Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[N+:21]([O-])=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[NH2:21])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)c(N)c1
Yield: 100 %

Procedure:
The trans-[3-(4-methyl-2-nitro-phenylamino)-cyclopentyl]-carbamic acid tert-butyl ester (320 mg, 0.95 mmol) and palladium on charcoal (10% Pd on carbon, 35 mg) in methanol (15 mL) were shaken at 52 psi of hydrogen pressure for 2.5 hours. The mixture was filtered through Celite®. Solvents were evaporated to yield trans-[3-(2-amino-4-methyl-phenylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a pale brown oil (290 mg). This material (290 mg, 0.95 mmol) was dissolved in a solution (5 mL) of acetic acid and trimethyl orthoacetate (4:1 v/v). The mixture was stirred at 70° C. for 60 minutes and solvents were evaporated. The residue was extracted with ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous phase was again extracted with a portion of ethyl acetate and each organic phase was washed with brine. The extracts were combined, dried over sodium sulfate, filtered and evaporated to give trans-[3-(2,5-dimethyl-benzoimidazol-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester as a light brown foam (320 mg). 1H-NMR is consistent with the assigned structure. LC-MS showed a single peak, C19H27N3O2 (m/e) calcd 329.2103, obsd 330.2 (M+H).
Reaction SMILES: [BrH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:13]#[CH:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3]>>[Br:1][C:13]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH2:2][CH3:3])[CH:6]=1)=[CH2:14]
Reactant: C#Cc1ccc(OC)c(OCC)c1
Reactant: Br
Product: C=C(Br)c1ccc(OC)c(OCC)c1
Yield: 93.3 %

Procedure:
According to the General Procedure D, HBr (33% in acetic acid, 1.22 ml, 0.51 g, 6.25 mmol) and 3-Ethoxy-4-methoxyphenylacetylene (1.10 g, 6.25 mmol) are converted to give after workup and chromatography (SiO2 PE/EE 5:1, Rf=0.35) the title compound (1.53 g, 5.83 mmol) as a brown oil; C11H13BrO2 (257.13).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][C:9]2[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])[CH:16]=[CH:15][N:14]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4,5-trifluorobenzaldehyde and 2-chloropyridin-4-ol.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.[F:18][C:19]([F:32])([F:31])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][S:27](Cl)(=[O:29])=[O:28])=[CH:22][CH:21]=1>>[CH3:8][C:5]1[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3](=[O:17])[C:2]([NH:1][S:27]([CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:31])[F:32])=[CH:25][CH:24]=2)(=[O:29])=[O:28])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Product: Cc1ccc(NS(=O)(=O)Cc2ccc(C(F)(F)F)cc2)c(=O)n1CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared from tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (EXAMPLE 1, STEP 1-3), and [4-(trifluoromethyl)phenyl]methanesulfonyl chloride using the procedure of EXAMPLE 9 (STEP 2), and was obtained as a white solid compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[CH:19]2[CH3:25])[CH:3]=1.C(=O)(O)[O-].[Na+].[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:38](=[O:39])[CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:20]([CH3:24])[C@@H:19]2[CH3:25])[CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1NCCN(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)C1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1[C@H](C)N(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1C(=O)Cc1ccccc1
Reaction time: 2 h

Procedure:
To a vigorously stirred solution/suspension of the product from example 71 part a) (0.189 g) and solid sodium bicarbonate (0.215 g) in DCM (2 ml) and water (2 ml) was added phenylacetyl chloride (0.14 ml) dropwise. The mixture was stirred for 2 h. The organic layer and 1 further DCM extract were combined, dried (Na2SO4) and purified by passage through SCX resin eluting with MeCN, MeOH followed by 7M NH3 in MeOH. The basic fractions were concentrated in vacuo to give the sub-titled product as a white foam (0.205 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N: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.[NH2-].[Na+].ClC(S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O)(Cl)Cl.O>O1CCCC1>[F:35][C:34]([F:37])([F:36])[CH2:33][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)[CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: C1=Cc2ccccc2N(CC2CNCCO2)c2ccccc21
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)CN1CCOC(CN2c3ccccc3C=Cc3ccccc32)C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2-morpholinylmethyl)-5H-dibenz[b,f]azepine (0.23 g) in tetrahydrofuran was added sodium amide (0.063 g). The resulting mixture was stirred at 40° C for 30 minutes. To the reaction mixture was added trifluoroethyl trichloromethylsulfonate (0.265 g) in tetrahydrofuran at room temperature. The resulting mixture was stirred at 50° C for 5 hours. After cooling, the reaction mixture was admixed with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-trifluoroethyl-2-morpholinylmethyl)-5H-dibenz[b,f]azepine. M.P. 97°-98° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:28][CH:27]=1
Reactant: CNC(=O)COC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNC(=O)COC(=O)N1CCCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cn2)CC1
Temperature: 150 °C
Yield: 57.5 %

Procedure:
0.12 g (0.3 mmol) of 2-(methylamino)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1,4-diazepane-1-carboxylate, prepared in step 11.3., 0.25 g (1.2 mmol) of 4-(trifluoromethoxy)-phenylboronic acid and 0.9 ml (1.8 mmol) of aqueous sodium carbonate solution (2M), suspended in 3.5 ml of toluene and 0.8 ml of ethanol are introduced into a Pyrex reactor. 0.07 g (0.06 mmol) of tetrakis-(triphenylphosphine)palladium is then added and, after sealing the reactor, it is maintained at 150° C. for 15 minutes under microwave irradiation. The organic phase is recovered after separation of the phases by settling, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 30/70/5 mixture of ethyl acetate, cyclohexane and methanol. After crystallization from diisopropyl ether, 0.078 g of product is obtained in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][CH3:14])[C:10](=[S:15])[NH:9][C:8]=2[CH:16]=1)([O-])=O.C(O)(=O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][CH3:14])[C:10](=[S:15])[NH:9][C:8]=2[CH:16]=1
Reactant: CCC1Oc2ccc([N+](=O)[O-])cc2NC1=S
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCC1Oc2ccc(N)cc2NC1=S

Procedure:
1 g of 6-nitro-2-ethyl-1,4-benzoxazine-3-thione is dissolved with 7.6 ml of glacial acetic acid and 1 ml of water, and it is mixed with 950 mg of iron powder. After several hours at room temperature, it is poured onto water. The crystals are suctioned off and washed with water, dissolved again with ethyl acetate and washed neutral with brine, the organic phase is dried with magnesium sulfate and concentrated by evaporation. After column chromatography with hexane/ethyl acetate, a yield of 811 mg results.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:34])/[CH:23]=[C:24](\[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)/[CH3:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C([O-])(=O)C.[NH4+:39]>CO>[CH3:25]/[C:24](/[C:26]1[CH:27]=[C:28]([C:32]([NH2:33])=[NH:39])[CH:29]=[CH:30][CH:31]=1)=[CH:23]/[C:22](=[O:34])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1
Reactant: C/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: C/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)but-2-enamide (90 mg, 0.19 mmol) in 5 ml anhydrous methanol cooled in an ice bath was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (144 mg, 2 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1Z)-1-methyl-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)-benzenecarboxamidine (35 mg, 20%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 435.1
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:59]=[CH:58][C:10]([CH2:11][C:12]2[CH:13]=[C:14]([C@H:19]3[C@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:23]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@H:22]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:20]3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:9][CH:8]=1)C=C.C([O-])(=O)C.[Na+]>C(O)(=O)C.[Pd](Cl)Cl>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([C@H:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[O:20]2)=[CH:13][C:12]=1[CH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][OH:4])=[CH:59][CH:58]=1
Reactant: C=CCOCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 70 °C
Yield: 42 %

Procedure:
(2S,3S,4R,5R,6R)-2-(3-(4-(2-(allyloxy)ethyl)benzyl)-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran (intermediate BK) (50 mg, 0.061 mmol) was taken up in 90% aqueous acetic acid (1 mL), and sodium acetate (30.4 mg, 0.37 mmol) was added, followed by palladium(II)chloride (27.4 mg, 0.154 mmol). The mixture was heated at 70° C. for 5 h. Solvent was evaporated and the residue was taken up in 2 mL DCM and the mixture was filtered through a short Celite® pad. The pad was washed with a copious amount of DCM until all material had eluted. After evaporation of solvent, the residue was purified by TLC using 4:1 hexane:EtOAc to obtain intermediate BL (20 mg, yield 42%). LC-ESI-MS (m/z): 770 (M+H), 791 (M+H+Na).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=3[O:23][CH3:24])[NH:11][C:7]=2[CH:6]=1)=O.[CH3:27][NH2:28]>>[CH3:27][NH:28][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:13]=3[O:23][CH3:24])[NH:11][C:7]=2[CH:6]=1)=[O:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(NS(C)(=O)=O)cc3OC)[nH]c2c1
Reactant: CN
Product: CNC(=O)c1ccc2nc(-c3ccc(NS(C)(=O)=O)cc3OC)[nH]c2c1
Yield: 67 %

Procedure:
One and one-half grams (4.0 mmol) of 5-methoxycarbonyl-2-(2'-methoxy-4'-methanesulfonylamino-phenyl)-benzimidazole and 10 ml of methylamine were heated for four hours to 120° C. in a steel canister. Then, excess methylamine was evaporated off, and the residue was dissolved in a small amount of water and neutralized with concentrated hydrochloric acid. After the solution was evaporated, the crude product obtained was purified by chromatography (150 gm of silica gel; eluant: methylene chloride with 10% ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[C:11]([C:12](=[CH:17][O:18][CH3:19])[C:13]([O:15][CH3:16])=[O:14])=[C:10]([O:20][CH3:21])[N:9]=[CH:8][N:7]=1.[Br:25]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[C:11]([C:12](=[CH:17][O:18][CH3:19])[C:13]([O:15][CH3:16])=[O:14])=[C:10]([O:20][CH3:21])[N:9]=[CH:8][N:7]=1
Reactant: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(CBr)c1

Procedure:
Methyl α-[4-(3-methylphenoxy)-6-methoxy-pyrimidin-5-yl]-β-methoxyacrylate (2.7, 8.4 mmol), N-bromosuccinimide (1.6 g, 6 mmol) and a catalytic amount of AIBN are refluxed in CCl4 for 90 minutes. Filtration of the succinimide and evaporation of the solvent gives the methyl α-[4-(3-bromomethylphenoxy)-6-methoxy-pyrimidin-5-yl]-β-methoxyacrylate as a colorless oil.
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1>C1COCC1.[Pd]>[C:11]1([CH2:10][CH2:9][C:1]2[CH:2]=[CH:3][C:4]([CH2:7][OH:8])=[CH:5][CH:6]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCc1ccc(C=Cc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCc1ccc(CCc2ccccc2)cc1

Procedure:
Hydrogenating 10 g (48 mmol) of 4-stilbenemethanol (Aldrich; Milwaukee/U.S.A.) in 100 ml of THF, in the presence of 0.5 g of 5% Pd/C under low pressure and at RT, filtering through ®Celite (filtering aid based on kieselguhr; Johns-Manville Corp., obtainable from Fluka, Buchs, Switzerland) and evaporating the filtrate affords the title compound, approximately 15% of which, according to the 1H-NMR spectrum, consists of p-(2-phenylethyl)toluene: TLC Rf (A)=0.62; 1H-NMR (200 MHz, CDCl3): 2.92 (s, 4H), 4.68 (s, 2H), 7.15-7.35 (m, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].C(Cl)Cl>>[OH:47][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(#Cc1nc2c(N3CCOCC3)ccnn2c1C1CCNCC1)c1ccc2ccccc2n1

Procedure:
A solution of compound 41e (0.50 g, 0.93 mol) in TFA/DCM (1:3, 10 mL) was stirred at rt for 2 h. The resulting mixture was concentrated under reduced pressure to obtain compound 41f as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H26N6O: 439.2 (M+H). found: 439.2.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1.C>C(O)C.[OH-].[Na+]>[CH:24]1([NH:27][C:3]2[N:8]=[C:7]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]3=[CH:5][N:4]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NC3CC3)ncc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and cyclopropylamine (1.2 ml) in ethanol (20 ml) was heated for 18 hours at 90° C. in a pressure vessel. Further cyclopropylamine (1 ml) was added and the reaction mixture was stirred in a pressure vessel for 18 hours at 100° C. and then for 20 hours at 120° C. The cooled reaction mixture was evaporated under reduced pressure to yield a residue which was dissolved in 1 Normal sodium hydroxide. The resultant solution was treated with charcoal, filtered, and the filtrate neutralized by the addition of concentrated hydrochloric acid which caused the precipitation of a crude product. The crude product was eluted from a silica column with chloroform as eluant, and the combined fractions containing product were evaporated under reduced pressure to yield a residue. This was twice recrystallized from methanol to yield the title compound, 0.23 g, m.p. 207.5-208.5° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=1)([CH3:9])[CH3:8].CI>CC(C)=O>[CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([O:18][CH3:1])=[O:17])[CH:11]=1)([CH3:9])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1ccn(CC(=O)O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)Cn1ccc(C(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
Potassium carbonate (298 mg, 2.15 mmol) was added to a solution of 2-(3-isopropylpyrrol-1-yl)acetic acid (180 mg, 1.07 mmol) in acetone at 0° C. and the reaction was stirred at 0° C. for 15 min. Methyl iodide (0.13 mL, 2.15 mmol) was added at 0° C. and the mixture refluxed for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to give the crude compound. Purification by column chromatography over neutral alumina by using 1-2% ethyl acetate in petroleum ether as eluent afforded methyl 2-(3-Isopropylpyrrol-1-yl)acetate (135 mg, 69%) as a liquid.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C@H:9]([OH:16])[CH2:10]OS(C)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].[Cl-].[Na+]>COCCOC>[O:16]1[CH2:10][C@@H:9]1[CH2:8][O:7][C:6]1[CH:17]=[CH:18][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CS(=O)(=O)OC[C@@H](O)COc1ccc(C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: N#Cc1ccc(OC[C@H]2CO2)cc1
Yield: 100.6 %

Procedure:
A solution of 2.71 g of (2S)-1-(4-cyanophenoxy)-3-methane-sulfonyloxypropan-2-ol in 40 ml of 1,2-dimethoxyethane was stirred with 1.0 g of powdered sodium hydroxide at room temperature for 22 h. 10 ml of saturated sodium chloride solution was added, and the mixture was extracted twice with ether. Washing with 5% sodium hydrogen carbonate, drying over magnesium sulfate, filtration and evaporation gave 1.76 g of crystalline material, m.p. 67.5° C., [α]D20 -14.7° (c=1, acetone).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:5]=1[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])=O.S(C)C>C1COCC1>[CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:12]=[C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][C:4]=1[NH:3][CH3:1])([CH3:11])[CH3:10]
Reactant: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1NC=O
Solvent: C1CCOC1
Solvent: CSC
Product: CNc1ccc(Oc2ccccc2)cc1C(=O)NC(C)C
Temperature: 50 °C
Yield: 29.6 %

Procedure:
A solution of 44A (55 mg, 0.19 mmol) in THF (1 mL) at 0° C. was treated with BH3.SMe2 (0.09 mL, 0.93 mmol). The resulting yellow solution was warmed to 50° C. for 1 hour, and then cooled to 0° C. and quenched with MeOH (0.25 mL). The resulting solution was treated with acetic acid (0.1 mL) and warmed to 50° C. for 6 hours. The solution was concentrated to dryness and purified by chromatography (SiO2, 10% MeOH in CHCl3) to afford 44B (16 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[N:18]([O-])=O.[Na+]>>[N+:1](=[C:2]1[CH2:15][N:6]([C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:5](=[O:16])[NH:4][C:3]1=[O:17])=[N-:18]
Reactant: Nc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Product: [N-]=[N+]=C1CN([C@H]2C[C@H](O)[C@@H](CO)O2)C(=O)NC1=O

Procedure:
acidifying said 5-amino-deoxyuridine compound and reacting the acidified product with sodium nitrite to produce a 5-diazo-deoxyuridine compound; and
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][N:26]=[CH:25][CH:24]=4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][N:26]=[CH:25][CH:24]=4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32]
Reactant: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc4cnccc4nc3C)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (compound 406) (590 mg) was dissolved in trifluoroacetic acid (6 ml) to preapre a solution. Methanesulfonic acid (0.6 ml) was added to the solution, and the mixture was stirred at 70° C. for one hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-2-methyl-[1,6]naphthyridine (456 mg, yield 98%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1OC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c(F)cc1OC
Temperature: 12.5 °C
Reaction time: 0.75 h
Yield: 64.3 %

Procedure:
To a solution of methyl 4-fluoro-2-methoxybenzoate (50 g, 271.50 mmol) in sulfuric acid (150 mL) was added a solution of potassium nitrate (35.6 g, 352.48 mmol) in sulfuric acid (30 mL) dropwise with stirring for 45 min at 0-25° C. in an ice/water bath. The reaction was then quenched by the addition of water/ice. The solids were collected by filtration to afford methyl 4-fluoro-2-methoxy-5-nitrobenzoate as a white solid (40.0 g, 64%).