Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5].[OH-].[NH4+:12]>C(O)C>[NH2:12][C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CC(C)C(Cl)=C(C#N)C#N
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C(N)=C(C#N)C#N
Temperature: 0 °C
Reaction time: 1.3 h

Procedure:
A solution of 191.3 g of 3-chloro-2-cyano-4-methyl- 2-pentenenitrile in 300 ml of ethanol was added slowly, maintaining the temperature below 40°, during 1.3 hours, to a mixture of 800 ml of concentrated ammonium hydroxide and 1000 ml of ethanol. The mixture was stirred for 3 hours, then poured over 2000 ml of ice. The solid was collected, washed with water and dried to obtain 122.0 g of 3-amino-2-cyano-4-methyl-2-pentenenitrile, mp 186°-188°.
Reaction SMILES: O([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)S(C(F)(F)F)(=O)=O.[CH2:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:18](=[CH2:19])[CH2:17][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:11]=1)#[N:16]
Reactant: C=CC[Si](C)(C)C
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C=C(C[Si](C)(C)C)c1ccc(C#N)cc1
Yield: 54 %

Procedure:
Table 1, Entry 8. In the reaction tube were mixed 4-cyanophenyl triflate (0.251 g,1.0 mmol), allyltrimethylsilane (0.571 g, 5.0 mmol), palladium acetate (0.00673 g, 0.030 mmol), DPPF (0.0366 g, 0.066 mmol), potassium carbonate (0.207 g, 1.5 mmol) and 1.0 ml acetonitrile.under nitrogen. The contents of the flask were irradiated for 5.00 min with an effect of 50 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml diethyl ether. The combined extracts were washed two times with 25 ml saline and concentrated to an oil. The crude product was purified by repeated Kugelrohr distillation. The yield was 54% (clear oil).
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:13](=[O:14])[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[S:9][C:8]=3[S:19][C:5]=2[CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH:1]1[C:6]2[C:7]3[C:13](=[O:14])[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[S:9][C:8]=3[S:19][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2Sc2sc3c(c21)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2Sc2sc3ccccc3c21
Yield: 42.3 %

Procedure:
In the same manner as in Example 77 and using 1,2,3,4-tetrahydro[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one (1.2 g), dichlorodicyano-p-benzoquinone (2.1 g) and toluene (20 ml), [1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one (500 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-])=[CH:9][CH:8]=[CH:7]2.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14].C(O)(=O)C>C1(C)C=CC=CC=1>[C:13]([O:16][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cccc2cccc(O)c21
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc2cccc(O)c2n1
Temperature: 135 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
64 g (397 mmol) of 8-hydroxyquinoline N-oxide, 550 ml of acetic anhydride and 40 ml of acetic acid are placed in a 1 l round-bottomed flask. The reaction mixture is heated at reflux (135° C.) for 24 h, 40 ml of acetic acid are then again added and heating is continued for 1 h 30. The reaction mixture is allowed to return to ambient temperature and 400 ml of toluene are added. A precipitate appears and is filtered off. A further 400 ml of toluene are added and filtration is carried out. The precipitate is washed with 200 ml of ethyl ether and is dried in a desiccator under vacuum over phosphorus pentoxide to provide to provide 70.5 g of 2-acetoxy-8-hydroxyquinoline in the form of a brown solid. (Yield: 88%)
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14]Br)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16]1([CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=1)[OH:17].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:17][C:16]2[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(O)cc2)CC1
Yield: 52.4 %

Procedure:
A mixture of 5.0 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 10.0 g of hydroquinone, 10.0 g of anhydrous potassium carbonate and 250 ml of absolute butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 4:1) gave 2.9 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]phenol; m.p. 100°-101° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C[N+]([O-])=O>[F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(O)ccc1F
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1c(F)ccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 17.1 %

Procedure:
6-Fluoro-3-hydroxybenzoic acid (100 mg, 0.64 mmol) was dissolved in CH3NO2 (10 mL) and cooled to 0° C. HNO3 (90%, 31 μL, 0.64 mmol) was added and the reaction was left at 0° C. for 4 h and then at room temperature over night. Evaporation and purification by flash chromatography on SiO2 (Toluene-EtOAc-HOAc) gave the product (22 mg). 1H NMR (CD3OD): δ 7.32 (t, J=9.0 Hz, 1 H), 7.15 (dd, J1 =9.3 Hz, J2 =4.4 Hz, 1 H); 13C NMR: δ 164.97, 153.68 (d, J=247 Hz), 148.78, 122.67, 122.56, 122.45, 122.13.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:7]=1[F:13])=[O:4].O1CCCC1.[CH2:27]([N:29](CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[NH2:1][C@@H:2]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:27]#[N:29])=[CH:8][C:7]=1[F:13])=[O:4]
Reactant: CCN(CC)CC
Reactant: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(I)cc1F
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)[C@H](N)C(=O)Nc1ccc(C#N)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
To an argon degassed and dried flask was added (2S,3S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide (796 mg, 1.99 mmol), zinc cyanide (352 mg, 2.99 mmol), tetrakis-triphenylphosphine palladium (0) (116 mg, 0.1 mmol) and dry tetrahydrofuran (4 mL). After heating at 80° C. for 8 hours there was no reaction. To the cooled mixture was added 2-dicylohexylphosphino-2′-6′-dimethoxybiphenyl (42 mg, 0.1 mmol) and the reaction mixture heated again to 80° C. for 90 minutes, again no reaction occurred. To the cooled mix was added triethylamine (840 μl, 5.99 mmol) and the reaction mixture heated at 80° C. for 2 hours, again no reaction occurred. To the cooled mix was added 2-dicylohexylphosphino-2′-6′-dimethoxybiphenyl (84 mg, 0.2 mmol) and still no reaction occurred after 2 hours at 85° C. To the cooled mix was added rac-2-2′-bis(diphenylphosphino)-1-1′binaphthyl (125.6 mg, 0.2 mmol) and dry toluene (2 mL). After heating at 85° C. for 40 hours the reaction mix was dissolved in ethyl acetate (50 mL) and washed with 1.5 N aqueous potassium hydrogen sulfate solution, saturated aqueous sodium bicarbonate solution and the aqueous layers were back extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by chromatography over silica gel gradient eluted from 5 to 15% v/v ethyl acetate in hexanes to give (2S,3S)-2-amino-N-(4-cyano-2-fluoro-phenyl)-3-phenyl-butyramide as a yellow residue after concentration of the product containing fractions (120 mg, 20.2% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][C@H:34]([OH:36])C)N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[C:4]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:3][N:2]([CH2:1][C@H:34]([OH:36])[CH3:33])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: C[C@@H](O)CNN
Product: C[C@@H](O)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (R)-1-Hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.42 (m, 2H), 8.18 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.61 (s, 1H), 7.54 (m, 1H), 7.36 (d, J=9.1 Hz, 2H), 7.12 (m, 2H), 6.99 (d, J=8.7 Hz, 2H) 5.37 (s, 2H), 4.30 (m, 1H), 4.21 (dd, J=13.6, 2.5 Hz, 1H), 4.03 (dd, J=13.6, 7.9 Hz, 1H), 1.26 (d, J=6.2 Hz, 3H); MS: (M+H m/z=437.2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1.Cl.[CH2:18](O)[CH3:19]>>[NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:18][CH3:19])=[O:14])=[CH:8][CH:9]=1
Reactant: CCO
Reactant: NCCc1ccc(C(=O)CCC(=O)O)cc1
Agent: Cl
Product: CCOC(=O)CCC(=O)c1ccc(CCN)cc1

Procedure:
On to a mixture of 127.2 g. (0.49 mole) of the acid obtained according to (b) and 800 ml. ethanol is passed, while stirring, gaseous hydrogen chloride and the reaction mixture is heated to reflux temperature for 2 hours, whereafter it is then strongly cooled. The precipitated crystals are filtered off with suction, washed with cold ethanol and dried over anhydrous calcium chloride. Yield 137.1 g. (97% of theory) of hydrochloride; m.p. 162°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9](Br)=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[CH3:13][C:14]1[N:15]=[N:16][NH:17][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([N:17]2[CH:18]=[C:14]([CH3:13])[N:15]=[N:16]2)=[C:8]2[NH:7][CH:6]=[CH:5][C:4]=12
Reactant: Cc1c[nH]nn1
Reactant: COc1cnc(Br)c2[nH]ccc12
Product: COc1cnc(-n2cc(C)nn2)c2[nH]ccc12
Temperature: 130 °C
Reaction time: 17 h

Procedure:
4-Methoxy-7-bromo-6-azaindole (120 mg) was added in portions to a melted of 4-methyl-1,2,3-triazole (219 mg) under argon at 110-120° C. The mixture was heated to 130° C. and was stirred at 130° C. for 17 hours. The reaction mixture was cooled to room temperature and the resulting residue was purified by column chromatography using EtOAc/Hexane (6:4) mixture as eluent which afforded 4-methoxy-7-(4-methyl-1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridine as a tan solid. 1H NMR (400 MHz, DMSO-D6): δ 2.38 (s, 3H), 4.01 (s, 3H), 6.66 (dd, 1H, J=2.9, 2.6), 7.53 (dd, 1H, J=2.9, 2.8), 7.70 (s, 1H), 8.62 (s, 1H), 11.78 (bs, 1H). MS: 230.3 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:18][C:14]1[C:12]2[N:13]=[C:9]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2c(CBr)cccc2s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of 2-(bis(tert-butoxycarbonyl)amino)-4-methylbenzothiazole (1.09 g, 3.00 mmol) in carbon tetrachloride (15 ml) were added N-bromosuccinimide (694 mg, 3.90 mmol) and 2,2′-azobis(isobutyronitrile) (99 mg, 0.20 mmol) and the mixture was stirred under nitrogen atmosphere at 80° C. for 2 hr. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The crude residue was subjected to column chromatography (eluent: n-hexane:chloroform=60:40 to 50:50) to obtain the title compound (1.26 g, 95%).
Reaction SMILES: O.[NH2:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][C:5]=2[O:17][CH:18]([CH3:23])[C:19](OC)=[O:20].CC(C)([O-])C.[K+].[Cl-].[NH4+]>O1CCCC1>[CH3:23][CH:18]1[C:19](=[O:20])[NH:2][C:3]2=[C:16]3[C:11](=[N:10][C:9]4=[CH:8][CH:7]=[CH:6][C:5](=[C:4]24)[O:17]1)[CH2:12][CH2:13][CH2:14][CH2:15]3
Reactant: COC(=O)C(C)Oc1cccc2nc3c(c(N)c12)CCCC3
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of the methyl α-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]propionate hydrate (3.7 g) in dry tetrahydrofuran (65 ml) was added potassium t-butoxide (1.62 g). The reaction mixture was stirred at room temperature for one hr, saturated ammonium chloride solution (18.2 ml) was added, and stirring was continued for one hr. The mixture was concentrated. The solution was cooled, the solid was collected, washed with water, and dried to yield 2.90 g (90%) of product, mp 200° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.3 min, m/z=487.1; 1H NMR (CD3OD) 1.25-1.37 (m, 1H), 1.55 (d, 3H), 1.61 (m, 1H), 1.95 (m, 2H), 2.17-2.28 (m, 1H), 2.36 (m, 1H), 2.48 (m, 1H), 3.12 (m, 1H), 3.48 (m, 2H), 3.94 (s, 3H), 5.58 (m, 1H), 6.86 (d, 1H), 7.07 (m, 4H), 7.35 (m, 4H), 7.86 (dd, 1H), 8.28 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[CH2:23]=O.Cl>C(O)=O>[CH3:23][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1
Reactant: C1=Cc2ccccc2C(=CC2CNCCO2)c2ccccc21
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CCOC(C=C2c3ccccc3C=Cc3ccccc32)C1
Reaction time: 6.5 h

Procedure:
A mixture of 5-(morpholin-2-yl)methylidene-5H-dibenzo[a,d]cycloheptene (0.35 g), 90% formic acid (0.7 g) and 37% formalin (0.65 ml) was stirred at 95° - 100° C for 6.5 hours. After cooling, 4N hydrochloric acid was added thereto, and the resulting mixture was evaporated to dryness under reduced pressure, neutralized with ammonia water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-methylmorpholin-2-yl)methylidene-5H-dibenzo-[a,d]cycloheptene as oily material. M.P., 237° - 238° C (decomp.) (oxalate).
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[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][CH2:16]1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: C1CCC2NCCCC2C1
Product: Nc1nnc(N2CCCC3CCCCC32)c(-c2ccccc2)n1
Yield: 3.2 %

Procedure:
6-(Octahydroquinolin-1(2H)-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg, 7%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (1.00 g, 3.96 mmol) and decahydroquinoline (0.60 g, 4.36 mmol) according to the general procedure of Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:24]C(=O)C(F)(F)F)[C:5]2=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:24][C:6]1[C:5]2[C:4]3[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=4)[CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]=[N:8][CH:7]=1
Reactant: O=C(Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cncc2[nH]c3c(NC(=O)c4cccnc4)cc(Cl)cc3c12
Temperature: 60 °C
Yield: 9.4 %

Procedure:
N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-nicotinamide (38 mg, 0.088 mmol, 1 equiv.) was suspended in 5 ml of MeOH and a 2 ml aqueous solution of K2CO3 (121 mg, 0.92 mmol, 10 equiv.) was added thereto. The resulting clear solution was heated at 60° C. for 11 hr. After cooling to RT, fine solids precipitated that were captured by filtration and washed with 10 ml of water to give 2.78 mg (10%) of N-(4-amino-6-chloro-9H-β-carbolin-8-yl)-nicotinamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CCCCCC>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:21]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[CH3:11]
Reactant: COc1ccc(Br)c(F)c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)cc2F)c(C)c1

Procedure:
A mixture of 4-bromo-3-fluoro anisole (500 mg, 2.44 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (INTERMEDIATE 37, 875 mg, 3.17 mmol), tetrakis(triphenylphosphine) palladium (282 mg, 5% mol) and Na2CO3 (569 mg, 5.37 mmol) in 20 mL of water/EtOH/toluene (1:2:4) was heated at reflux for 4 h. TLC (CH2Cl2/hexane (1:1)) showed that the reaction was complete. The solvents were removed. Water (10 mL) was added. The organic was extracted with CH2Cl2 (3×10 mL). The combined CH2Cl2 layers were washed with brine and then dried (Na2SO4). The title compound was obtained after flash chromatography using CH2Cl2/hexanes (6:4) as the eluent. 1H NMR (500 MHz, CDCl3): δ 7.98 (s, 1H), 7.92 (dd, J=8.0, 1.5 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.16 (t, J=8.5 Hz, 1H), 6.80 (dd, J=8.5, 2.5 Hz, 1H), 6.77 (dd, J=11.5, 2.5 Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11]([NH:3][C:2]([CH3:4])([CH3:1])[C:5]([OH:7])=[O:6])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 2-methylalanine (CAN 62-57-7, 30.9 g, 0.3 mol) and sodium hydroxide (20 g, 0.5 mol) in water (500 mL) was added benzyl chloroformate (61.4 g, 0.36 mol) at ice-water bath temperature. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting solution was washed with ethyl acetate (2×80 mL), then the aqueous layer was adjusted to pH=2 with conc. hydrochloric acid and the solution was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude target compound (26 g, 36%) which was used directly for the next step without further purification; MS: m/e 238.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C1COCC1.[BH4-].[Na+].Cl>CCOC(C)=O.CO>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: O=Cc1cccc(-c2ccc(N3CCOCC3)cc2)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cccc(-c2ccc(N3CCOCC3)cc2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
2-Fluoro-4′-(morpholin-4-yl)biphenyl-3-carboaldehyde (288 mg) was mixed with THF (3 ml), and NaBH4 (40 mg) was added thereto. MeOH (3 ml) was added to the reaction mixture dropwise, followed by stirring at room temperature for 30 minutes. EtOAc and 1 M hydrochloric acid were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-4′-(morpholin-4-yl)biphenyl-3-yl]methanol (259 mg).
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:9]([CH:10]2[CH2:12][CH2:11]2)[C:8]2[CH:13]=[C:14]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:15]([F:17])=[CH:16][C:7]=2[N:6]=1)(=[O:3])[NH2:2].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32].N12CCCN=C1CCCCC2>C1COCC1>[CH:10]1([N:9]2[C:8]3[CH:13]=[C:14]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]4)[C:15]([F:17])=[CH:16][C:7]=3[N:6]3[C:31](=[O:32])[NH:2][C:1](=[O:3])[CH:4]=[C:5]23)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(N)=O)n3C2CC2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)[nH]c(=O)cc2n3C2CC2)CC1
Yield: 85.7 %

Procedure:
tert-Butyl 4-[2-(carbamoylmethyl)-1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate (980 mg, 2.53 mmol) is suspended in THF (15 ml) and treated with 1,1'-carbonyldiimidazole (760 mg, 2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 ml). The reaction mixture is heated to 60° for 2 hours, whereby white crystals separate. The suspension is then cooled to 0°. The crystals are filtered off and recrystallized from ethanol. There are obtained 760 mg (73%) of tert-butyl 4-[5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido-[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[CH:4][N:3]=1.[OH:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20]>>[OH:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1)=[O:20]
Reactant: C[C@H]1COCCN1c1ccnc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1ccnc(-c2ccc(NC(=O)NCCO)cc2)n1

Procedure:
Method as described for example 49 using (S)-4-(2-chloropyrimidin-4-yl)-3-methylmorpholine (intermediate 3) and 1-(2-hydroxyethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 18). The mixture was purified by prep HPLC at high pH to afford the title compound. (24 mg, 15%).