Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:18][CH2:17][C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1)=O.ClS([N:25]=[C:26]=[O:27])(=O)=O.CO.C[O-].[Na+]>ClCCl>[CH2:17]1[C:9]2=[C:10]([C:26]([NH2:25])=[O:27])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5][CH2:18]1
Reactant: O=C(N1CCc2cc3ccccc3n2CC1)C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1c2n(c3ccccc13)CCNCC2
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl)-1-ethanone (448 mg, 1.6 mmol) in dichloromethane (20 mL) is treated with chlorosulfonyl isocyanate (0.19 mL, 2.1 mmol). The resulting golden homogenous solution is stirred for 1 hour and treated with methanol (10 mL) and a solution of 25% sodium methoxide in methanol (2 mL, 8.8 mmol). The reaction mixture quickly turns to a white suspension and after 30 min is filtered to give a crude white solid. This material is triturated with hot methanol, filtered through a pad of celite, and concentrated to 184 mg of a white solid that is further purified by LC (230-400 silica gel) eluting with 9:1:89 methanol/NH4OH/dichloromethane to afford 137 mg of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole-11-carboxamide as a white solid. IR (drift) 3353, 3341, 3173, 1641, 1602, 1549, 1463, 1432, 1418, 1322, 1314, 778, 740, 729, 654 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:43]=[C:42]([NH:44][CH:45]3[CH2:50][CH2:49][CH:48]([OH:51])[CH2:47][CH2:46]3)[N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][N:39]3[CH2:52][CH3:53])[CH:31]=[CH:32][CH:33]=1>CN(C=O)C>[CH2:52]([N:39]1[CH:38]=[N:37][C:36]2[C:40]1=[N:41][C:42]([NH:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47][CH2:46]1)=[N:43][C:35]=2[NH:34][C:30]1[CH:29]=[C:28]([NH:27][C:10](=[O:12])[C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:33]=[CH:32][CH:31]=1)[CH3:53]
Reactant: CCn1cnc2c(Nc3cccc(N)c3)nc(NC3CCC(O)CC3)nc21
Reactant: O=C(O)C#Cc1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1cnc2c(Nc3cccc(NC(=O)C#Cc4ccc(Cl)cc4)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Reaction time: 3 h

Procedure:
To the solution of 190 mg (1 mmol) of (4-chlorophenyl)-propargylic acid in 20 ml of DMF at 0° C. is added 165 mg (1.1 mmol) of HOBT and 210 mg (1.1 mmol) of EDC. After 3 h at 0° C., 367 mg (1 mmol) of 4-[6-(3-Amino-phenylamino)-9-ethyl-9H-purin-2-ylamino]-cyclohexanol (example 77, stage 1.2) is added. After 1 h at 0° C. and 2.5 h at RT, the solvent was removed under reduced pressure. The crude product is purified by means of column chromatography on silica gel, trituration in diethyl ether and recrystallisation from ethanol to obtain 110 mg (0.21 mmol) of N-{3-[9-Ethyl-2-(trans-4-hydroxy-cyclohexylamino)-9H-purin-6yl-amino]-phenyl}-3-(4-chlorophenyl)-propargylic acid amide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]([S:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH:18]([OH:20])[C:17]([CH3:22])([CH3:21])[C:16]=2[CH:23]=1)(=[O:10])=[O:9])[CH3:7].C(N(CC)CC)C>CCOCC>[CH3:7][N:6]([S:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH:18]([O:20][C:1]([CH3:2])=[O:3])[C:17]([CH3:21])([CH3:22])[C:16]=2[CH:23]=1)(=[O:10])=[O:9])[CH3:5]
Reactant: CN(C)S(=O)(=O)Oc1ccc2c(c1)C(C)(C)C(O)O2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC1Oc2ccc(OS(=O)(=O)N(C)C)cc2C1(C)C

Procedure:
At -8°C to -12°C and while stirring, 10.3 parts by weight of acetyl chloride was added to a solution of 28.7 parts by weight of 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl dimethylaminosulfonate and 14.1 parts by weight of triethylamine in 110 parts by weight of ether. The mixture was worked up as in Example 1, the compound 2,3-dihydro-3,3-dimethyl-2-methylcarbonyloxybenzofuran-5-yl dimethylaminosulfonate being obtained in the form of crystals; melting point: 67° to 68°C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:47])=[C:9]([CH2:11][O:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][N:21]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:45][CH3:46])[N:10]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:47])=[C:9]([CH2:11][O:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:32][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:45][CH3:46])[N:10]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(Cc3ccc(Oc4ccccc4)cc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
After a mixture of ethyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (1500 mg), 1N sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (1330 mg, yield: 93%). This was recrystallized from acetone-hexane. Melting point: 153–154° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1)=[O:4].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)=[O:4])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1cccc(NC(=O)CCl)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: N#Cc1cccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)c1

Procedure:
The title compound is prepared from 2-chloro-N-(3-cyano-phenyl)-acetamide and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 88-90° C. (diethylether)
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[OH:36].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=4[OH:36])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1

Procedure:
A stirred mixture of 6-fluoro-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 13 mmol), NaHCO3 (1.1 g), several crystals of KI, 1-[4-(3chloropropoxy)-3-hydroxyphenyl]ethanone, and acetonitrile (100 ml) was refluxed for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 5.7 g of a thick yellow oil The oil was chromatographed on a Waters Prep 500 LC on silica gel, eluting with 7% methanol/methylene chloride. Concentration of the appropriate fraction afforded a yellow oil, which upon standing yielded 3.5 g of the compound as a pale, yellow solid. The solid was recrystallized from ethyl alcohol to afford 2.7 g (50%) of 1-413-[4-(6fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-hydroxyphenyl]ethanone as a pale yellow solid, m.p.=122-24° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[CH:3]=[C:2]([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)[N:7]=[C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=[CH:10][C:5]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (3.1 g, 7.4 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.7 g, 8.7 mmol) and Pd(PPh3)4 (0.428 g, 0.370 mmol.) in 1,4-dioxane (20 mL) was purged with argon for 10 min. Then, 2M Na2CO3 (2.8 g, 26.41) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired intermediate (2.8 g, 73.7%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH2:8]([O:15][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CCC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 5.0 g (0.05 mol) of succinic acid anhydride, 5.4 g (0.05 mol) of benzyl alcohol, 16.25 g (0.05 mol) of cesium carbonate, and 50 ml of N,N-dimethylforamide was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and then poured into 200 ml of ethyl acetate. The mixture was washed with saturated aqueous NaCl containing 0.35 N HCl (3×100 mL). The ethyl acetate phase, which contains the product, was collected and dried over anhydrous MgSO4. The MgSO4 was removed via filtration, and the ethyl acetate was removed under reduced pressure. The crude product was purified by crystallization in diethyl ether and hexane to provide 7.34 g of succinic acid monobenzyl ester, 70.47%.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Cc1nn(-c2ccc(CCN)cc2)c(C)c1I
Reactant: Cc1ccc(B(O)O)cc1C
Product: Cc1ccc(-c2c(C)nn(-c3ccc(CCN)cc3)c2C)cc1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanamine (step 4) and 3,4-dimethylbenzeneboronic acid: MS (ESI) m/z 320 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:17][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNC1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 7-Methoxy-3,4-dihydro-1-H-naphthalen-2-one (5.0 g, 28.4 mmol) and propylamine (2.8 mL, 34 mmol, 1.2 eq) in 1,2-dichloroethane (150 mL) under inert atmosphere was added sodium triacetoxyborohydride (15 g, 71 mmol, 2.5 eq) in a single portion. The reaction was allowed to stir at room temperature for 20 h then concentrated in-vacuo. The residue was partitioned between 10% aq. KOH (150 mL) and ethyl acetate (75 mL). The organic layer was washed with brine, dried and concentrated. The resulting material was dissolved in diethyl ether (100 mL) and treated with 1M HCl in ether (28.4 ML). The solid was collected and dried under vacuum to afford 6.23 g of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl-propyl-amine as hydrochloride salt.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:15]1([CH:23]=[C:21](O)[CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16]>[Cl-].[Cl-].[Zn+2].O=P(Cl)(Cl)Cl>[OH:16][C:15]1[C:23]2[C:12](=[O:14])[C:3]3[CH:4]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]4=[CH:11][C:2]=3[O:1][C:21]=2[CH:20]=[C:18]([OH:19])[CH:17]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cc3ccccc3cc2oc2cc(O)cc(O)c12
Temperature: 80 °C
Yield: 9.8 %

Procedure:
A mixture of 3-hydroxy-2-naphthoic acid (2.0 g, 10.63 mmol), phloroglucinol (1.34 g, 10.63 mmol), ZnCl2 (3.30 g, 24.24 mmol) and POCl3 (40 mL) was stirred under reflux at 80° C. for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and was very slowly added to 1 L of ice water. The resulting solid was allowed to stand (1 d), filtered, washed with water, and then dried under reduced pressure to obtain an ocherous compound. This compound was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give the title compound (289 mg, 9.8%) as a yellow solid.
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)C.[OH:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([NH:35][NH2:36])=O>C(O)(=O)C>[OH:29][C:30]1[CH:31]=[C:32]([C:33]2[N:5]3[C:4]([CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]([N:15]([CH:22]([CH3:23])[CH3:24])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:14])[C:7]4[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=43)=[N:36][N:35]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Reactant: NNC(=O)c1cccc(O)c1
Solvent: CC(=O)O
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3cccc(O)c3)n2-c2ccccc21)c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (177 mg, 0.466 mmol) in glacial acetic acid (4 mL) was added 3-hydroxy benzohydrazide (90 mg, 0.591 mmol). The reaction was heated to 120° C. for 3 hours, was cooled to room temperature, and was concentrated in vacuo. The residue was triturated with 50% Et2O in hexanes and the solids were filtered. The solids were dissolved in CH2Cl2 and the organic solution was washed with aqueous NaHCO3, dried (MgSO4) and concentrated to provide 244 mg of 2-[1-(3-hydroxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD3OD) δ 7.74 (s, 2H), 7.56-7.18 (m, 10H), 6.91 (m, 1H), 4.86 (m, 1H), 4.30-4.10 (m, 2H), 3.98 (d, 1H), 3.71 (d, 1H), 1.06 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.B(F)(F)F.[C:20](=O)(O)[O-].[Na+]>>[CH3:20][O:14][C:13]([C:3]1[C:2]([OH:1])=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:12])=[N:10]2)=[CH:5][CH:4]=1)=[O:15]
Reactant: O=C([O-])O
Reactant: Cc1ccc2ccc(C(=O)O)c(O)c2n1
Agent: FB(F)F
Agent: [Na+]
Product: COC(=O)c1ccc2ccc(C)nc2c1O

Procedure:
8-Hydroxy-2-methyl-7-quinolinecarboxylic acid (as reported by Meek, W. H. et al., in J. Chem. Eng. Data 1969, 14(3), 388-91) is reacted with methanolic boron trifluoride solution for several hours. The resulting mixture is added to an aqueous solution of sodium bicarbonate to give finally a basic solution. The solution is extracted with chloroform. The chloroform extract is dried over anhydrous sodium sulfate and concentrated and the residue is crystallized from a suitable solvent such as isooctane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([NH:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:15])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1sc(CC)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of methyl 2-amino-5-ethylthiophene-3-carboxylate (7.07 g), ethyl chloroformate (4.4 mL) and toluene (100 mL) was stirred at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as colorless oil (9 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=O.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6](=[O:8])[NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCOCC2)c(Cl)c1
Yield: 40 %

Procedure:
A mixure of 507 mg of ethyl α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 5) and 407 mg of N-(2-aminoethyl)morpholine was stirred at 110°-115° C. (bath temperature) for 1 hour. The mixture was cooled and poured into water. The crystals which precipitated were collected by filtration. These crude crystals were recrystallized from a mixture of methanol and ethyl acetate to give 255 mg of the title compound as a white powder melting at 179°-181° C. (with decomposition). The filtrate was extracted with ethyl acetate, dried and concentrated by evaporation under reduced pressure, followed by trituration of the residue with ethyl acetate to give a further 91 mg of the title compound as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=O)[C:8]3([CH2:11][NH:12][C:4]=2[CH:3]=1)[CH2:10][CH2:9]3.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>O1CCCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[S:25])[C:8]3([CH2:11][NH:12][C:4]=2[CH:3]=1)[CH2:10][CH2:9]3
Reactant: O=C1Nc2ccc(Br)cc2NCC12CC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: S=C1Nc2ccc(Br)cc2NCC12CC2
Yield: 44.1 %

Procedure:
A solution of 7-bromo-4,5-dihydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropan]-2(1H)-one (267 mg, 1.0 mmol) and Lawesson's reagent (606 mg, 1.5 mmol) in tetrahydrofuran (15 mL) was heated to 80° C., and maintained at the same temperature for 1 hours. The mixture was concentrated. To the residue was added water (50 mL), extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL*2), dried by sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1) to afford 7-bromo-4,5-dihydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2(1H)-thione (125 mg, 44%).
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(OC([N:25]1[CH2:29][C@H:28]([CH3:30])OS1(=O)=O)=O)(C)(C)C>>[CH2:10]([O:9][C:7]([N:6]1[CH2:5][CH2:4][C:3](=[O:17])[NH:25][CH2:29][C@H:28]1[CH3:30])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)CCNC(=O)OCc1ccccc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: C[C@@H]1CNC(=O)CCN1C(=O)OCc1ccccc1

Procedure:
In analogy to the procedure described in intermediate 78A, 3-benzyloxycarbonylamino-propanoic acid methyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (Bioorg. Med. Chem. Lett. 2006, 16, 1207) gave the title compound. Colorless gum, MS: m/e=263.1 (MH+).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:4]=1)=[O:2].CN(C=O)C.[H-].[Na+].[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:36][CH2:37]I)[C:32]([O:34][CH3:35])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[C:11]([O:10][C:9]([N:8]([C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[CH2:37][CH2:36][C@H:31]([NH:30][C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:29])[C:32]([O:34][CH3:35])=[O:33])=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCN(C(=O)OC(C)(C)C)c1ncc(C=O)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
To a dry 2-5 mL microwave vial under N2 is added tert-butyl (5-formylthiazol-2-yl)carbamate (100 mg, 0.438 mmol) and anhydrous DMF (2.5 mL). The resulting dark solution stirred at room temp for 5 min, treated with sodium hydride (22.13 mg, 0.876 mmol), flushed with N2 for 15 min, then treated with material from Example 115 (301 mg, 0.876 mmol) and securely capped. The resulting dark solution is stirred at room temp for 30 min, then heated in a microwave heating unit for 15 min at 80° C. under high power. The reaction is diluted with ethyl acetate (200 mL), washed with water (6×25 mL), brine (1×25 mL), dried over Na2SO4, filtered, the solvent removed in vacuo and the resulting residue purified by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using 100% CH2Cl2 to 75% EtOAc/CH2Cl2 over 11 column volumes to give 176.7 mg (91%) of the title compound as a thick oil, LC/MS (Condition A): ret. T=3.83 min, (M+Na) 466.