Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][NH:5][C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:3]1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: N#Cc1ccc(Nc2nc(=O)cc[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile (0.12 mol) in POCl3 (90 ml) was stirred and refluxed under Argon for 20 minutes. The reaction mixture was slowly poured onto 750 ml ice/water, and the solid was separated by filtration. The solid was suspended in 500 ml water, and the pH of the suspension was adjusted to neutral by adding a 20% NaOH solution. The solid was again separated by filtration, suspended in 200 ml 2-propanone, and 1000 ml CH2Cl2 was added. The mixture was heated until all solid had dissolved. After cooling to room temperature, the aqueous layer was separated, and the organic layer was dried. During removal of the drying agent by filtration, a white solid formed in the filtrate. Further cooling of the filtrate in the freezer, followed by filtration, yielded 21.38 g (77.2%) of [4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[NH:33][C:34]([C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([O:41][CH3:42])=[O:40])=[N:35][N:36]=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[NH:33][C:34]([C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([O:41][CH3:42])=[O:40])=[N:35][N:36]=4)=[CH:30][CH:31]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: COC(=O)C(F)(F)C(F)(F)c1nnc(-c2ccc(N)cc2)[nH]1
Product: CCC(C(=O)Nc1ccc(-c2nnc(C(F)(F)C(F)(F)C(=O)OC)[nH]2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 88 mg (0.28 mmol, 1.1 eq.) of methyl 3-[5-(4-aminophenyl)-4H-1,2,4-triazol-3-yl]-2,2,3,3-tetrafluoropropanoate were reacted according to General Method 1. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 96 mg (purity 94%, 56% of theory)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].[BH4-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: O=Cc1cc2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1cc2ccccc2o1
Yield: 94.5 %

Procedure:
2-Benzofurancarbaldehyde (2.2 g, 15 mmol) was dissolved in 25 mL of methanol. To this solution was added sodium borohydride (0.28 g, 7.5 mmol) in small portions over a period of 20 minutes. Then 2 mL of water were added and the mixture was evaporated. The residue was dissolved in ethyl acetate (75 mL) and washed with water (3×75 mL), dried (MgSO4) and evaporated, providing 2.1 g of benzofuran-2-yl-methanol, in 95% yield; 1H NMR (CDCl3) δ 2.03 (t, J=6.1 Hz, 1H), 4.77 (d, J=6.1 Hz, 214), 6.66 (s, 1H), 7.19-7.32 (m, 2H), 7.45-7.50 (m, 1H), 7.53-7.57 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C1COCC1>[C:16]1([C@H:22]([NH:24][CH:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: C[C@@H](N)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](NC1CCCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
A mixture of 4-oxoazepane-1-carboxylic acid tert-butyl ester (90 g, 422 mmol) and (R)-1-phenylethanamine (56.4 g, 465 mmol) in THF (1000 mL) was stirred at rt for 15 min and STAB (107.4 g, 510 mmol) was added. The mixture was cooled to 0° C. in an ice bath, then acetic acid (26.7 g, 450 mmol) was added. The mixture was stirred overnight at rt then concentrated in vacuo, residue dissolved in DCM (800 mL) and washed with sat. NaHCO3 sol. (2×300 mL), dried (Na2SO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (gradient 0% to 3% MeOH in DCM) to give tert-butyl 4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (90 g, 67.0%) as a mixture of two diastereoisomers.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(F)F
Product: O=C(Cl)c1ccccc1C(F)F

Procedure:
A solution of 2-(difluoromethyl)benzoic acid 53 (1.8 g, 10 mmol) in thionyl chloride (25 ml) was heated at reflux for 3 h. The reaction mixture was concentrated and dried under vacuum to give 54. The crude acid chloride was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl methyl(piperidin-3-yl)carbamate (1.00 g, 4.67 mmol) in THF (25 mL) was added triethylamine (0.70 mL, 5.0 mmol) and 2-chloro-5-nitropyridine (500 mg, 3.1 mmol). The reaction mixture was then stirred at room temperature for 16 h, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acetate/hexanes) afforded the desired product (1.03 g, 99%) as a yellow solid. ESI MS m/z 337 [C16H24N4O4+H]+
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[C:3]=1[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([CH:36]=1)[C:34]#[N:35]>CN(C=O)C>[C:34]([C:33]1[CH:36]=[C:29]([CH:30]=[CH:31][C:32]=1[O:37][CH:38]([CH3:40])[CH3:39])[CH2:28][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[C:3]=1[CH3:20])#[N:35]
Reactant: CCOC(=O)CC1CCn2c1cc1c(C)c(O)ccc12
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCn2c1cc1c(C)c(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Temperature: 65 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (100 mg, 0.366 mmol) in DMF (3 mL) was added cesium carbonate (155 mg, 0.476 mmol), followed by 5-(chloromethyl)-2-isopropoxybenzonitrile (100 mg, 0.476 mmol). The reaction mixture was heated at 65° C. for 15 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by column chromatography to give the title compound (130 mg) as a colorless oil. LCMS m/z=447.7 [M+H]+; 1H NMR (400 ME-1z, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 1.42 (d, J=6.0 Hz, 6H), 2.25-2.32 (m, 1H), 2.42 (s, 3H), 2.58 (dd, J=16.0, 8.4 Hz, 1H), 2.82-2.92 (m, 2H), 3.73-3.80 (m, 1H), 3.95-4.02 (m, 1H), 4.08-4.15 (m, 1H), 4.20-4.27 (m, 2H), 4.62-4.69 (m, 1H), 4.96 (s, 2H), 6.13 (s, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.6, 2.2 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][O:34]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: Nc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)O)ccc2O3)cc1
Solvent: ClCCl
Product: Nc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)cc1

Procedure:
(E)-3-{1′-[2-(4-Amino-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (108 mg, 0.225 mmol) was suspended in DCM (5 ml). TEA (0.09 ml, 0.67 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-amino-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (37 mg) as a yellow solid, which was then dissolved in DCM (3 ml) and treated with 4 M HCl in dioxane (0.1 ml, 0.4 mmol) as described in Example 55, Step D, giving a light yellow solid (28 mg, di-hydrochloride salt).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(C#N)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 4-iodo-benzonitrile (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.00 (s, 1H), 7.93 (d, 1H), 7.74-7.76 (m, 2H), 7.35-7.51 (m, 9H), 7.10 (t, 1H), 6.56-6.72 (m, 2H), 6.35 (d, 1H), 4.95 (s, 2H), 3.91 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[Br:16].[CH3:17][Si](C)(C)Cl>CO>[NH2:1][C:2]1[C:3]([Br:16])=[CH:4][C:5]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([O:14][CH3:17])=[O:13])=[CH:6][C:7]=1[Br:8]
Reactant: Nc1c(Br)cc(C(=O)/C=C/C(=O)O)cc1Br
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)/C=C/C(=O)c1cc(Br)c(N)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5.6 g (0.016 mol) of trans-4-(4-amino-3,5-dibromophenyl)-4-oxobutenoic acid, 50 mL of anhydrous methanol, and 4.0 g (0.0368 mol) of trimethylchlorosilane was stirred for 3 days at ambient temperature. The solvent was removed in vacuo, the residue was divided between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate, evaporated down once more in vacuo, and yielded 5.8 g (100% of theoretical) of a colorless oil which was used without any further purification. MS: M+=361/363/365 (Br2).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1.[CH2:32]([O:34][C:35](=[O:44])[CH2:36][N:37]1[C:41]([CH:42]=O)=[CH:40][N:39]=[CH:38]1)[CH3:33]>C1C=CC=CC=1>[CH2:32]([O:34][C:35]([CH2:36][N:37]1[C:41](/[CH:42]=[C:10]2\[CH2:9][N:8]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][C:11]\2=[O:14])=[CH:40][N:39]=[CH:38]1)=[O:44])[CH3:33]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)Cn1cncc1C=O
Solvent: c1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Yield: 18.5 %

Procedure:
To a solution of 1-(triphenylmethyl)piperidin-4-one (3.66 g) in benzene (40 ml) was added pyrrolidine (0.97 ml), and the mixture was heated under reflux for 3.5 hours. To this mixture was added a solution of ethyl(5-formyl-1H-imidazol-1-yl)acetate (1.95 g) in benzene (10 ml) under cooling using an ice bath. Then, the whole was heated further under reflux for 8.5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography using hexane and ethyl acetate (1:3) as an eluent to afford the title compound (1.0 g, yield: 19%) as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH:6]([NH2:13])[C:7](=O)[C:8]([F:11])([F:10])[F:9])[CH3:3].C(OC([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][C:23]1=[O:29])=O)(C)(C)C.C([O-])(=O)C.[Na+]>O.O1CCOCC1>[CH2:2]([O:4][C:5]([C:6]1[NH:13][C:25]2[CH2:26][CH2:27][NH:22][C:23](=[O:29])[C:24]=2[C:7]=1[C:8]([F:11])([F:10])[F:9])=[O:14])[CH3:3]
Reactant: CCOC(=O)C(N)C(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1[nH]c2c(c1C(F)(F)F)C(=O)NCC2
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A stirred mixture of 2-amino-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester hydrochloride (7.54 g, 32 mmol), 2,4-dioxo-piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 29.1 mmol) and sodium acetate (2.39 g, 29.1 mmol) in water (35 ml) and dioxane (35 ml) was heated to reflux for 2 hours. The mixture was cooled down to room temperature, and extracted with 15 to 1 solvent mixture of ethyl acetate and methanol (160 ml×3), the combined organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by the silica gel column chromatography with dichloromethane:tetrahydrofuran:methanol (40:5:1) as eluents to give 3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (2.8 g, 35%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[C:6]=1[F:24])[CH3:2].I[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=3)[C:13]=2[CH3:23])[C:6]=1[F:24])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1F
Reactant: CCCn1cc(I)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 4-iodo-1-propyl-1H-pyrazole.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][C:29]=2[CH:34]=[O:35])=[CH:24][CH:23]=1>O1CCCC1>[Cl:13][C:14]1[C:19]([CH:34]([C:29]2[CH:30]=[N:31][N:32]([CH3:33])[C:28]=2[C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)[OH:35])=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=1
Reactant: Cc1ccc(-c2c(C=O)cnn2C)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 240 mL, 0.60 mol) was added drop-wise to a solution of diisopropylamine (85.2 mL, 0.60 mol) in tetrahydrofuran (600 mL) at −78° C. After the reaction had stirred for 30 minutes at −78° C., a solution of 4,6-dichloropyrimidine (89.4 g, 0.600 mol) in tetrahydrofuran (600 mL) was added drop-wise at about −90° C., and stirring was continued for 1 hour. To this mixture was added drop-wise a solution of 5-(4-methylphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (C3) (60.0 g, 300 mmol) in tetrahydrofuran (600 mL) at about −90° C. After completion of the addition, the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with acetic acid (60 g); the mixture was warmed to room temperature, and then concentrated under reduced pressure to remove tetrahydrofuran. The residue was dissolved in ethyl acetate (2 L) and washed with saturated aqueous sodium bicarbonate solution (1 L). The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. Recrystallization from ethyl acetate yielded the product as a white solid. Yield: 82.0 g, 235 mmol, 78%. 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 3.72 (s, 3H), 6.26 (s, 1H), 7.17 (br AB quartet, JAB=8 Hz, ΔνAB=32 Hz, 4H), 7.66 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH:11]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:11]([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)NC1CCCCC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (0° C.) solution of 4-bromobenzoyl chloride (5.305 g, 24.2 mmol) in tetrahydrofuran (20 ml) was added dropwise a solution of isopropyl cylcohexyl amine (6.841 g, 48.4 mmol) in tetrahydrofuran (THF) (7ml). After stirring for 1 hr at 0° C., the reaction was stirred at room temperature for 3 hr. and reflexed for 3 hr. The reaction was concentrated in vacuo and the residual mass was dissolved in ethyl ether and water. The layers were separated and the organic layer washed once with water, twice with 0.5N HCl, once more with water, twice with 5% aqueous NaHCO3 solution, and once with water. After drying over sodium sulfate, the organic layer was filtered, and the filtrate concentrated in vacuo to give the crude product. This material was purified by chromatography on silica el suing mixtures of EtOAc, and hexane as eluents to give the title compound.
Reaction SMILES: [S:1]1[CH2:6][S:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:14]>O1CCCC1>[O:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]([CH:2]2[S:3][CH2:4][S:5][CH2:6][S:1]2)([OH:14])[CH3:12])=[CH:20][CH:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1SCSCS1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Oc2ccccc2)cc1)C1SCSCS1
Temperature: -60 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
In 30 ml of anhydrous tetrahydrofuran was suspended 2.6 g of 1,3,5-trithiane, and 12 ml of 1.6M n-butyl lithium was added dropwise under an argon atmosphere at a temperature of about -20° C. After completion of the dropwise addition, the resulting mixture was stirred for 2 hours. Next, the reaction mixture was cooled to about -60° C., and then a solution of 4.0 g of 4-phenoxyacetophenone dissolved in 10 ml of tetrahydrofuran was dropped thereinto. After completion of the dropping, the reaction temperature was slowly raised to 0° C. The mixture thus obtained was stirred at 0° C. for another 1 hour. Thereafter, the same treatment as in Example 1 was carrid out to obtain a crude product, which was then purified by a silica gel column chromatography (chloroform) to give 3.4 g of the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]1.NN>C(O)(C)C.[Ni].C(O)C>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: N#CCCCN1CCN(c2ncccn2)CC1
Agent: [Ni]
Agent: NN
Solvent: CC(C)O
Solvent: CCO
Product: NCCCCN1CCN(c2ncccn2)CC1
Yield: 68.1 %

Procedure:
4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyronitrile (115.7 g; 0.5 mole) was dissolved in 1.5 L isopropyl alcohol. Approximately 50 mL of a suspension of Raney nickel in anhydrous ethanol was added and the resulting reaction mixture was heated to reflux and hydrazine (120 g) was slowly added dropwise. On completion of the reaction, the spent catalyst was removed by filtration and the filtrate was concentrated in vacuo to a yellow oil which was distilled to yield 80.1 g (60%) of product, boiling point 135°-145° C. at 0.10 mm. (The nitrile used in this reaction is described in Wu, et al., Journal of Medicinal Chemistry, 15, page 477-479 (1972).)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1>C1COCC1>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(NC(=O)C#Cc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
A solution of 0.26 g (1 mmol) of (4′-chlorobiphenyl-4-yl)propynoic acid and 0.12 mL (1.1 mmol) of N-methylmorpholine in 20 mL of absolute THF is combined at −15° C. with 0.14 mL (1.1 mmol) of isobutyl chloroformate and stirred for ten minutes. Then 0.226 g (1.1 mmol) of 4-(4-methylpiperazin-1-ylmethyl)phenylamine dissolved in 7 mL of THF is added and the reaction mixture is stirred for 2 hours until ambient temperature is reached. The reaction mixture is evaporated down and the residue is dissolved in dichloromethane. The organic phase is washed twice with water and then dried over sodium sulfate. The desiccant is filtered off and the solvent is distilled off. The residue is triturated with ether and suction filtered. The purification is carried out by column chromatography on silica gel (dichloromethane/methanol/ammonia (90/10/0.1)). Yield: 60 mg (14% of theory); melting point: 182° C.-185° C.; C27H26ClN3O (M=443.97); calc.: molecular ion peak (M+H)+: 444/446 (Cl); found: molecular ion peak (M+H)+: 444/446 (Cl); Rf value: 0.4 (silica gel, dichloromethane/methanolic ammonia (90:10:0.1)).