δ 8.4 (bs, 1H), 8.2 (m, 2H), 7.9 (d, 2H), 7.6 (m, 5H), 7.5 (m, 3H), 7.4 (m, 1H), 6.0 (d, 1H), 4.4 (m, 2H), 4.0 (m, 2H), 3.8 (m, 3H), 3.6 (m, 3H), 3.5-(m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH3:32])[CH2:9][CH2:10][CH2:11][NH:12]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO.Cl>O>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH3:32])[CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: COc1ccccc1OCCN(C)CCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccccc1OCCN(C)CCCN
Reaction time: 7.5 h
Yield: 87.7 %

Procedure:
12.9 g (0.0268 mol) of N-[2-(2-methoxyphenoxy)ethyl]-N-methyl-N'-(triphenylmethyl)-1,3-propanediamine and 250 ml of methanol are introduced into a 1 l round-bottomed flask. A stream of gaseous hydrochloric acid is passed for 15 min while cooling with a mixture of water and ice. The mixture is allowed to return to room temperature and is then brought to the reflux temperature for 7.5 h. The mixture is concentrated to dryness and the residue is taken up in ethanol and concentrated again. The residue is taken up in water, the mixture is basified, the supernatant oil is taken up in dilute hydrochloric acid and extraction is carried out with diethyl ether. The acidic aqueous phase is then treated with sodium hydroxide until the pH is basic and extraction is carried out with dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. There are obtained 5.6 g of a yellow oil which is used as is in the following stage.
Reaction SMILES: C(N=[N+]=[N-])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH2:19][CH2:18]2)([O-:14])=[O:13].[NH2:24][C:25](N)=[O:26].[ClH:28]>CCOCC>[ClH:28].[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:25](=[O:26])[NH:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:19][CH2:18]2)([O-:14])=[O:13]
Reactant: [N-]=[N+]=NC(=O)c1cccnc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: NC(N)=O
Agent: Cl
Solvent: CCOCC
Product: O=C(Nc1cccnc1)N1CCc2cc([N+](=O)[O-])ccc21
Yield: 76 %

Procedure:
This material was prepared from nicotinoyl azide (0.43 g, 2.9 mmol) and 5-nitroindoline (0.38 g, 2.3 mmol), and conversion of the precipitated urea to the salt using excess HCl in ether, following the procedure of Example 2. This gave the title compound (0.64 g, 76%) as a light yellow powder, m.p. 244°-7° C. (dec.).
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[CH:13][N:12]=[C:11]1[CH2:15][NH2:16].[CH3:17][C:18]1[N:19]=[C:20]([N:26]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:27]2=[O:38])[S:21][C:22]=1[C:23](O)=[O:24]>>[CH3:17][C:18]1[N:19]=[C:20]([N:26]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:27]2=[O:38])[S:21][C:22]=1[C:23]([NH:16][CH2:15][C:11]1[O:10][CH:14]=[CH:13][N:12]=1)=[O:24]
Reactant: NCc1ncco1
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1ncco1
Yield: 58 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-2-ylmethanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 58% yield: 1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.07 (s, 1H), 6.34-6.37 (m, 1H), 4.70 (d, J=5.3 Hz, 2H), 4.16-4.11 (m, 2H), 3.64-3.58 (m, 2H), 3.43-3.39 (m, 2H), 2.63 (s, 3H), 2.21-2.08 (m, 2H), 1.91-1.81 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.4, 160.6, 157.6, 155.6, 153.4, 139.2, 127.2, 117.2, 42.9, 42.3, 42.0, 37.2, 31.7, 31.3, 30.9, 30.6, 20.2, 17.3; MS (ES+) m/z 417.7 (M+1).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[Br:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](O)=[O:14].CC(C)=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[Br-:11].[OH:14][C:13]1[N+:6]2[C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[S:3][C:2]=2[S:1][C:12]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1nc2c(s1)CCCC2
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Oc1c(-c2ccccc2)sc2sc3c([n+]12)CCCC3
Product: [Br-]

Procedure:
9.0 g. (0.053 moles) 2-mercapto-4,5,6,7-tetrahydrobenzothiazole and 10.75 g. (0.053 moles) α-bromophenylacetic acid are dissolved in 500 ml. of acetone, to which is further added 50 ml. each of glacial acetic acid and acetic anhydride. The mixture is heated in an open flask and the volume reduced to 100 ml. The precipitated solid is collected. The solid weighs 13 g. (67%) and melts at 233°-235° C.(dec.).
Reaction SMILES: [CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].CCOCC.[C:16]1([P:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH:1]1([P:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[cH-]ccc2c1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=CC(P(c2ccccc2)c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 83.5 %

Procedure:
In the drybox lithium indenide (8.00 g, 65.52 mmol) dissolved in 50 mL of THF was added within 15 minutes to a 180 mL ether solution of diphenylchlorophosphine (14.46 g, 65.52 mmol) (diphenylchlorophosphine was distilled before use (97° C. @ 0.4 torr)). After stirring overnight, LiCl was separated by filtration giving a yellow solution. Solvent was removed under vacuum leaving an off-white solid. This solid was triturated with 40 mL of hexane. Hexane was removed by decanting and the solid was dried under reduced pressure to give 16.43 g of off-white solid. Yield 84 percent.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:35][C:34]([N:33]([CH3:38])[CH3:32])=[O:37]
Reactant: CN(C)C(=O)CCl
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC(=O)N(C)C)c3ccccc32)cc1
Yield: 6.9 %

Procedure:
A mixture of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g), N,N-dimethyl-2-chloroacetamide (0.19 g) and potassium carbonate (0.22 g) is refluxed for 24 hours. The reaction solution is concentrated and water is added to the resulting residue. The mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-[N-methyl-N-(dimethylaminocarbonylmethyl)amino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.05 g) as colorless amorphous.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>C(O)C>[F:13][C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([F:28])([F:24])([F:25])([F:26])[F:27])=[CH:19][CH:18]=3)[N:7]2[N:8]=1)([F:14])[CH3:12]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: Cc1cc(Cl)n2nc(C(C)(F)F)nc2n1
Solvent: CCO
Product: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)n2nc(C(C)(F)F)nc2n1
Temperature: 50 °C

Procedure:
A suspension of Intermediate 3 (5.84 g, 25.09 mmol) and 4-aminophenylsulfur pentafluoride (MANCHESTER, 5.5 g, 25.09 mmol) in ethanol (150 mL) was heated at 50° C. for 1 h. Heating resulted in the precipitation of a solid. The reaction mixture was concentrated under vacuum, redissolved in DCM (300 mL) and washed with aq. Na2CO3 (2×350 mL). The organic layer was dried over Na2SO4 and filtered. Then 8 g of silica gel were added and the mixture was concentrated under vacuum to dryness. The residue was purified (silica gel column, eluting with Hexane/EtOAc mixtures from 100:0 to 50:50%) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[CH:11]1[CH2:15][C:14](=O)[N:13]([CH3:17])[C:12]1=O.C(OCC)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1[CH:11]1[CH2:15][CH2:14][N:13]([CH3:17])[CH2:12]1
Reactant: CN1C(=O)CC(C2C=Cc3ccccc3C2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN1CCC(C2C=Cc3ccccc3C2)C1

Procedure:
The 3-(1,2-dihydro-2-naphthalenyl)-1-methyl-2,5-pyrrolidinedione, 60 g, is taken up in dioxane and added dropwise to a suspension of 40 g of lithium aluminum anhydride (LAH) in 2 l. diethyl ether. After 5 hours at reflux, the mixture is decomposed with K2CO3 solution and filtered. Evaporation of the organic layer leaves 42.8 g of 3-(1,2-dihydro-2-naphthalenyl)-1-methylpyrrolidine which is distilled at 125°-150°/0.2 mm IR and NMR consistent, 28 g yield (54%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-:20])=[O:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.O.O.O.O.[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([S:37]([O-:39])=[O:38])=[CH:33][CH:32]=1.[Na+]>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[C:2]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)(=[O:39])=[O:38])=[N:3][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:18]([O-:20])=[O:19])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(S(=O)(=O)c2ccc(C)cc2)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Yield: 57.9 %

Procedure:
A mixture of 0.379 g of 2-chloro-3,4- diethoxycarbonyl-5-nitro-6-phenylpyridine, 0.5 g of sodium p-toluenesulfinate tetrahydrate and 15 ml of ethanol was heated under reflux for 3 hours. After concentration, the concentrate was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography with n-hexane/ethyl acetate (4:1) as the eluent. The eluate was concentrated to give crystals. The obtained crystals were recrystallized from the same solvent, to give 0.289 g of the title compound as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[C:3](/[C:12](=[N:25]/[O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)/[CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.NN.O>C(O)C>[CH:28]1([CH2:27][O:26]/[N:25]=[C:12](/[C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)\[CH2:13][NH2:14])[CH2:29][CH2:30]1
Reactant: O=C1c2ccccc2C(=O)N1C/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NC/C(=N\OCC1CC1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To 98 mg of (E)-N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(cyclopropylmethoxyimino)ethyl]phthalimide in 3 ml of ethanol, 76 mg of hydrazine monohydrate was added, and the mixture was stirred at 80° C. for 1 hour. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3). The resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using methanol-chloroform (1:10) as the eluent to obtain 65 mg of the desired product as a pale yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:9]=[C:8](F)[CH:7]=2)#[N:2].CO.C[C:26](C)([O-:28])C.[K+].Cl>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:9]=[C:8]([O:28][CH3:26])[CH:7]=2)#[N:2]
Reactant: CN1CCC(Oc2cc(F)cc3ncc(C#N)c(O)c23)CC1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OC2CCN(C)CC2)c2c(O)c(C#N)cnc2c1
Temperature: 70 °C
Yield: 73 %

Procedure:
A mixture of 3-cyano-7-fluoro-4-hydroxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline (600 mg), methanol (0.40 ml) and potassium tert-butoxide (1.0M solution in tetrahydrofuran; 10.0 ml) in anhydrous dimethyl sulphoxide (20 ml) was heated at 70° C. for 16 hours. The solution was cooled and then diluted with water (100 ml). Dilute hydrochloric acid was added until pH6 was reached and the by-product precipitate (3-cyano-4-hydroxy-5,7-dimethoxyquinoline) was filtered off. The filtrate was pumped onto a cation exchange cartridge (Waters Oasis MCX 6.0 g) and washed on with water. The column was flushed successively with water (200 ml), methanol/water (1:1; 200 ml) and methanol (200 ml). The product was eluted off the column with methanol containing triethylamine (1%). The fractions containing the product were combined and evaporated. This gave the title compound as an white solid (460 mg, 73%); NMR spectrum: (DMSOd6) 1.67 (m, 2H), 1.83 (m, 2H), 2.12 (m, 2H), 2.15 (s, 3H), 2.64 (m, 2H), 4.31 (m, 1H), 6.31 (d, 1H), 6.56 (d, 1H), 8.16 (s, 1H); Mass spectrum: M+H+ 314.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[CH:7][C@@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9].C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][C:23]([CH3:25])=O>>[CH3:22][C:23]1([CH3:25])[O:9][C@@H:8]2[C@@H:10]([C@@H:12]([CH2:14][OH:15])[O:13][CH:7]2[OH:6])[O:11]1
Reactant: CC(C)=O
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Concentrated sulfuric acid (0.3 mL) was added to a suspension of D-ribose (12.5 g, 83 mmol) in acetone (125 mL). The reaction mixture was stirred at room temperature for 90 min to obtain a clear solution which was then neutralized with saturated aqueous sodium carbonate. The mixture was filtered over Celite® and concentrated in vacuo.