Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12]Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:16][N:17]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]([OH:36])[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:22]=[N:21][C:20]=2[N:19]([CH3:37])[C:18]1=[O:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:16][N:17]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][CH:28]([OH:36])[CH2:29][N:30]3[CH2:31][CH2:32][N:33]([CH2:12][CH2:11][CH2:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH2:34][CH2:35]3)[CH:22]=[N:21][C:20]=2[N:19]([CH3:37])[C:18]1=[O:38]
Reactant: O=S(=O)(CCCCl)c1ccccc1
Reactant: Cn1c(=O)c2c(ncn2CC(O)CN2CCNCC2)n(C)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2CC(O)CN2CCN(CCCS(=O)(=O)c3ccccc3)CC2)n(C)c1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.13 Moles of 3-phenylsulfonyl-1-chloropropane were combined with 0.14 moles of 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypropyl]piperazine dihydrochloride and 0.3 moles potassium carbonate in 600 grams dimethylformamide. The mixture was stirred overnight at 60° C. After cooling, the reaction mixture was poured into water, extracted with CH2Cl2, washed with water, dried, and evaporated with gentle heating. The residue was recrystallized from ethanol to give the free base form of 1-[3-(1,3-Dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypropyl]-4-(3-phenylsulfonylpropyl)piperazine, m.p. 168° C. The dihydrochloride was obtained by adjunction with 12N hydrogen chloride solution as described in Example III, m.p. 190° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:7]=1.[OH-].[Na+]>O.CCO.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:19][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:9][C:8]2=[O:18]
Reactant: O=C(C=Cc1cccc(Cl)c1)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CC(c2cccc(Cl)c2)Oc2ccc(Br)cc21
Reaction time: 8 h
Yield: 82 %

Procedure:
1-(5-Bromo-2-hydroxyphenyl)-3-(3-chlorophenyl) prop-2-en-1-one (23 g, 68 mmol) was dissolved in H2O (513 mL) and EtOH (171 mL). Then NaOH (2.74 g, 68 mmol) was added. The mixture was stirred overnight and filtered to give a solid cake. The cake was dissolved in EtOAc and washed with H2O twice. The organic layer was dried and filtered. The filtrate was concentrated to give 6-bromo-2-(3-chlorophenyl)chroman-4-one (18.82 g, 82%). 1H-NMR (CDCl3): 2.87 (m, 1H), 3.02 (m, 1H), 5.44 (m, 1H), 6.96 (d, 1H), 7.31 (m, 1H), 7.37 (m, 2H), 7.48 (s, 1H), 7.58 (m, 1H), 8.02 (d, 1H).
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:14][CH2:15][CH:16](N)[CH3:17]>C(=S)=S>[CH3:17][CH:16]1[CH2:15][NH:14][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13]1
Reactant: CCCCCCCCCCCC#N
Reactant: CC(N)CN
Solvent: S=C=S
Product: CCCCCCCCCCCC1=NC(C)CN1
Yield: 74.9 %

Procedure:
18.13 g (100 mmoles) of undecyl cyanide, 9.3 g (125 mmoles) of 1,2-diaminopropane and 0.5 ml of carbon disulfide were heated to 125° C. for 24 hrs. and then worked up as mentioned under Example 23. Kugelrohr distillation at 163°-165° C./1.2-1.4 mm Hg gave 17.85 g (75%) of product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[I:10]I>ClC1C=CC=CC=1.[Cu](Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([I:10])[CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: II
Reactant: CCc1ccccc1O
Agent: Cl[Cu]Cl
Solvent: Clc1ccccc1
Product: CCc1cc(I)ccc1O

Procedure:
A solution of 119.9 ml of 2-ethylphenol in 500 ml of chlorobenzene was treated with 126.9 g of iodine and 134.5 g of copper(II) chloride and stirred under reflux for 5.5 hours. After cooling the reaction mixture was filtered and the residue was washed with methylene chloride. The combined filtrates were washed with aqueous sodium thiosulphate solution and ice-water. The organic phases were dried over sodium sulphate and concentrated. The residue was crystallized from hexane and gave 79.3 g of 2-ethyl-4-iodo-phenol. The mother liquor was chromatographed over silica gel and gave a further 41 g of 2-ethyl-4-iodo-phenol; MS (EI) m/z 248 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].ClCCl.CO>ClCCl.C(OCC)(=O)C.CO>[CH3:40][O:39][C:35]1[CH:34]=[C:30]([CH:29]=[C:28]([O:27][CH3:26])[C:36]=1[O:37][CH3:38])[C:31]([N:13]1[CH2:14][CH2:15][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][OH:18])[CH2:12]1)=[O:32]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2(CCO)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (2.27 g, 9.03 mmol) and N-methylmorpholine (2.48 mL, 22.6 mmol) in anhydrous dichloromethane (100 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add 3,4,5-trimethoxybenzoyl chloride (2.2 g, 9.5 mmol) as a solution in dichloromethane (30 mL). Warm to ambient temperature. After 18 hours, extract the reaction mixture with a saturated solution of potassium carbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 95% dichloromethane/methanol to obtain a residue. Combine the residue and dichloromethane (100 mL), and extract 3 times with 1M hydrochloric acid solution and saturated solution of potassium carbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 20/1 ethyl acetate/methanol to obtain an oil: Rf=0.14 (silica gel, 20/1 ethyl acetate/methanol). Dry in vacuo at 110° C. to obtain the title compound as a glass: mp; 60-62° C. Elemental Analysis calculated for C24H31NO7: C 64.70; H 7.01; N 3.14; Found C 64.40; H 7.21; N 2.85.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[CH2:13][CH2:12]1.[F:14][C:15]1[CH:24]=[CH:23][C:18](CB(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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.Cl[Pd]Cl.[Fe+2]>[CH:11]1([C:4]2[CH:5]=[CH:6][C:7]([C:9]#[N:10])=[N:8][C:3]=2[CH2:2][C:18]2[CH:23]=[CH:24][C:15]([F:14])=[CH:16][CH:17]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1ccc(C2CC2)c(CBr)n1
Reactant: OB(O)Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Temperature: 110 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
A mixture of 6-bromomethyl-5-cyclopropyl-pyridine-2-carbonitrile (0.1 g, 0.4 mmol), 4-fluoro-benzylboronic acid (CAN 1765-93-1, 0.1 g, 0.7 mmol), Pd(dppf)Cl2 (CAN 95464-05-4, 50 mg, 0.068 mmol), Cs2CO3 (0.2 g, 0.6 mmol) in 1.4-dioxane (10 mL) was stirred for 12 h at 110° C. under a nitrogen atmosphere. The mixture was filtered, concentrated and purified by flash column chromatography (silica gel, 3 g, eluting with 25% ethyl acetate in petroleum ether) to give the title compound (80 mg, 75%) as yellow solid; MS (EI): m/e=253.2 [M+H]+.
Reaction SMILES: NC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC#N)C=CC=1OC.[CH3:24][O:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1.[Mg].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[N+:46]([O-:48])=[O:47])[CH:41]=[O:42]>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:41]([C:28]2[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=2)[OH:42])[CH:43]=[CH:44][C:45]=1[N+:46]([O-:48])=[O:47]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1N
Agent: [Mg]
Product: COc1cc(OC)cc(C(O)c2ccc([N+](=O)[O-])c(OC)c2)c1
Yield: 72.7 %

Procedure:
(3-Methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol was prepared analogously to 3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using 3,5-dimethoxy-bromobenzene (4.4 g, 20.1 mmol), magnesium turning (1.0 g, 20.1 mmol) and 3-methoxy-4-nitro-benzaldehyde (3.0 g, 16.8 mmol) to afford (3-methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.9 g, 73%): 1H NMR (CDCl3) δ 7.79 (d, J=8 Hz, 1H), 7.22 (s, 1H), 7.00-6.99 (dd, J=2, 9.1 Hz, 1H), 6.48 (d, J=2 Hz, 2H), 6.40 (d, J=2 Hz, 1H), 5.75 (d, J=3 Hz, 1H), 3.96 (s, 3H), 3.77 (s, 6H), 2.45 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=CC3[NH:48][C:49](=[O:52])[O:50]C=3C=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[NH:48][C:49](=[O:50])[O:52][C:22]=5[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1[nH]c2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2o1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)oc54)c3=O)cc2)CCC1
Yield: 48 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-8-phenyl-3H-chromeno[7,8-d]oxazole-2,6-dione was reacted to give the title compound as a yellow oil (66 mg, 48%). LCMS (Method G): RT=3.95, [M+H]+=525.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.C(Cl)Cl.B(Cl)(Cl)Cl>CO>[F:34][C:31]([F:32])([F:33])[C:30]([C:27]1[CH:28]=[CH:29][C:24]([N:11]2[CH2:12][CH2:13][N:14]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH2:15][C@@H:10]2[CH2:9][OH:8])=[CH:25][CH:26]=1)([OH:36])[CH3:35]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COCc2ccccc2)cc1)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CO)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
A 2-L round-bottomed flask was charged with 2-(4-((2R)-2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (54.4 g, 101 mmol) and 200 mL of CH2Cl2. After cooling to 0° C., BCl3 (1M in CH2Cl2, 302 mL, 302 mmol, Sigma-Aldrich, St. Louis, Mo.) was added over 10 min. After 30 min at 0° C., the mixture was carefully diluted with MeOH and then concentrated and purified via column chromatography on silica gel (0 to 3% MeOH in CH2Cl2) to give 1,1,1-trifluoro-2-(4-((2R)-2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (42.7 g) as a tan foam.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([S:10]([C:13]2[C:14]([S:25][CH3:26])=[N:15][N:16]3[C:21]([OH:22])=[CH:20][C:19]([CH2:23]Cl)=[N:18][C:17]=23)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCO.CN(C=O)C>[C:4]1([S:10]([C:13]2[C:14]([S:25][CH3:26])=[N:15][N:16]3[C:21]([OH:22])=[CH:20][C:19]([CH2:23][N:2]([CH3:3])[CH3:1])=[N:18][C:17]=23)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CSc1nn2c(O)cc(CCl)nc2c1S(=O)(=O)c1ccccc1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCO
Product: CSc1nn2c(O)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
5 ml of a 33% solution of dimethylamine in EtOH were added to a solution of 1.4 g (3.7 mmol) of 3-benzenesulphonyl-5-chloromethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated, the residue was partitioned between 0.5N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 4:1) yielded 1.3 g (92%) of 3-benzenesulphonyl-5-dimethylaminomethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige powder, m.p.>220°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10]([OH:12])=O)[C:6]=1[CH3:7].[CH3:44][N:45]([CH3:57])[C:46]1[NH:52][CH2:51][C:50]2[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=2[CH2:48][N:47]=1.C(N(C(C)C)C(C)C)C>ClCCCl.C1COCC1.CN(C1C=CN=CC=1)C>[CH2:35]([N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:52]2[CH2:51][C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[CH2:48][N:47]=[C:46]2[N:45]([CH3:57])[CH3:44])=[O:12])[N:4]=1)=[O:43])[CH2:36][CH2:37][CH3:38]
Reactant: CN(C)C1=NCc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3CN=C2N(C)C)c(C)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.8 %

Procedure:
To a solution of 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 36 mg, 0.058 mmol) in DCE (1.0 mL) was added 1-chloro-N,N-2-trimethylprop-1-en-1-amine (15 μL, 0.12 mmol). The resulting reaction mixture was stirred at room temperature for 1.5 h. A solution of N,N-dimethyl-2,5-dihydro-1H-benzo[e][1,3]diazepin-3-amine (Rodriguez, H. R. et al., J. Org. Chem., 33:670-676 (1968)) (11 mg, 0.058 mmol) in THF (1.0 mL) was then added, followed by DMAP (7 mg, 0.058 mmol) and i-Pr2EtN (50 μL, 0.29 mmol). The resulting reaction mixture was stirred at room temperature for 12 h, then concentrated in vacuo and purified by preparative HPLC to give the title compound (11 mg, 24%). 1H NMR (DMSO-d6, mixture of amide rotamers) δ 10.31 (br s, 1H), 8.56 (br s, 1H), 8.32-7.87 (m, 7H), 7.77-7.57 (m, 2.5H), 7.33-7.05 (m, 3H), 6.98 (br s, 0.5H), 5.09-4.53 (m, 3H), 4.08 (br s, 2H), 3.86-2.85 (m, 9H), 2.14 (s, 3H), 1.71-1.41 (m, 3H), 1.36-1.07 (m, 3H), 0.99-0.80 (m, 4.5H), 0.54 (br s, 3.5H); MS(ESI+) m/z 796.8 (M+H)+.
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[C:15]3[CH:30]=[CH:29][CH:28]=[N:27][C:16]3=[N:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([F:26])[CH:20]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]>CO.[OH-].[OH-].[Pd+2]>[F:5][C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[C:15]3[CH2:30][CH2:29][CH2:28][NH:27][C:16]3=[N:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([F:26])[CH:20]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(-c2nc3cccnc3nc2-c2ccc(C)c(F)c2)cc1F
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)c(F)c2)NCCC3)cc1F

Procedure:
To Pd(OH)2 (20% on carbon, 50% water wet) (30 mg, 0.214 mmol) and ammonium formate (557 mg, 8.84 mmol) was added a solution of 2,3-bis(3-fluoro-4-methylphenyl)pyrido[2,3-b]pyrazine (step 1)(307 mg, 0.884 mmol) in MeOH (3 ml) and the reaction mixture was heated to reflux for 5 h. A further portion of Pd(OH)2 (20% on carbon, 50% water wet) (30 mg, 0.214 mmol) was added and the mixture was heated to reflux for 6 h. The reaction mixture was filtered through Celite® (filter material) and washed with MeOH and EtOAc. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid; LCMS; Rt 1.07 mins MS m/z 352 [M+H]+Method 2minLC_v003
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl.[O-]S([O-])=O.[Na+].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:21])=[CH:6][CH:7]=1
Reactant: Fc1ccc(SCCCCl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(CCCCl)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A solution of 3-chloropropyl 4-fluorophenyl sulfide (77.5 mg, 0.380 mmol) in CH2Cl2 (2.00 mL) was cooled to 0° C. To this solution m-CPBA (78.7 mg, 0.460 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min, then at 23° C. for 4 h. The resulting crude mixture was diluted with 10% aqueous Na2SO3 (10 mL), the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using 2.5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 3-chloropropyl 4-fluorophenyl sulfoxide (47.8 mg, 57.0%).
Reaction SMILES: [C:1]([N:11]1[CH2:19][C@H:18]([F:20])[CH2:17][C@H:12]1[C:13]([O:15]C)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[Na+]>CO>[C:1]([N:11]1[CH2:19][C@H:18]([F:20])[CH2:17][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)[C@@H]1C[C@@H](F)CN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@@H](F)CN1C(=O)OCc1ccccc1

Procedure:
Following the procedure of Example 19(d), the methyl ester product from part (d) is saponified with 11.5 ml. of 2 N sodium hydroxide in 50 ml. methanol to give 5.3 g. of the desired product as a pale yellow viscous oil. This material is converted to the cyclohexylamine salt by treatment with 2 g. of cyclohexylamine in 25 ml. of ethanol. 4.7 g. of cyclohexylamine salt are obtained; m.p. 188°-191° (s. 183°); [α]D25 -42° (c=1%, methanol). Crystallization from 55 ml. of isopropanol gives 3.7 g. of colorless cyclohexylamine salt; m.p. 194°-196° (s. 187°); [α]D25 -44° (c=1%, methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]=[C:15]1[O:19][C:17](=[O:18])[CH2:16]1>CN(C=O)C>[C:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)(=[O:18])[CH2:16][C:15]([CH3:14])=[O:19]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
1-tert-Butoxycarbonylpiperazine (5.02 g) was dissolved in DMF (90 mL), and diketene (2.50 mL) was added thereto at room temperature. The mixture was stirred for 1.5 hr and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried. The solvent was evaporated under reduced pressure to give 1-acetoacetyl-4-tert-butoxycarbonylpiperazine (6.26 g) as a pale-brown powder.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17]4[N:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=4[CH2:15][N:14]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:13]=3[CH:41]=2)=[O:8])[CH:3]=1.I[C:43]1C=CC2NC3N=C(C(F)(F)F)C=CC=3CN(S(C3C=CC(OC(F)(F)F)=CC=3)(=O)=O)C=2C=1.C([Mg]Cl)(C)C.CON(C)C(C1C=C(C)NN=1)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17]4[N:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:16]=4[CH2:15][N:14]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:13]=3[CH:41]=2)([OH:8])[CH3:43])[CH:3]=1
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21
Reactant: Cc1cc(C(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)n[nH]1
Agent: CC(C)[Mg]Cl
Agent: CON(C)C(=O)c1cc(C)[nH]n1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C(C)(O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(5-Methyl-1H-pyrazol-3-yl)[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]methanone To a solution of 8-iodo-6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (950 mg, 1.544 mmol, intermediate 61) in 5 ml of THF was added a solution of isopropyl magnesium chloride (3.47 ml, 6.95 mmol) in THF (2M) at 0° C. The solution was stirred at 0° C. for 30 min, then a mixture of N-methoxy-N,5-dimethyl-1H-pyrazole-3-carboxamide (261 mg, 1.544 mmol) in 3 mL of toluene was added. The reaction mixture was stirred for 2 hr at 0° C. and then allowed to warm to rt overnight. The reaction was quenched by the addition of 4 mL of 0.5 N HCl. The resulting viscous residue was washed with ethyl acetate (30 mL×2) and acetone (20 mL×2). The combined washes were evaporated under reduced pressure and the residue was crystallized from CH2Cl2 to give the title compound as a light yellow solid; Mass Spectrum: m/e=598 (M+1).
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Yield: 100 %

Procedure:
Reaction of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate from the previous step with an excess of TFA (10 mL) in CH2Cl2 (50 mL) at room temperature for 2 hrs, followed by treatment with aq. NH3 gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole in 100% yield: mp (EtOH) 228-231° C.: 1H NMR (CDCl3) δ 7.90 (d, J=7.9 Hz, 1H), 7.50 (t, JHF=53.5 Hz, 1H), 7.34 (t, J=8.3 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 3.87 (m, 8H), 3.78 (m, 4H), 2.95 (m, 4H); Anal. Calcd. for C20H24F2N8O2: C, 53.8; H, 5.4; N, 25.1. Found: C, 53.8; H, 5.6; N, 25.3%.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([CH3:17])[CH:9]=2)[CH2:4]1>CO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][CH:3]([N:2]([CH3:18])[CH3:1])[CH2:4]2)=[CH:9][C:10]=1[CH3:17]
Reactant: Cc1cc(N2CCC(N(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N2CCC(N(C)C)C2)ccc1N
Reaction time: 5 h

Procedure:
A suspension of dimethyl-[1-(3-methyl-4-nitrophenyl)pyrrolidin-3-yl]amine (200 mg) and palladium (10% on carbon, 10 mg) in methanol (10 mL) was vigorously stirred under an atmosphere of hydrogen at atmospheric pressure for 5 hours. The catalyst was then filtered off with suction and the filtrate was concentrated. The product with the molecular weight of 219.33 (C13H21N3) was obtained in this way; MS (ESI): 220 (M+H+).