Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]1[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][NH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([N:8]1[CH2:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:5][C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1CNc2ccccc2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C(C)=O)c2ccccc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
Acetyl chloride (23 □L, 0.33 mmol) was added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Example 3a, 55 mg, 0.27 mmol), DMAP (1.6 mg, 0.013 mmol), and Hunig's base (63 □L, 0.36 mmol) in dichloromethane (2 mL). The solution was stirred at 25° C. for 24 h, then the reaction mixture was diluted with dichloromethane (60 mL) and the mixture was extracted with 0.1 M sodium carbonate (7 mL) and half-saturated brine (7 mL). The organic layer was dried over sodium sulfate and concentrated. Purification of the product by flash column chromatography (40% EtOAc/hexane) afforded the title compound (46 mg, 0.18 mmol). MS m/z: 250 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](B(O)O)[CH:22]=2)[CH:17]=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:2]3[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:22]=2)[CH:17]=[CH:16]1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Product: Nc1nnc(-c2ccc3cc[nH]c3c2)c(-c2ccccc2)n1
Yield: 23.4 %

Procedure:
6-(1H-Indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine (107 mg, 23%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.4 g, 1.59 mmol) and indol-6-boronic acid (0.256 g, 1.59 mmol) according to the general procedure of Example 1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1)(=O)=O.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=S(=O)(Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccccc1-c1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1
Temperature: 100 °C
Yield: 51.7 %

Procedure:
To a solution of 3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl trifluoromethanesulfonate (21.0 mg, 0.08 mmol) in DMF (1 mL) was added Pd(PPh3)2Cl2 (5 mg, 0.007 mmol), 2-chlorophenyl boronic acid (15 mg, 0.096 mmol), and Na2CO3 (21.0 mg in 0.5 mL water). The reaction mixture was heated at an oil bath temperature of 100° C. for about 12 hours. The mixture was cooled to RT and water (20 mL) was added. The aqueous layer was washed with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and purified by silica-gel column chromatography (30% EtOAc/hexanes) to give the title compound as a brown solid (15 mg, 55%). 1H-NMR (300 MHz, CDCl3) δ 9.14 (d, 1H, J=9.2 Hz), 8.52 (s, 1H), 8.32 (d, 1H, J=5.3 Hz), 7.74-7.71 (m, 1H), 7.56-7.52 (m, 2H), 7.46-7.42 (m, 2H), 5.61 (bs, 1H), 2.88 (m, 1H), 0.89 (m, 2H), 0.66 (m, 2H); MS (ESI) (M+H)+ 363.
Reaction SMILES: CS(C)=O.[C-:5]#[N:6].[Na+].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:13]([CH:19]=1)[C:14](Cl)=[N:15][O:16][CH3:17]>C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:13]([C:14](=[N:15][O:16][CH3:17])[C:5]#[N:6])[CH:19]=1
Reactant: CON=C(Cl)c1cc(Cl)ccc1OCc1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C#N)c1cc(Cl)ccc1OCc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
Dimethyl sulfoxide (3 ml) and 95% sodium cyanide (0.31 g, 6 mmol) were added to 5-chloro-2-(4-chlorobenzyloxy)-α-methoxyiminobenzyl chloride (1.03 g, 3 mmol), and the mixture was stirred at 100° C. for 4 hours. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetatein-hexane) to give 5-chloro-2-(4-chlorobenzyloxy)-α-methoxyiminophenylacetonitrile (0.92 g, 91.5%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=3)=[O:20])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2cccc(Cl)c2)n(C2CC2)c1=O
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2cccc(Cl)c2)n(C2CC2)c1=O)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30.0 mg (0.102 mmol) of [3-(3-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 104A, 19.7 mg (0.112 mmol) of 3-trifluoromethylbenzylamine and 16.6 mg (0.123 mmol) of HOBt are placed in 0.75 ml of dimethylformamide and treated with 25.5 mg (0.133 mmol) of EDC hydrochloride. This is stirred overnight at room temperature and the reaction solution is purified directly by preparative HPLC [Method 9]. 20 mg (43% of theory) of the target compound are thus obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH2:11][OH:12])([CH3:10])[CH2:7][C:6]=2[C:13]=1[CH3:14].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[CH3:10][C:8]1([CH2:11][OH:12])[CH2:7][C:6]2[C:13]([CH3:14])=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:23]4[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=4)[CH2:27][CH2:28]3)[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]=2[O:9]1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CO)O2
Reactant: CC(C)c1ccc(N2CCNCC2)cc1
Product: Cc1c(C)c(N2CCN(c3ccc(C(C)C)cc3)CC2)c(C)c2c1OC(C)(CO)C2
Yield: 6.3 %

Procedure:
By using (5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (330 mg, 1.16 mmol) synthesized in Reference example 123 and 1-(4-isopropylphenyl)piperazine (774 mg, 3.78 mmol), the reaction was carried out in the same manner as Example 1 to obtain the title compound 30 mg (yield 6%). Melting point was 160 to 163° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: Brc1cccs1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cccs2)cc1

Procedure:
2-Bromothiophene and 4-ethylphenylboronic acid were treated in a manner similar to Reference Example 20-(1) to give the target compound.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:20]=1)(C)(C)C>C(OCC)(=O)C>[CH3:26][N:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[CH:20]=[C:15]([NH2:14])[CH:16]=[N:17][CH:18]=1.[ClH:1]
Reactant: Cn1cccc1-c1cncc(NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cccc1-c1cncc(N)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4M hydrogen chloride/1,4-dioxane (1 ml) was added to an ethyl acetate (2 ml) solution containing tert-butyl(5-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)carbamate (80 mg) obtained in the 1st step, followed by stirring at room temperature for 15 hours. An insoluble precipitate was collected by filtration, and a light brown solid of 5-(1-methyl-1H-pyrrol-2-yl)pyridin-3-amine•hydrochloride (42 mg) was thus obtained.
Reaction SMILES: [Al].[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH2:12]([C:7]1[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:10]=[CH:9][C:8]=1[OH:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)c1ccc(O)cc1
Reactant: C=CCCCCCCCC(C)C
Agent: [Al]
Product: CC(C)CCCCCCCCCc1cc(C(C)C)ccc1O
Yield: 75.4 %

Procedure:
15 g of aluminium is dissolved in 2,720 g (20 moles) of para-isopropylphenol in a five-necked flask having an inner capacity of 5,000 ml, followed by reaction with 1,176 g (7 moles) of isododecene (propylene tetramer) in the same manner as in Example 2 to obtain 1,608 g of 2-isododecyl-4-isopropylphenol. This product has a hydroxyl value of 184.0 (the theoretical: 184.3) and a boiling point of 152° C. to 160° C. under a vacuum of 1.2 Torr.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]([C:21]34[CH2:30][CH:25]5[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]5)[CH2:22]3)[CH2:28]4)=[O:20])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[N:11]1[C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[C:14]([NH:18][C:19]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:20])=[N:13][CH:12]=1
Reactant: [H][H]
Reactant: O=C(Nc1ncnc2c1CCN(Cc1ccccc1)C2)C12CC3CC(CC(C3)C1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ncnc2c1CCNC2)C12CC3CC(CC(C3)C1)C2

Procedure:
Adamantane-1-carboxylic acid (7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide (1.1 g, 2.64 mmole) was suspended in 30 ml of methanol. To the mixture was added palladium hydroxide on carbon (20% wt, 0.41 g) and the reaction was shaken under 60 PSI of hydrogen gas for 16 hrs. The mixture was filtered through celite and the filtrate was concentrated to give the desired product as an off white solid (0.8 g).
Reaction SMILES: [O:1]=[C:2]1[C@@H:6](OS(C)(=O)=O)[CH2:5][CH2:4][NH:3]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[C:18]1([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:17]2.CCN(C(C)C)C(C)C>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[C:18]1([CH2:23][CH2:22][N:21]([CH:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:20][CH2:19]1)[CH2:17]2
Reactant: CS(=O)(=O)O[C@H]1CCNC1=O
Reactant: COc1ccc2c(c1)CC1(CCNCC1)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc2c(c1)CC1(CCN(C3CCNC3=O)CC1)C2=O
Temperature: 85 °C
Yield: 77.3 %

Procedure:
To a 250 mL round bottom flask was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (2) (4.76 mmol, 852 mg) and 5-methoxyspiro[indene-2,4′-piperidin]-1(3H)-one (3) (4.32 mmol, 1.00 g) in DIEA (17.29 mmol, 3.02 mL) and acetonitrile (20 mL). The solution was then heated to 85° C. for 90 min. The reaction was concentrated in vacuo and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (1.05 g, 77% yield). Calculated MS=306.2. found MS (ESI) m/e 307.3 (M+H+); HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.253 min.
Reaction SMILES: Br[CH2:2][C@H:3]1[C@@:5]2([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]23)[CH2:4]1.Cl.[CH2:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]3[C@@:5]3([CH2:4][C@H:3]3[CH2:2][NH:31][CH2:29][CH3:30])[N:11]=2)=[CH:13][CH:14]=1
Reactant: CCN
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CBr)c1nnc(C)n1-2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Reaction time: 96 h
Yield: 69.6 %

Procedure:
To a solution of (1S,2R)-2-(bromomethyl)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro-[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine](50 mg, 0.108 mmol) in anhydrous N,N-dimethylformamide (3 mL) were added ethanamine hydrochloride (221 mg, 2.71 mmol) and Hunig's base (473 μl, 2.71 mmol) at rt. After 4 days at rt, silica gel was added to the reaction, and the solvent was removed under vacuum. The dry silica gel was packed and the product was purified by chromatography (Hexane/EtOAc 5:5 to 0:10 then DCM/MeOH 10:0 to 9:1). A second chromatography was performed (2-propanol 100% then DCM/MeOH 9:1) to give a tan solid (32 mg). LRMS (M+H)+: 426 m/z.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[S:11][CH:12]=2)[N:5]=[C:4]2[C:16]3[C:22]([Cl:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:17]=3[O:18][C:3]=12.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[S:11][CH:12]=2)[N:5]=[C:4]2[C:16]3[C:22]([Cl:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:17]=3[O:18][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2oc3c(O)cc(-c4csc(C(C)C)n4)nc3c2c1Cl
Product: COc1ccc2oc3c(Cl)cc(-c4csc(C(C)C)n4)nc3c2c1Cl

Procedure:
The crude 10C (8.75 g, 23.34 mmol) was added to POCl3 (200 mL) The mixture was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, POCl3 was evaporated under reduced pressure. The residue was poured into crushed ice under stirring. The yellow solids were collected by filtration and purified by flash chromatography to give product M10 (0.66 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=3[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[C:24](OC(=O)C)(=[O:26])[CH3:25]>S(=O)(=O)(O)O>[C:24]([O:1][CH2:2][CH:3]1[C:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=3[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Agent: O=S(=O)(O)O
Product: CC(=O)OCC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Reaction time: 0.5 h

Procedure:
13-Hydroxymethyldibenzo(a,c)fluorene (215.2 mg, 0.727 mmol) was dissolved in acetic anhydride (5 ml). To this solution was added one drop of sulfuric acid (2M). The reaction mixture was stirred for 30 min. A white precipitate was obtained which was filtered and washed with water (150 ml). The solid was finally dried to constant weight over P2O5 in a vacuum desiccator to afford 13-acetoxymethyldibenzo(a,c)fluorene as a white solid, (206.3 mg, 84%); m.p. 135°-136° C.; (Found: C, 84.9; H, 5.33 C24H18O2 requires: C, 85.2; H, 5.33%; t.l.c. Rf (D) 0.57; Rf (E) 0.68; νmax (CH2Cl2) 3030 (CH stretching, aryl) 2980, 2920 (CH stretching, alkyl) 1735 (CO, ester), 1610, 1600, 1570 (aromatic rings) cm-1 ; λmax 366 (1184), 338 (25160), 322 (27528), 265 (52688), 246 (53020) nm; δH (CDCl3, 200 MHz), 8.86-8.69 (3H, m, aromatic), 9.38 (1H, d, 3J=7.9 Hz, aromatic), 8.30-8.25 (1H, m, aromatic), 7.78-7.35 (7H, m, aromatic), 5.16 (1H, dxd, 3Ja,c =4.1 Hz, 2Ja,b =10.8 Hz, Ha, CH2), 4.56 (1H, dxd, 3Jc,a =4.1 Hz, 3Jc,b =9.3 Hz, Hc), 3.76 (1H, dxd, 2Jb,a =10.8 Hz, 3Jb,c =9.3 Hz, Hb, CH2), 2.17 (3H, s, CH3); δC (CDCl3, 50 MHz) 171.0 (CO, ester), 146.7, 142.1, 138.7, 134.8 131.1, 130.1, 128.7, 128.6 (quaternary aromatic C's), 127.6, 127.0, 126.8, 126.2, 126.1, 125.7, 124.9, 124.8, 124.3, 123.4, 123.3, 122.9 (aromatic CH's), 67.3 (CH2), 46.5 (CH), 20.9 (CH3); m/z (EI) 338, 277, 265, 139, 43.
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH:24]4[CH2:29]COC[CH2:25]4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.Cl.[C:39](N)(C)(C)C>>[C:24]([NH:23][C:21]([C:15]1[N:11]2[CH2:12][CH2:13][O:14][C:8]3[CH:7]=[CH:6][C:5]([C:4]#[C:3][C@@:2]([OH:1])([C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[CH3:31])=[CH:30][C:9]=3[C:10]2=[N:17][C:16]=1[C:18]([NH2:20])=[O:19])=[O:22])([CH3:25])([CH3:29])[CH3:39]
Reactant: CC(C)(C)N
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Agent: Cl
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC(C)(C)C)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing oxan-4-amine hydrochloride with tert-butylamine hydrochloride, off-white solid (58.7 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[CH:10]=[C:11]([CH2:13][N:14]([CH3:16])[CH3:15])[N:12]=[C:4]2[CH:3]=1.[OH-:17].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([OH:17])[N:5]2[CH:10]=[C:11]([CH2:13][N:14]([CH3:16])[CH3:15])[N:12]=[C:4]2[CH:3]=1
Reactant: [OH-]
Reactant: CSc1nc(Cl)cc2nc(CN(C)C)cn12
Agent: [K+]
Product: CN(C)Cc1cn2c(O)nc(Cl)cc2n1

Procedure:
In analogy to Example 33A, 150 mg (98% of theory) of the product are obtained from 150 mg (0.58 mmol) of 1-[7-chloro-5-(methylsulphanyl)imidazo[1,2-c]pyrimidin-2-yl]-N,N-dimethylmethanamine (Example 97A) by heating in methanolic potassium hydroxide solution.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:23]([O-])([N+]([O-])=O)=[O:24]>>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 70.4 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-galactopyranosyl)urea are obtained as yellow caramel.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]=[C:8]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])[C:9]([CH3:11])=O)([O-:3])=[O:2].[NH2:21]/[C:22](/[CH3:28])=[CH:23]\[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[CH3:14][O:13][P:12]([O:15][CH3:16])([C:8]1[CH:7]([C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[NH:21][C:9]=1[CH3:11])=[O:17]
Reactant: COC(=O)/C=C(/C)N
Reactant: COP(=O)(OC)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(P(=O)(OC)OC)C1c1cccc([N+](=O)[O-])c1
Yield: 44.1 %

Procedure:
To a mixture of 1.85 grams of dimethyl 1-(3-nitrobenzylidene)-acetonylphosphonate and 0.75 gram of methyl 3-aminocrotonate was added 25 ml of isopropanol and the mixture was heated to reflux for four hours with stirring. The reaction mixture was concentrated in vacuo, to the residue was added ether, the resulting crystals were collected by filtration, and recrystallized from ethyl acetate to afford 1.08 grams (yield 42%) of methyl 5-dimethoxyphosphinyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate, pale yellow crystals, melting point 221°-3° C.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1/[CH:11]=[C:12]1\[CH2:13][N:14]([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])[CH2:15][CH2:16][CH:17]\1[SH:18])([OH:4])=[O:3].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[ClH:1].[C:39]([S:18][CH:17]1[CH2:16][CH2:15][N:14]([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:20]([CH:22]2[CH2:23][CH2:24]2)=[O:21])[CH2:13]/[C:12]/1=[CH:11]\[C:7]1[N:6]([CH2:5][C:2]([OH:4])=[O:3])[CH:10]=[CH:9][N:8]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cn1ccnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1nccn1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of (E)-3-{[1-(carboxymethyl)-1H-imidazol-2-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanylpiperidine hydrochloride (85.6 mg) in dichloromethane (4 ml) were added triethylamine (120 μl) and acetic anhydride (80 μl) at 0° C. After the mixture was stirred at room temperature for 3 hours, solvents were removed under reduced pressure and the residue was purified by silica gel chromatography using methanol and dichloromethane (5:95 to 25:75) as eluents to afford the free base of the title compound (57.7 mg, yield: 71%) as a colourless oil.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:31]#[N:32].[Na+].O>CN1CCCC1=O.O.O.O.O.O.O.[Ni](Cl)Cl>[O:30]=[C:10]1[CH:9]([CH2:8][C:3]2[C:2]([C:31]#[N:32])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]21[C:29]1[C:20](=[CH:21][C:22]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:28]=1)[O:19][CH2:18]2
Reactant: O=C1C(Cc2ncccc2Br)c2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: [C-]#N
Agent: Cl[Ni]Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cccnc1CC1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 200 °C
Yield: 289 %

Procedure:
3′-[(3-Bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.233 g, 0.500 mmol), nickel (II) chloride hexahydrate (0.113 g, 0.500 mmol), and sodium cyanide (0.050 g, 1.0 mmol) were combined in 1-methyl-2-pyrrolidone (1 mL) and heated at 200° C. for 30 min under microwave irradiation. The reaction mixture was allowed to cool to ambient temperature, poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was subjected to column chromatography, and eluted with a 50% to 75% gradient of ethyl acetate in hexanes, to afford 2-[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-3′-yl)methyl]pyridine-3-carbonitrile (0.593 g, 29%) as a colorless solid: mp 230-233° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.38 (dd, J=7.9, 1.5 Hz, 1H), 7.56 (dd, J=7.8, 4.9 Hz, 1H), 7.27-7.15 (m, 2H), 7.04 (d, J=7.5 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.74 (ABq, 2H), 4.19-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 158.2, 155.0, 153.1, 144.6, 143.1, 142.1, 138.2, 132.4, 129.1, 124.0, 123.4, 121.9, 116.5, 112.2, 109.8, 108.0, 99.1, 79.8, 64.7, 64.1, 57.7, 44.1; MS (ES+) m/z 412.0 (M+1).