Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].C[O:36][C:37](=[O:40])[CH2:38]Cl>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([CH2:38][C:37]([OH:40])=[O:36])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: COC(=O)CCl
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(CC(=O)O)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridine-6-ylamine (150.0 mg, 0.355 mmol), cesium carbonate (463 mg, 1.42 mmol) and DMF (4 mL) at rt was charged with chloroacetic acid methyl ester (37 μL, 0.43 mmol) and heated to 40° C. overnight. The solvent was removed in vacuo, and the material was dry-loaded onto silica gel for column chromatography, eluting with 2-5% MeOH/DCM. The fractions containing the pure ester were concentrated in vacuo and redissolved in EtOH (4 mL). The solution was charged with 2M aq. LiOH (0.9 mL) at rt, and stirred for 10 min. The solvents were removed in vacuo to afford the title compound as an orange solid. MS (ES+): m/z 497.97 (100) [MH+]. HPLC: tR=2.36 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24]C3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.[C:34]([C:36]1[CH:43]=[CH:42][C:39](CBr)=[CH:38][CH:37]=1)#[N:35]>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:39]3[CH:42]=[CH:43][C:36]([C:34]#[N:35])=[CH:37][CH:38]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: N#Cc1ccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)cc1

Procedure:
Title compound 19 was prepared by the methods used in the preparation of compound 17, except that p-cyano-benzyl bromide was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3—CD3OD 10:1) δ 7.70 (d, J=7.8 Hz, 1H), 7.56-7.63 (m, 3H), 7.46 (m, 3H), 7.29 (d, J=7.8 Hz, 1H), 5.47 (s, 1H), 5.16-5.36 (ABq, J=51.1, 14.7 Hz, 2H), 5.11 (s, 2H), 3.36-3.47 (m, 2H), 2.90-3.07 (m, 2H), 2.79 (s, 1H), 2.15 (s, 1H), 1.95 (s, 1H), 1.73 (s, 2H). MS (ES) [m+H] calc'd for C25H25N6O2, 441.2; found 441.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1([CH2:26]O)[CH2:25][CH2:24][CH2:23]1.CO>ClCCl>[CH:22]1([CH2:26][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: OCC1CCC1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCC1CCC1
Yield: 92 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclobutanemethanol (32 μL, 0.34 mmol) as the coupling partner. Chromatography (1:1 methanol:dichloromethane) through SiO2 yielded 56 mg (92%) of the titled compound. ESI-MS m/z 360 (MH+), 358 (M−H−).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH2:13][CH2:14][OH:15])[C@H:11]([O:16][Si](C(C)(C)C)(C)C)[C@@H:10]([O:24][Si](C(C)(C)C)(C)C)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>C(O)(=O)C>[CH2:1]([N:8]1[C@H:12]([CH2:13][CH2:14][OH:15])[C@H:11]([OH:16])[C@@H:10]([OH:24])[C:9]1=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1[C@@H](CCO)N(Cc2ccccc2)C(=O)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CC(=O)O
Product: O=C1[C@H](O)[C@@H](O)[C@@H](CCO)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
1,200 ml of a 60% aqueous solution of acetic acid was added to 125.5 g of (3R*,4S*,5R*)-1-benzyl-3,4-bis(tert-butyldimethylsilyloxy)-5-(2-hydroxyethyl)-2-pyrrolidinone which had been prepared according to the procedure described in J. Org. Chem. 60, 103-108 (1995) by using D-tartaric acid as the starting material. After this mixture was refluxed overnight and concentrated under reduced pressure, 300 ml of concentrated aqueous ammonia and 500 ml of methanol were added to the resulting residue, followed by stirring at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (using a 10:1 mixture of chloroform and methanol as the eluent) to obtain 35 g of (3R*,4S*,5R*)-1-benzyl-3,4-dihydroxy-5-(2-hydroxyethyl)-2-pyrrolidinone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][NH:32][CH3:33].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:33])[C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:25]
Reactant: CNCCCCl
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)N(C)CCCCl)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.5 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 200 mg, 0.56 mmol) and 3-chloro-N-methylpropan-1-amine hydrochloride (177 mg, 1.23 mmol) in DMF (4 mL) was added N-methylmorpholine (0.25 mL, 2.30 mmol), followed by HATU (234 mg, 0.616 mmol). The reaction was stirred at ambient temperature for 18 hours, then diluted with H2O (10 mL), and extracted EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the desired product as a white foamy solid (129 mg, 52% yield). MS (apci) m/z=447.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.C1(C2[N:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH:18]([CH2:24][OH:25])[O:17]2)C=CC=CC=1.[H-].[Na+]>>[Cl:1][C:2]1[C:7]([O:25][CH2:24][CH:18]([OH:17])[CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Reactant: Cc1cnc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cnc(Cl)c(OCC(O)CNC(C)C)n1

Procedure:
Analogously to the description in Example 11, 8.2 g (0.05 mol) of 2,3-dichloro-5-methyl-pyrazine, 11 g (0.05 mol) of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine and 3.4 g of a 50% strength suspension of sodium hydride in paraffin oil give 2-chloro-3-(3'-isopropylamino-2'-hydroxy-propoxy)-5-methyl-pyrazine, melting point 109°-110° C. when crystallised from benzene. The fumarate prepared therefrom by means of fumaric acid crystallises from methanol-ether, melting point 164°-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1.C(Cl)(Cl)Cl.C(O)C>[NH2:8][CH2:9][C:10]([N:11]([CH3:12])[C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:21][C:6]=1[C:7](=[N:23][OH:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:13]
Reactant: NO
Reactant: CN1C(=O)CN=C(c2ccccc2Cl)c2cc(N)ccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CN(C(=O)CN)c1ccc(N)cc1C(=NO)c1ccccc1Cl

Procedure:
A solution of 5.0 g (16.68 mmol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one and 1.74 g (22.02 mmol) of hydroxylamine hydrochloride in 50 ml of pyridine is heated to reflux for 2 hours under argon. After cooling, the mixture is taken up in 600 ml chloroform/ethanol (4:1) and washed with 250 ml of water. The aqueous phase is adjusted to pH 8, saturated with sodium chloride and extracted with chloroform overnight in a perforator. After drying and evaporating the solvent, the residue is suspended in hot tert.-butyl methyl ether and filtered off. There is obtained 2,4'-diamino-2'-[o-chloro-α-(hydroxyimino)benzyl]-N-methylacetanilide of melting point 150° (decomposition).
Reaction SMILES: C(OC(=O)[CH:5]([C:17]#[N:18])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[N+:14]([O-:16])=[O:15])C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:17]#[N:18])=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: CCOC(=O)C(C#N)c1ccc(OC)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(CC#N)c([N+](=O)[O-])c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
To cyano-(4-methoxy-2-nitro-phenyl)-acetic acid ethyl ester (945 mg, 3.58 mmol) was added 30 mL of a saturated solution of aqueous sodium carbonate. The mixture was stirred overnight at 55° C. After cooling to room temperature, the mixture was diluted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified on a Biotage (Biotage Inc.) 10 g silica column, eluting with 0-40% EtOAc in heptanes to provide 258 mg (37%) of (4-methoxy-2-nitro-phenyl)-acetonitrile.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[CH3:18][C:19]([C:22]1[CH:23]=[C:24]([S:33][CH2:34][CH2:35][CH:36]=[O:37])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:32][C:29]([C:26]1[CH:25]=[C:24]([S:33][CH2:34][CH2:35][CH:36]([OH:37])[CH2:14][C:13]([O:16][CH3:17])=[O:15])[CH:23]=[C:22]([C:19]([CH3:18])([CH3:20])[CH3:21])[C:27]=1[OH:28])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reactant: COC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.5 g of diisopropylamine in 25 ml of tetrahydrofuran (THF), stirred at -78° C. in an atmosphere of nitrogen, was added 6.5 ml of 1.6M n-butyllithium in hexane. The mixture was stirred at -78° C. for 5 min after which a solution of 1.2 g of methyl acetate in 5 ml of THF was added. The mixture was again stirred at -78° C. for 5 min. Then a solution of 1.75 g of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanal, the product of Example 3, in 20 ml of THF was added. The reaction mixture was stirred at -78° C. for 1/2 hr. A saturated solution of ammonium chloride was carefully added, and the resultant mixture was allowed to warm to room temperature. The mixture was extracted with ether. The ether extract was washed with water, dried over anydrous MgSO4, and distilled to dryness under reduced pressure. The residual oil was chromatographed on silica gel. Elution with hexane-ethyl acetate followed by crystallization from aqueous methanol gave the product mp. 77°-80° C.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:10](=[O:11])[NH:9][C:7](=[O:8])[C:5]1=[O:6].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH3:3][N:4]1[C:5](=[O:6])[C:7](=[O:8])[N:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]1=[O:11]
Reactant: CN1C(=O)NC(=O)C1=O
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(=O)N(C)C1=O

Procedure:
2.7 g of potassium hydroxide was dissolved in 150 ml of ethanol. 5.1 g of 1-methylparabanic acid and 10 ml of ethyl bromoacetate were added thereto and the solution was heated under reflux for 6 hours. After cooling, the insoluble substance was filtered off and ethanol was distilled away. The residue was dissolved in ethyl acetate, washed with 5% sodium carbonate and brine, dried over anhydrous sodium sulfate, and passes through silica gel column. Ethyl acetate was distilled away and the residue was recrystallized from hexane to give 3.1 g of ethyl 1-methyl-2,4,5-trioxoimidazolidine-3-acetate (Compound 1).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][C:3]=1[F:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>>[F:24][C:3]1[CH:4]=[C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)[CH:22]=[CH:23][C:2]=1[NH:1][C:38]([C:34]1[C:33](=[O:41])[N:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)[CH:37]=[CH:36][CH:35]=1)=[O:39]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Yield: 75.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 181 using Compound 185 (50 mg, 0.16 mmol) and 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (44 mg, 0.19 mmol) to provide 187 (65 mg, 78% yield) as a dark solid. LC-MS (M+H=537, obsd.=537).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15]CC3C=CC=CC=3)[C:7]2=[N:6][C:5]=1[CH3:23].[H][H]>[Pd].CO>[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:23]
Reactant: [H][H]
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c(=O)c1CCCl
Agent: [Pd]
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Yield: 99 %

Procedure:
To a stirred mixture of 84 parts of phosphoryl chloride and 540 parts of methylbenzene were added 20 parts of 3-(phenylmethoxy)-2-pyridinamine. The mixture was stirred at 50° C. and 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone were added. The reaction mixture was stirred for 5 hours at 90° C. Another portion of 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone was added and stirring was continued for 30 minutes at 90° C. The solution was allowed to stand overnight at 90° C. The whole was poured into crushed ice and treated with an ammonium hydroxide solution 25%. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2-propanol. The product was filtered off, washed with a mixture of 2-propanol and 1,1'-oxybisethane and dried at 50° C., yielding 20.5 parts (62.3%) of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 141.1° C. (intermediate 1) b) A mixture of 3.3 parts of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2.0 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry, yielding 2.4 parts (99%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as an oily residue. (intermediate 2)
Reaction SMILES: C([O:3][C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[CH2:6][O:7][CH3:8])C.[Li+].[OH-]>CO>[CH3:9][C:5]([CH3:10])([CH2:6][O:7][CH3:8])[C:4]([OH:11])=[O:3]
Reactant: CCOC(=O)C(C)(C)COC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCC(C)(C)C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 2,2-dimethyl-3-methoxypropionic acid ethyl ester (1.17 g, 8.00 mmol) in an aqueous MeOH solution (MeOH/H2O=1/1, 24 mL) was added LiOH (560 mg, 16.0 mmol) at rt. After the rection mixture was stirred for 30 min., the solvent was removed in vacuo, and the residue was diluted with 1N HCl and EtOAc. The organic layer extracted with EtOAc, and the organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2>C(O)CCC>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH2:8][CH2:2][CH2:3][CH3:4])=[O:19])=[CH:16][C:3]1=2
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: CCCCO
Product: CCCCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Reaction of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, Example 2, with n-butanol as described in Example 5 provides n-butyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12](Cl)=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])=[S:17])[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C(=O)C>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]1[S:17][C:12]2[CH:11]=[CH:10][C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])=[CH:14][C:13]=2[N:15]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c(NC(=S)NCCCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc2sc(NCCCO)nc2c1
Temperature: 130 °C

Procedure:
A mixture of 14 parts of N-(5-benzoyl-2-chlorophenyl)-N'-(3-hydroxypropyl)thiourea, 5 parts of sodium hydride dispersion 75% and 180 parts of N,N-dimethylacetamide is stirred and heated quickly to 130° C. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off and crystallized from ethanol, yielding 1.8 parts of {2-[(3-hydroxypropyl)amino]-5-benzothiazolyl}phenylmethanone; mp. 162° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(N=C=NC(C)C)(C)C.[C:45]([CH2:47][NH:48][C:49]([C:51]1([NH2:57])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:50])#[N:46]>C(#N)C.C(O)(=O)C>[C:45]([CH2:47][NH:48][C:49]([C:51]1([NH:57][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)=[CH:18][CH:17]=2)[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:50])#[N:46]
Reactant: CCCN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: N#CCNC(=O)C1(N)CCCCC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1

Procedure:
In an alternative procedure the acetic acid internal salt of 4-[4-(1-propyl)-piperazin-1-yl]-benzoic acid is treated in acetonitrile with HOBt, NMM and diisopropylcarbodiimide (DICI), and after stirring for 1 hr at 40° C. a solution of 1-amino-cyclohexanecarboxylic acid cyanomethyl-amide in acetonitrile is added. On completion of the reaction, the product is precipitated by addition of water to the reaction mixture, filtered and following digestion with ethanol is dried to the end product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][N:16]=2)=[C:11]([CH3:25])[N:10]=[N:9]1.COC(=O)C1C=CC(OCC2N(C3C=CC(F)=CC=3)N=NC=2C)=NC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)=[C:11]([CH3:25])[N:10]=[N:9]1
Reactant: COC(=O)c1ccc(OCc2c(C)nnn2-c2ccccc2F)nc1
Agent: COC(=O)c1ccc(OCc2c(C)nnn2-c2ccc(F)cc2)nc1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Yield: 85.5 %

Procedure:
As described for example 61a, methyl 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinate (160 mg, 0.47 mmol), instead of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted to the title compound (132 mg, 86%) which was obtained as a white solid. MS: m/e=327.2 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH2:6][S:5][CH:4]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:3]=12.O.[CH2:16](O)[CH2:17][OH:18]>Cl>[OH:18][CH2:17][CH2:16][O:1][C:2]1[CH2:7][CH2:6][S:5][CH:4]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:3]=12
Reactant: OCCO
Reactant: NS(=O)(=O)C1=CC2=C(O)CCSC2S1
Agent: Cl
Solvent: O
Product: NS(=O)(=O)C1=CC2=C(OCCO)CCSC2S1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
5,6-Dihydro-4-hydroxythieno[2,3-b]thiopyran-2-sulfonamide, (2.0 g, 0.008 mole) was dissolved in ethylene glycol (20 ml), treated with concentrated hydrochloric acid (10 drops), and stirred at room temperature for 24 hours. The mixture was poured into water (100 ml) and extracted repeatedly with ethyl acetate. Evaporation of the washed and dried ethyl acetate extract left the crude product as an oily solid. Trituration with 10% ethanol in ether followed by recrystallization of the obtained solid (1.35 g) from ethyl acetate gave 885 mg (37%) of product, m.p. 110°-113° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[C:15]([CH3:42])=[C:16]([C:20]2[C:32]3[C:31]4[C:26](=[CH:27][C:28]([N:33]5[CH2:37][CH2:36][CH2:35][C:34]5=[O:38])=[CH:29][CH:30]=4)[NH:25][C:24]=3[C:23]([C:39]([NH2:41])=[O:40])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1.Cl>C(O)(C)C>[CH3:42][C:15]1[C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:19][CH:18]=[CH:17][C:16]=1[C:20]1[C:32]2[C:31]3[C:26](=[CH:27][C:28]([N:33]4[CH2:37][CH2:36][CH2:35][C:34]4=[O:38])=[CH:29][CH:30]=3)[NH:25][C:24]=2[C:23]([C:39]([NH2:41])=[O:40])=[CH:22][CH:21]=1
Reactant: Cc1ccc2ncnc(Cl)c2c1
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N4CCCC4=O)ccc3c12
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2ncnc(Nc3cccc(-c4ccc(C(N)=O)c5[nH]c6cc(N7CCCC7=O)ccc6c45)c3C)c2c1
Temperature: 140 °C
Yield: 20 %

Procedure:
A suspension of 4-chloro-6-methylquinazoline (prepared by the procedure used in Steps 1 and 2 of the preparation of Intermediate 32-1, 16.81 mg, 0.094 mmol) and 4-(3-amino-2-methylphenyl)-7-(2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide (Intermediate 65-1, 25 mg, 0.063 mmol) in isopropanol (0.75 mL) was treated with hydrogen chloride (4 M in 1,4-dioxane) (0.019 mL, 0.075 mmol) and heated by microwave irradiation in a sealed tube at 140° C. for 45 min. The mixture was concentrated and the residue was purified by preparative HPLC. The residue from concentration of the appropriate effluent fractions was partitioned between NaHCO3 (aq) and EtOAc, and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were dried and concentrated to provide 4-(2-methyl-3-(6-methylquinazolin-4-ylamino)phenyl)-7-(2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide as a tan solid (7.4 mg, 20%). 1H NMR (400 MHz, methanol-d4) δ 8.43 (1H, s), 8.22 (1H, s), 7.97 (1H, d, J=7.7 Hz), 7.84 (1H, d, J=1.3 Hz), 7.67-7.77 (2H, m), 7.46-7.58 (2H, m), 7.36 (1H, dd, J=7.3, 1.5 Hz), 7.21-7.30 (2H, m), 7.13 (1H, d, J=7.9 Hz), 3.98-4.07 (2H, m), 2.65 (2H, t, J=8.1 Hz), 2.60 (3H, s), 2.18-2.28 (2H, m), 1.96 (3H, s). Mass spectrum m/z 541.5 (M+H)+.