Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[C:18]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:19]3[C:24]=2[C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[NH2:25][C:23]1[C:24]2=[C:16]([C:11]3[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[CH:17]=[C:18]([CH:26]3[CH2:31][CH2:30][N:29]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:28][CH2:27]3)[N:19]2[N:20]=[CH:21][N:22]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cc(F)cc(OCc4ccccc4)c3)c12
Product: CN(C)C(=O)CN1CCC(c2cc(-c3cc(F)cc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 17 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 355 and using 5-[3-(benzyloxy)-5-fluorophenyl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and 2-chloro-N,N-dimethylacetamide as starting material, 20 mg (17%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 7.89 (s, 1H), 7.47-7.36 (m, 5H), 6.89 (s, 1H), 6.82 (d, 1H), 6.74 (d, 1H), 6.52 (s, 1H), 5.56 (s, 2H), 5.13 (s, 2H), 3.25-3.20 (m, 1H), 3.18 (s, 2H), 3.10 (s, 3H), 3.02-2.98 (m, 2H), 2.92 (s, 3H), 2.26 (t, 2H), 2.11-2.08 (m, 2H), 1.82-1.78 (m, 2H); LC-MS m/z [M+H]+ 503.9, RT 2.77 min.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]2=[C:12]([C:15]([O:17][CH2:18]C)=[O:16])[N:13]=[CH:14][N:5]2[C:4]2[CH:20]=[CH:21][S:22][C:3]1=2.[C-]#N.[K+]>CO>[O:1]=[C:2]1[N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]2=[C:12]([C:15]([O:17][CH3:18])=[O:16])[N:13]=[CH:14][N:5]2[C:4]2[CH:20]=[CH:21][S:22][C:3]1=2
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2

Procedure:
1.50 g of ethyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylate are stirred at 50° C. for 20 hours together with 100 g of powdered potassium cyanide in 10 ml of methanol. The solution is concentrated and the residue is taken up in chloroform. The insoluble material is filtered off under suction and the filtrate is evaporated. After recrystallisation of the residue from chloroform/hexane, there is obtained methyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylate of melting point 192°-193° C.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])=[CH:23][C:22]=1[F:34]>>[F:34][C:22]1[CH:23]=[C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])[CH:25]=[CH:26][C:21]=1[NH:20][C:3]([C@@H:5]1[CH2:6][C@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[C@@H:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-2-hydroxy-cyclo-pentyl}-amide. Yellow solid. MS: 482.3 ([M+H]+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:40][CH2:41][CH3:42]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]([CH2:40][CH2:41][CH3:42])[C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(C(=O)O)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
(5-Benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (0.09 g, 0.23 mmol) in THF (1.2 ml) was added dropwise to a solution of LHMDS in hexanes (0.49 ml, 0.49 mmol, 1.0M) at −15° C. After 30 min iodopropane (0.08 ml, 0.82 mmol) in THF (0.3 ml) was added and the mixture was stirred for a further 30 min at −15° C. The mixture was then quenched by pouring onto a mixture of ice and HCl solution (2M aq). This was then extracted with EtOAc (×2), washed with NaHSO3 solution (10% aq) and the organics were dried (MgSO4) and then concentrated in vacuo to afford a yellow oil. The oil was purified by flash column chromatography (EtOAc:petroleum ether) to afford 2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid (0.016 g, 0.04 mmol) in 18% yield. 1H NMR (CDCl3) δ 7.69-7-63 (m, 4H), 7.47-7.42 (m, 2H), 7.40 (t, 2H), 7.35-7.31 (m, 1H), 7.13-7.09 (m, 2H), 7.01-6.99 (m, 1H), 5.11 (s, 2H), 3.63-3.59 (m, 1H), 2.11-2.03 (m, 1H), 1.84-1.75 (m, 1H), 1.36-1.26 (m, 2H) 0.92 (t, 3H); LCMS method (A), (M-H−) 385, RT=4.9 min.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][F:11])=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH:14]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=C(C)O[N:35]=2)=[CH:30][CH:29]=1)[C:15]1[NH:16][C:17](=[O:26])[N:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1.O.[C:41]([OH:44])(=[O:43])[CH3:42]>CO.[Fe]>[C:41]([OH:44])(=[O:43])[CH3:42].[F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][F:11])=[CH:6][C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH:14]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([NH2:38])=[NH:35])=[CH:32][CH:33]=1)[C:15]1[NH:16][C:17](=[O:26])[N:18]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[N:19]=1
Reactant: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: [Fe]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(OCCF)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1

Procedure:
After adding 1.2 g of iron powder to a solution of 1.2 g of 5-{[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one in 18 ml of a methanol:water:acetic acid=1:1:1 mixed solvent, the mixture was stirred at 65° C. for 24 hours and 30 minutes under a nitrogen atmosphere. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give the title compound (750 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.1 %

Procedure:
To a solution of 4-methylbenzoic acid (1.07 g, 7.82 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (3.00 g, 15.6 mmol) and N,N-dimethylpyridin-4-amine (2.01 g, 15.6 mmol) in DCM (50 mL) was added methanesulphonamide (1.53 g, 15.6 mmol) and the resulting mixture stirred for 18 hours at room temperature under nitrogen. The reaction mixture was poured into water (100 mL) and extracted with DCM (2×75 mL). The combined organics were dried over magnesium sulphate and evaporated in vacuo, azeotroping with toluene (2×20 mL) to yield a crude solid (2.14 g). The solid was dissolved in DCM (100 mL) and washed with aqueous hydrochloric acid solution (2 M, 2×50 mL). The organic layer was extracted with saturated solution of sodium carbonate (2×50 mL) and the aqueous washed with DCM (50 mL). The basic aqueous layer was acidified to pH 2 with 2 M aqueous hydrochloric acid and extracted with DCM (2×50 mL). The combined organic extracts were washed with water (20 mL), dried over magnesium sulphate and evaporated in vacuo to yield the first crop of the title compound as a white solid (368 mg). All aqueous layers from the extraction process were then evaporated in vacuo to yield a white solid which was triturated with DCM (50 mL). The organics were dried over magnesium sulphate and evaporated in vacuo to yield a white solid, which was redissolved in DCM (50 mL), washed with hydrochloric acid (2 M, 20 mL) dried over magnesium sulphate and evaporated in vacuo to yield a second crop of the title compound as a white crystalline solid (578 mg, combined yield of 56%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH3:4].O=[C:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12.C([BH3-])#N.[Na+].[ClH:31]>C(#N)C.C(O)(=O)C>[ClH:31].[CH2:3]([N:2]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH3:1])[CH3:4]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=O)=C21
Reactant: CCNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCN(C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O

Procedure:
Compound No. 26 may also be prepared as follows: 8.5 ml of glacial acetic acid are added to the solution of 8.9 g of N-methyl-ethylamine in 100 ml of acetonitrile, followed by 7.5 g of 1-(2-oxo-propyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one and 1.7 g of sodium cyanoborohydride. The mixture is refluxed overnight, an additional1.7 g of sodium cyanoborohydride is added and refluxing is continued for an additional day. The mixture is cooled, acidified to pH=1 with hydrochloric acid and evaporated. Water is added to the residue, the mixture is washed with diethyl ether, filtered and the aqueous filtrate basified to pH=10-11 with 3 N aqueous sodium hydroxide. It is extracted with chloroform, the extract dried, evaporated and the residue is dissolved in the minimum amount of ethanol. The solution is combined with 2.15 ml of 8 N ethanolic hydrochloric acid, the precipitate collected and recrystallized from ethanol, to yield the 1-[2-(N-ethyl-N-methylamino)-propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one hydrochloride, melting at 256°-257°.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([Br:27])=[C:10]([F:26])[CH:11]=3)[N:6]=1.[CH3:28]S(O)(=O)=O.C([O-])(O)=O.[Na+]>CO>[Br:27][C:9]1[CH:8]=[C:7]2[C:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:24][CH3:28])([CH3:23])[CH3:25])[CH:18]=3)[O:13][C:12]2=[CH:11][C:10]=1[F:26]
Reactant: CC(C)(O)C#Cc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)c(F)cc1O2
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)C#Cc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)c(F)cc1O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(2′-amino-7-bromo-8-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol (0.580 g, 1.342 mmol) in 10 mL MeOH was treated with methanesulfonic acid (0.871 mL, 13.42 mmol). The resulting solution was allowed to stir at RT for 72 hours and was then heated at 85° C. for 3 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and was extracted with EtOAc (3×25 mL). The organics were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatgraphy [0-100% (95:5 EtOAc/MeOH)/CH2Cl2] afforded 7-bromo-8-fluoro-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:55])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([Cl:54])[CH:48]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:56][C:57]1[C:61]([C:62](Cl)=[O:63])=[C:60]([CH3:65])[O:59][N:58]=1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:54][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][C:50]=1[Cl:53])[CH2:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C@H:37]2[CH2:36][O:35][C:31]3=[CH:32][C:33]4[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]5[CH:13]=[CH:12][C:11]([C:14]6[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=6[CH3:21])=[CH:10][CH:9]=5)[C:5]([OH:4])=[O:55])=[O:24])[N:26]([C:62]([C:61]5[C:57]([CH3:56])=[N:58][O:59][C:60]=5[CH3:65])=[O:63])[CH2:27][C:28]=4[CH:29]=[C:30]3[O:38]2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1noc(C)c1C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3c(C)noc3C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexa hydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (25 mg) was dissolved in 1:1 EtOAc and saturated aqueous NaHCO3 and 3,5-dimethyl-isoxazole-4-carbonyl chloride (3 eq.) were added. After stirring at room temperature for 1 hour, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified by over silica (hexanes to 8:2 hexanes-EtOAc to 6:4 hexanes-EtOAc to 6:4 hexanes-EtOAc+2% MeOH to DCM+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (16 mg). LCMS (m/z): 862.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[C:17](OCC)(=[O:21])[C:18]([CH3:20])=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:16]=[C:18]([CH3:20])[C:17]2=[O:21])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)=O
Reactant: COc1ccc(Nc2ccccc2N)cc1
Product: COc1ccc(-n2c(=O)c(C)nc3ccccc32)cc1

Procedure:
Preparation as in Example 1 but using N-(4-methoxyphenyl)benzene-1,2-diamine and ethyl pyruvate gave the title compound mp 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])=[CH:4][CH:3]=1.[CH3:17][N:18]=[C:19]=[O:20].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C1(C)C=CC=CC=1>[CH3:17][NH:18][C:19]([N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:10]1=[O:16])=[O:20]
Reactant: CN=C=O
Reactant: O=C1NCCCCC1Sc1ccc(Cl)cc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Product: CNC(=O)N1CCCCC(Sc2ccc(Cl)cc2)C1=O

Procedure:
25.6 g (0.1 mol) of 3-[(4-chlorophenyl)thio]-azacycloheptan-2-one together with 5.7 g (0.1 mol) of methyl isocyanate and 100 mg of dibutyl-tin dilaurate in 150 ml of absolute toluene are boiled under reflux for 5 hours. After the mixture has cooled, the solvent is stripped off in vacuo, and the oily residue is used for further reactions.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:37])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[F:37][C:24]([F:23])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5 g, 26.8 mmol) in DCM (200 ml) was added DIPEA (9.85 ml, 56.4 mmol) and then 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (4.55 ml, 26.8 mmol). The reaction mixture was stirred for 1.5 hours at rt. The reaction mixture was then evaporated to dryness in vacuo. The residue was then dissolved in 1,4-dioxane (100 ml) and 4M HCl in 1,4-dioxane (50 ml) was added, along with a few drops of distilled water. The reaction mixture was stirred for 3 hrs. Then the reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in DCM (200 ml) and washed with 2M aq. NaOH (50 ml, twice). The organic layer was dried over anhydrous magnesium sulphate, the solid removed by filtration, and filtrate evaporated to dryness in vacuo. The residue was not a solid so was dissolved in ether and evaporated in vacuo to remove any remaining solvent. The title compound (8.02 g) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:24])[CH:19]=[N:18][C:17]=2[C:16]([C:30]([OH:32])=O)=[CH:15][CH:14]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>C(Cl)Cl.CO>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:30]([C:16]2[C:17]3[N:18]=[CH:19][C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[CH3:24])=[N:21][C:22]=3[C:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])=[CH:14][CH:15]=2)=[O:32])[CH:35]=1
Reactant: Nc1cccnc1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncc(N(C)CCN(C)C)nc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3cccnc3)c3ncc(N(C)CCN(C)C)nc23)c1Cl

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylic acid (Step 85.1) and 3-aminopyridine. Title compound: ESI-MS: 555.0/557.2 [M+H]+; tR=3.16 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[NH:10][N:9]=1)=[O:7])C>CO>[C:16]1([C@@H:14]([CH3:15])[CH2:13][C:11]2[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cc(C[C@H](C)c2ccccc2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](Cc1cc(C(=O)O)n[nH]1)c1ccccc1
Yield: 45.6 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 11.9 mmol) was added to a stirring, room temperature solution of 79 (0.6153 g, 0.2.38 mmol) in MeOH (6 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (7 min): The reaction was concentrated, redissolved in H2O, and extracted with EtOAc (1 mL): 10% aq. HCl was added dropwise to the aqueous layer until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.250 g (45.6%) of 80. 1H (CD3OD, 400 MHz): δ 7.30-7.23 (2H, m), 7.22-7.13 (3H, m), 6.62 (1H, s), 3.14 (1H, app sex, J=7.3 Hz), 3.03 (2H, d, J=7.8 Hz), 1.31 (3H, d, J=6.8 Hz) ppm. 13C (CD3OD, 100 MHz): δ 162.00, 149.20, 146.35, 141.76, 129.62, 127.93, 127.64, 109.16, 41.21, 35.22, 22.11 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.11; CH2 carbons: 35.22; CH carbons: 129.62, 127.93, 127.64, 109.16, 41.21 ppm. HPLC: 8.771 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:31])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of 2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (185.0 g, 630 mmol) and Lawesson's reagent (279.4 g, 690 mmol) in toluene (1.5 L) was heated to 120° C. for 3 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give the crude product which was purified by chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (133.0 g, 72%) as a yellow liquid. 1H NMR (CDCl3, 400 MHz): δ 8.02 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 6.70 (m, 1H), 5.07 (d, J=15.2 Hz, 2H), 4.28 (q, J=7.2 Hz, 2H), 1.75 (d, J=7.6 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.C1(C)C=CC=CC=1.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].N1CCCCC1.C(O)(=O)C>>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:31]2[S:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:8][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ccncn1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1ccncn1

Procedure:
To 2.3 g (8 mmol) 4-[2-(methylpyrimidin-4-yl-amino)-ethoxy]-benzaldehyde in 40 ml toluene 1.06 g (8.9 mmol) of 90% 2,4-thiazolidinedione is added. Then, 0.06 ml (0.78 mmol) piperidine and 0.044 ml (0.78 mmol) acetic acid are further added thereto. The mixture is heated to reflux for 5 h while separating the water that is formed with a Dean-Stark apparatus.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10]3([CH:16]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[N:15]4[C:27](=[O:49])[CH:28]([NH:29]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C@H:14]4[S:13]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:50]1([CH3:60])[CH:55]=[CH:54][C:53]([S:56]([OH:59])(=[O:58])=[O:57])=[CH:52][CH:51]=1>CC(C)=O>[C:50]1([CH3:60])[CH:51]=[CH:52][C:53]([S:56]([OH:59])(=[O:57])=[O:58])=[CH:54][CH:55]=1.[C:50]1([CH3:60])[CH:51]=[CH:52][C:53]([S:56]([OH:59])(=[O:57])=[O:58])=[CH:54][CH:55]=1.[NH2:29][CH:28]1[C:27](=[O:49])[N:15]2[CH:16]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[C:10]3([S:13][C@H:14]12)[CH2:11][CH2:12][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH2:9]3
Reactant: O=C(OCc1ccccc1)C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC12CCN(c1ccccc1)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCN(c4ccccc4)CC3)S[C@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.2 %

Procedure:
A mixture of 1.33 g (0.002 mole) of benzyl 1'-phenyl-6-tritylamino-spiro [penam-2,4'-piperidine]-3-carboxylate (obtained in 7.3) and 0.76 g of p-toluenesulfonic acid in 10 ml of acetone is stirred at ambient temperature for 6 hours. After filtering and drying, there is obtained 1.40 g of benzyl 6-amino-1'-phenyl-spiro[penam-2,4'-piperidine]-3-carboxylate di-p-toluenesulfonate. Yield: 92%; M.P. 168°-169° C. (decomposition).