Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:13]([C:12]1[CH:16]=[CH:17][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)=[O:14]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Brc1ccsc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2sccc2Br)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
Treat a stirred, chilled (0° C.) solution of 3-bromothiophene (20 g, 0.123 mol) and dichloromethane (150 mL) with titanium tetrachloride in dichloromethane (184 mL, 1.0M) at such a rate as to maintain the temperature below 5° C. Add dropwise a solution of 4-methoxybenzoyl chloride (20.9 g, 0.123 mol) and dichloromethane (75 mL) at such a rate as to maintain the temperature below 5° C. Stir one hour at 0-5° C., then quench the reaction by addition of ice (100 mL) and 6N hydrochloric acid at such a rate that the internal temperature remains at or below 10° C. Add more water (100 mL), separate the organic phase, wash with water, dry (Na2SO4), filter and evaporate to an oil which solidifies. Recrystallize the solid from ether to afford the title compound as off-white crystals (19.7 g, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[C:19](OC)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:18]([N:13]2[C:14]3[C:10](=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)([CH2:23][CH3:24])[CH2:19][OH:20])=[CH:26][CH:27]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CO)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[4-(tert-butoxycarbonylamino)-1H-indazol-1-yl]-2-(4-chlorophenyl)butanoate (3.5 g, 7.90 mmol), in THF (140 mL) at 0° C. was added LiBH4 (0.7 g, 31.6 mmol). The mixture was allowed to stir overnight at RT. Then it was quenched with saturated NH4Cl (200 mL) carefully, and extracted with CH2Cl2. The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product. LC/MS m/z=416.3 [M+H]+.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.[C:22]([O:25][CH2:26][CH2:27]Br)(=[O:24])[CH3:23]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:23][C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: CC(=O)OCCBr
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
In an atmosphere of argon, a mixture of 34 mg (4.3 mmol) of lithium hydride and 5 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 804 mg (2.8 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 10 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 5 minutes. The mixture was further stirred for 50 minutes. To the mixture was then added a mixture of 704 mg of 2-bromoethyl acetate and 1 ml of DMF. The mixture was then stirred for 22 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/1 mixture of ethyl acetate and normal hexane). As a result, 708 mg of ethyl 2-[2-(4-chlorophenyl)imino-4-oxo-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]acetate was obtained as a low polarity substance, and 96 mg of ethyl 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetate was obtained as a high polarity substance. To a mixture of 89 mg of ethyl 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetate and 5 ml of ethanol was then added 14 mg of fumaric acid. The mixture was then stirred at room temperature for 1 hour. After the termination of reaction, the reaction was concentrated under reduced pressure, and then recrystallized from ethanol to obtain 104 mg of ethyl 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetate 0.5 fumarate.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([NH:50][C:51]1[S:52][CH:53]=[C:54]([CH2:56][O:57][NH2:58])[N:55]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:57][CH2:56][C:54]2[N:55]=[C:51]([NH:50][C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[S:52][CH:53]=2)/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NOCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CO
Product: O=C(O)/C(=N\OCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
3.1 g of 2-(2-tritylaminothiazol-4-yl)glyoxalic acid was dissolved in 170 ml of methanol, 2.9 g of the (2-tritylaminothiazol-4-yl)methoxyamine was added thereto, and stirred at room temperature for 4 hours. The formed precipitates were filtered off and washed with 20 ml of methanol to obtain 5.1 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-tritylaminothiazol-4-yl)methoxyimino]acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[C:11](#[N:14])[CH:12]=[CH2:13].N12CCN(CC1)CC2>C(OCC)C>[Br:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][CH2:13][C:12]([C:11]#[N:14])=[CH:4]2
Reactant: C=CC#N
Reactant: O=Cc1cc(Br)ccc1O
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: N#CC1=Cc2cc(Br)ccc2OC1
Yield: 70.6 %

Procedure:
A mixture of 2-hydroxy-5-bromobenzaldehyde XXIX (30 g, 0.15 mol), acrylonitrile (50 g, 0.75 mol), and 1,4-diazabicyclo[2.2.2]octane (Dabco, 4 g, 0.035 mol) was refluxed overnight. The reaction mixture was diluted with ethyl ether and washed with NaOH (1N), water, HCl (1N) and brine. The organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo to give 25 g of 6-bromo-2H-chromene-3-carbonitrile XXX (Yield 70%). MS: calc'd 237 (MH+), exp 237 (MH+).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:12]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=1[C:14](O)=[O:15])(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH3:22][O:21][C:18]1[CH:17]=[C:13]2[C:12]([C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:2][NH:3][C:14]2=[O:15])=[CH:20][CH:19]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccccc2)c(C(=O)O)c1
Solvent: CCO
Solvent: O
Product: COc1ccc2c(-c3ccccc3)n[nH]c(=O)c2c1
Yield: 13.9 %

Procedure:
10.55 g (210 mmol) of hydrazine hydrate are added to a solution of 5.4 g of 2-benzoyl-5-methoxy-benzoic acid in 50 mL of ethanol, and the mixture is refluxed for 2 hours 30 minutes. The reaction medium is cooled and then filtered. The precipitate obtained is washed with ethanol and then dried under reduced pressure at 40° C. 740 mg of product are obtained in the form of a white solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:29](=[O:31])[CH3:30])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc([C@@H]2Sc3cc(F)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cc(F)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 0.7 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride and 8 ml of acetic anhydride is heated at 100° C. for 4 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove acetic anhydride and acetic acid. Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of ethanol and ether. 0.68 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 1/3H2O is obtained.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]1(=[O:25])[N:17]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:16](=[O:24])[CH:15]=[CH:14]1.ON1C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43]2[N:44]([CH2:57][CH2:58][CH3:59])[N:45]=[C:46]3[C:55]=2[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[N:48]=[C:47]3[NH2:56])[CH2:38][CH2:37]1>CN(C=O)C.O>[NH2:56][C:47]1[C:46]2=[N:45][N:44]([CH2:57][CH2:58][CH3:59])[C:43]([CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([C:21](=[O:23])[CH2:20][CH2:19][CH2:18][N:17]4[C:13](=[O:25])[CH:14]=[CH:15][C:16]4=[O:24])[CH2:37][CH2:38]3)=[C:55]2[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[N:48]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC1CCNCC1
Reactant: O=C(O)CCCN1C(=O)C=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC1CCN(C(=O)CCCN2C(=O)C=CC2=O)CC1
Reaction time: 1 h
Yield: 37 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.266 g, 1.39 mmol) was added to a mixture of 4-maleimidobutyric acid (0.254 g, 1.39 mmol) and 1-hydroxybenzotriazole (0.187 g, 1.39 mmol) in DMF (13 mL). The mixture was stirred for 1 hour, then 1-(piperidin-4-ylmethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.450 g, 1.39 mmol) was added. The mixture was stirred for 1 hour, then water (60 mL) was added, and the mixture was stirred an additional hour. The aqueous layer was extracted with ethyl acetate (2×75 mL) and dichloromethane (2×75 mL). The organic layers were combined, washed with water (2×100 mL) and brine, and then concentrated under reduced pressure. The resulting residue was purified by HPFC on silica gel (gradient elution with 2-20% CMA in chloroform) to provide 0.251 g of 1-(4-{4-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]piperidin-1-yl}-4-oxobutyl)-1H-pyrrole-2,5-dione as a yellow foam. Anal. Calcd for C27H32N6O3.0.75H2O: C, 64.36; H, 6.68; N, 16.53. Found: C, 64.59; H, 6.73; N, 16.74.
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][N:24]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:37])=[O:8])[CH:25]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(C#N)cc2)c1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(C#N)cc2)c1)C(C)(C)C
Yield: 90 %

Procedure:
According to the procedure described in Example 1(a), 3(R)-(3-(4-cyanophenyl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to provide 1.2 g (90%) of 3(R)-[3-(4-cyanophenyl)-1H-pyrrol-1-yl ]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid as a yellow powder, mp 138-40° C. 1H NMR (CD3OD): δ 7.98 (bs, 1H), 7.82 (bd, 1H, J=8.4 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.50 (d, 2H, J=8.4 Hz), 7.38 (t, 1H, J=1.6 Hz), 6.92 (t, 1H, J=2.5 Hz), 6.55 (t, 1H, J=2.2 Hz), 5.28 (t, 1H, J=7.5 Hz), 4.19 (d, 1H, J=9.0 Hz), 2.98 (dd, 1H, J=6.9, 16.5 Hz), 2.64 (d, 3H, J=4.7 Hz), 0.98 (s, 9H). IR (KBr): 3317, 2963, 2225, 1648, 1550, 1410, 1180 cm−1. HRFABMS: Calculated for C22H26N4O4Cs (M+Cs+): 543.1008. Found 543.1021. Anal. Calculated for C22H26N4O4. 0.4EtOAc: C, 63.60; H, 6.60; N, 12.57. Found: C, 63.80; H, 6.77; N, 12.57.
Reaction SMILES: C1(NN=[CH:9][C@@H:10]([C@@H:12]([C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11])C=CC=CC=1.O.C(=[O:28])C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>C(O)C>[OH:19][C@@H:18]1[O:11][C@@H:10]([CH2:9][OH:28])[C@H:12]([OH:13])[C@@H:14]([OH:15])[C@H:16]1[OH:17]
Reactant: O=Cc1ccccc1
Reactant: OC[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=NNc1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: CCO
Solvent: O
Product: OC[C@@H]1O[C@@H](O)[C@H](O)[C@H](O)[C@H]1O

Procedure:
The hydrazone (20 g.) was then refluxed for 3 hours with a solution containing water (200 ml.), ethanol (40 ml.), benzaldehyde (25 ml.) and benzoic acid (2.5 g.). The solution was cooled and then decanted from benzaldehyde phenylhydrazone, extracted three times with chloroform, decolorized with carbon and concentrated at reduced pressure. The resulting syrup was further evaporated with several portions of absolute ethanol to remove residual water and the resulting syrup (10 g.) was left to crystallize. The crystals were filtered with ethanol to give α-L-mannopyranose, m.p. 125°-126°, [α]D -26.9°→-14.4° (24 hr., c 2.0, water) compared to m.p. 128°-132°, [α]D -14.5° (equilibrium, c 3.4, water).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][N:9]=[C:8]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][S:19][C:20](=[N:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])SC.C(N(CC)CC)C>C(#N)C>[CH3:18][S:19][C:20]([N:10]1[CH2:11][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9]1)=[N:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:25])=[O:26]
Reactant: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)SC
Reactant: c1ccc(C2CNN=C2c2cccnc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2cccnc2)=N1
Yield: 34.5 %

Procedure:
Part C: Crude 4-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole (9.81 g, 0.044 mol), [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester (12.99 gram, 0.044 mol) and triethylamine (47 mL) are successively dissolved in acetonitrile. The resulting mixture is heated at reflux for 70 hours. The resulting mixture is allowed to attain room temperature and concentrated in vacuo. The residue is dissolved in dichloromethane. The organic layer is washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatographic purification (eluant: methanol/dichloromethane=5/95 (v/v)) gives N-((4-chlorophenyl)sulfonyl)-4-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (7.15 gram, 35% yield). ESI-MS (MH+) 471.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4].[CH3:20][NH:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:20][N:21]([CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4])[CH3:22]
Reactant: CNC
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CC(=O)N1c2ccccc2NC(=O)c2cscc21

Procedure:
2.0 g of 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one, 6 ml of 40% strength aqueous dimethylamine solution and 10 ml of methylene chloride are stirred at 35° C. for 2 hours; 0.35 g of sodium carbonate is added, and the mixture is concentrated to dryness in vacuo. A little water is added; the solution is extracted repeatedly by shaking it with chloroform, and the organic solution is dried with sodium sulfate and concentrated to dryness. 1.9 g of 4-(dimethylaminoacetyl)-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one are thus obtained. 4-(Diethylaminoacetyl)-9,10-dihydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one [m. 196°-197° C. (from toluene)] is obtained analogously by reacting 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one with a corresponding amount of diethylamine (instead of dimethylamine).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[N:21]([CH3:24])=[C:22]=[O:23]>N1C=CC=CC=1>[O:20]=[C:10]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:22]([NH:21][CH3:24])=[O:23])[CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[O:11]1
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Reactant: CN=C=O
Solvent: c1ccncc1
Product: CNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (7.0 g, see preparation 7b) in pyridine (70 ml) was added isocyanatomethane (5 eq.) over 45 minutes. More isocyanatomethane (in total 20 eq.) was added over time until all starting material had been consumed. The solvent was evaporated under reduced pressure. The remaining solid material washed with EtOAc (50 ml) and gave 1-[4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-3-methyl-urea after drying in vacuo. Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 167.4, 155.3, 153.7, 151.2, 148.5, 146.6, 141.8, 132.6, 132.2, 129.2, 128.0, 118.7, 115.1, 114.7, 112.9, 111.5, 110.8, 109.1, 76.0, 45.2, 25.8.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[C:51]([F:54])([F:53])[F:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[C:51]([F:54])([F:53])[F:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3C(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethyl)benzene and isolated as light-yellow gum (7.8 mg, 43%). MS(m/e): 441.4 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]2[O:2][C:3](=[O:22])[C:4]3[CH:9]=[CH:8][N:7]=[CH:6][C:5]=3[CH:10]=2)=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccncc1C#Cc1ccc(C(C)(C)C)cc1
Solvent: O
Product: CC(C)(C)c1ccc(-c2cc3cnccc3c(=O)o2)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of 3-(4-tert-butyl-phenylethynyl)-isonicotinic acid methyl ester (786 mg, 2.68 mmol) and polyphosphoric acid (10 g) is heated to 80° C. and stirred at this temperature for three days. The reaction mixture is allowed to cool to room temperature and water is added. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford 3-(4-tert-butyl-phenyl)-pyrano[4,3-c]pyridin-1-one as olive green powder; HPLC/MS 2.16 min (A), [M+H] 280;
Reaction SMILES: Cl.[C:2]([C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH3:3].C(=O)(O)[O-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([N:8]1[CH2:7][CH2:6][C:5]([C:2](=[O:4])[CH3:3])([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:10][CH2:9]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A suspension of 4-Acetyl-4-(4-chlorobenzyl)-piperidine hydrochloride (0.600 g, 2.09 mmol) in acetonitrile (20 mL) was treated with solid sodium bicarbonate (200 mg, xs) and benzyl chloride (292 mg, 2.3 mol) and heated to reflux for 3 hours. The reaction was then cooled to room temperature, poured into saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 2% Methanol/chloroform to give 706 mg of the title compound. 1H NMR CDCl3 δ 7.25 (m, 5H), 7.22 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 3.45 (s, 2H), 2.78 (s 2H), 2.76 (m, 2H), 2.20-2.0 (m, 4H), 2.06 (s, 3H), 1.75-1.50 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.866 min, m/z=444.2; 1H NMR (CDCl3) 1.04-1.16 (d, 6H), 1.50 (d, 3H), 2.14-2.25 (m, 4H), 2.45 (m, 1H), 2.57 (s, 3H), 2.83 (m, 1H), 5.65 (m, 1H), 7.04 (d, 2H), 7.20-7.33 (m, 9H), 8.45 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]3[C:17](=[N:18][C:6]2=[N:5][N:4]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10]3=O)[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]3[C:17](=[N:18][C:6]2=[N:5][N:4]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10]3=[N:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:2]
Reactant: CCc1nnc2nc3c(nn12)C(=O)c1ccccc1-3
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCc1nnc2nc3c(nn12)C(=Nc1ccccc1)c1ccccc1-3
Temperature: 130 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a suspension of 1g/A (200 mg, 0.79 mmol) and molecular sieves in toluene (4 ml), aniline (72 μl, 0.79 mmol) was added. The mixture was stirred at 130° C. for 4 h, then the solvent was evaporated and he crude purified by flash chromatography (CH2Cl2/EtOAc/MeOH 80:18:2), affording 11 (231 mg, 90%) as orange solid in diastereoisomeric ratio 1:1.