Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:8][C:7](=[O:9])[CH:6]([C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:10]
Reactant: CO
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccc(Cl)cc1

Procedure:
To a stirred solution of 4-chloromandelic acid (10.7 g, 57.3 mmol) in methanol was added sulfuric acid (3.3 mL, 63.1 mmol). The reaction mixture was refluxed for 6 hours. The reaction mixture was concentrated, neutralized with sat. sodium carbonate solution, extracted with ether, washed with brine, dried, and concentrated. Purification by silica gel chromatography (40% ethyl acetate in hexanes) yielded 10.3 g of (4-chlorophenyl)hydroxyacetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([C@H:35]([CH3:40])[C:36]([O:38]C)=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@:10]([CH:35]([CH3:40])[C:36]([OH:38])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)([C@H](C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(C(C)C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of (S)-methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate (0.041 g, 0.067 mmol) from Step B above in MeOH/THF/H2O (1 mL/1 mL/2 mL) was added lithium hydroxide (8.02 mg, 0.335 mmol). The mixture was heated to 60° C. for 14 h. The reaction mixture was acidified with 1N HCl and extracted with EtOAc (×2). The organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and the filtrate was concentrated under reduced pressure to provide a colorless film. The crude material was purified by reverse phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to provide the title compound as the first eluting peak.
Reaction SMILES: C([O:4][CH:5]1[CH2:8][C:7]2([CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[N:19]=[CH:20][S:21][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)[CH2:6]1)(=O)C.O.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH:5]1[CH2:6][C:7]2([CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[N:19]=[CH:20][S:21][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)[CH2:8]1
Reactant: CC(=O)OC1CC2(CCN(C(=O)OCc3cscn3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(OCc1cscn1)N1CCC2(CC1)CC(O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
0.267 g (0.82 mmole) of the thiazol-4-ylmethyl 2-acetoxy-7-aza-spiro[3.5]nonane-7-carboxylate obtained in stage 1.2 is dissolved in 2 ml of methanol then 0.5 ml of water and 0.114 g (0.82 mmole) of potassium carbonate are added. After stirring for 1 hr at ambient temperature, the medium is concentrated under vacuum then taken up in water. The aqueous solution is extracted twice with dichloromethane then the organic phases are combined, dried over sodium sulphate, filtered and concentrated to dryness. 0.222 g of the expected product are obtained in the form of a colour-less oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C@H:61]1([C:68](O)=[O:69])[CH2:64][C@@H:63]([C:65]([OH:67])=[O:66])[CH2:62]1.C(=O)([O-])O.[Na+]>CN(C=O)C.O.C(#N)C>[F:36][C:30]1[CH:29]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:68]([C@@H:61]3[CH2:64][C@H:63]([C:65]([OH:67])=[O:66])[CH2:62]3)=[O:69])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:27]=[C:26]([F:25])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C(O)[C@H]1C[C@@H](C(=O)O)C1
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](C(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.3 %

Procedure:
HATU (82 mg, 0.21 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (70 mg, 0.18 mmol), DIEA (0.061 mL, 0.36 mmol) and cis-cyclobutane-1,3-dicarboxylic acid (38.7 mg, 0.27 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→490% ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (35.6 mg, 0.069 mmol, 38.5%) as a white solid.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl.[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[F:24][C:25]1([F:31])[CH2:30][CH2:29][N:28]([C:2]2[N:6]=[C:5]([N:7]3[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[CH2:9][CH2:8]3)[S:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: FC1(F)CCNCC1
Reactant: COc1ccc(CCN2CCN(c3nc(Br)ns3)CC2)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCN(c3nc(N4CCC(F)(F)CC4)ns3)CC2)cc1
Temperature: 200 °C

Procedure:
A mixture of 3-bromo-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole (55 mg, 143 μmol), 4,4-difluoropiperidine hydrochloride (67.8 mg, 430 μmol) and DIPEA (185 mg, 251 μl, 1.43 mmol) in N-Methyl-2-pyrrolidinone (1 mL) was heated with microwave at 200° C. for 2.5 h. The amber reaction solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 41.8 mg (69%) of the title compound as off-white solid. MS (m/e): 424.2 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>>[CH:1]1([CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C(O)CC(=O)O
Reactant: C1=NCCc2ccccc21
Product: O=C(O)CC1NCCc2ccccc21
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
A mixture containing 6.62 g of 3,4-dihydroisoquinoline and 5.13 of malonic acid is triturated in an oil bath at 120° C. The mixture thickens and becomes entirely solid; it is worked into a powder with a spatula. The total duration of heating is about 40 minutes. The mixture is cooled to about 60° C. and treated with 120 ml of MeOH and 20 ml of water, which dissolves the medium. A first crop is obtained under cold conditions and a second crop is then obtained by evaporating the filtrate and crystallizing the residue from acetone.
Reaction SMILES: Cl[C:2]1[C:3]([C@@H:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=3)=[CH:11][CH:10]=2)[CH3:8])=[N:4][S:5][N:6]=1.[OH-:25].[Na+]>CO>[F:22][C:21]([F:24])([F:23])[C:19]1[N:20]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C@H:7]([C:3]3[C:2]([OH:25])=[N:6][S:5][N:4]=3)[CH3:8])=[CH:10][CH:11]=2)[S:17][CH:18]=1
Reactant: [OH-]
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nsnc1Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nsnc1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
Intermediate 14b (1.09 g, 2.80 mmol) was dissolved in a solution of NaOH (0.11 g, 2.75 mmol) in CH3OH (10 ml). The reaction mixture was stirred for 1 h at 50° C. and then quenched with a saturated solution of NH4Cl (10 ml); the aqueous layer was extracted with CH2Cl2 (2×10 ml) and the combined organic phases, after drying over anhydrous Na2SO4, were evaporated under vacuum and crystallized from n-heptane to give the pure 4-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1,2,5-thiadiazol-3-ol (14) (0.625 g, 1.68 mmol) as a white solid (60%). [α]D=−33 (c=1; CH3OH); 1H-NMR (CDCl3): δ 9.25 (bs, 1H, NH), 8.35 (bs, 1H, OH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.00 (s, 1H), 3.85 (q, 1H, J=7 Hz) 1.75 (d, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11]O)[CH2:6]2)[C:3]1=[O:13].S(Cl)([Cl:17])=O.O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11][Cl:17])[CH2:6]2)[C:3]1=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(=O)C2CCC1CC2CCO
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)C(=O)C2CCC1CC2CCCl
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a stirred solution of 50 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octan-2-one (produced according to Example II) in 200 ml of dry pyridine is added 30 g of thionyl chloride. The mixture is stirred at 50° C. for 2 hours and then poured into 50 g of water. The resulting aqueous solution is extracted with three 200 ml portions of ether. The combined ether layers are washed with two 100 ml portions of 5% aqueous HCl and dried over anhydrous sodium sulfate. The ether is stripped and the residue is vacuum distilled, yielding about 42 g of 3,3-dimethyl-6-(2-chloroethyl)-bicyclo(2.2.2)-octan-2-one, having the structure: ##STR33##
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:43])[C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[O:36]COCCOC)=[CH:23][C:22]=2[F:44])[CH2:17][CH2:16]1)(C)(C)C>C(OCC)(=O)C>[ClH:35].[NH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:43])[C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[OH:36])=[CH:23][C:22]=2[F:44])[CH2:19][CH2:20]1
Reactant: COCCOCOc1ccc(Cl)cc1C(=O)Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CCN(c2ccc(NC(=O)c3cc(Cl)ccc3O)cc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 184.4 %

Procedure:
4N Hydrogen chloride/ethyl acetate solution (10.0 ml, 40.0 mmol) was added to a solution of (1-{4-[5-chloro-2-(2-methoxyethoxymethoxy)benzoylamino]-2-fluorophenyl}piperidin-4-yl)carbamic acid tert-butyl ester (compound of Reference Example 143; 0.15 g, 0.271 mmol) in ethyl acetate (2 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The precipitated crystal was collected by filtration and washed with ethyl acetate to give the title compound (0.10 g, 93%) as a colorless crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:11]([NH:17]C1C=CC=CC=1)[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1>>[CH2:9]1[O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:17][CH2:11][C:12]3[O:16][CH:15]=[CH:14][CH:13]=3)=[CH:3][C:4]=2[O:10]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: c1ccc(NCc2ccco2)cc1
Product: c1coc(CNc2ccc3c(c2)OCO3)c1
Yield: 86.1 %

Procedure:
Using the general procedure, 4-bromo-1,2-(methylenedioxy)benzene (120 μL, 1.0 mmol) was coupled with furfurylaniline (132 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (8:1) as eluent afforded the desired product as a colorless oil (187 mg, 87% yield). Rf=0.5 (hexane/ethyl acetate=5:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50](O)[CH2:51][O:52]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([O:48][CH2:49][C@H:50]2[CH2:51][O:52]2)[C@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)COS(=O)(=O)c3ccc(C)cc3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3CO3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (j) the (3S,4R,5R)-3-[(2S)-2-hydroxy-3-(toluene-4-sulfonyloxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was treated with sodium hydroxide solution in dimethylsulfoxide to yield the (3R,4R,5S)-3-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as light yellow foam; MS: 715 (M+H)+.
Reaction SMILES: C(CC[O:5][P:6]([O-])([O-:8])=[O:7])#N.[N:10]([C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:14]1)=[N+:11]=[N-:12].C1(N=C=NC2CCCCC2)CCCCC1.O>N1C=CC=CC=1.[OH-].[K+]>[P:6]([O:19][CH2:18][C@H:17]1[O:16][C@@H:15]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:14][C@@H:13]1[N:10]=[N+:11]=[N-:12])([OH:8])([OH:7])=[O:5]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
A freshly prepared pyridinium salt of 2-cyanoethylphosphate (8.05 g, 23.64 mmol) was added to a solution of 3'-azido-2',3'-dideoxyuridine (2.50 g, 9.7 mmol) in dry pyridine (50ml) and evaporated to dryness at 30° C. The concentrated residue was dissolved in pyridine (50 ml) and the solution again evaporated to dryness. The process was repeated twice and then the residue obtained was dissolved in dry pyridine (50 ml). Dicyclohexylcarbodiimide (8.08 g, 39.1 mmol) was added to the solution. The reaction mixture was stirred for 48 hours at room temperature. Water (10 ml) was added and the solution was then filtered to remove dicyclohexylurea. The clear solution was evaporated to dryness. The residue obtained was then dissolved in 1N KOH (250 ml) and heated for 15 minutes at 100° C. The cold solution was passed through a column of acidic Dowex 50 (H+), the effluent brought to pH 9 and passed through a column of Dowex (1×4 Cl-). A linear gradient elution of 0.015N HCl to 0.15N HCl afforded 3'-azido-2',3'-dideoxyuridine-5'-monophosphate in 73% yield.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][NH2:13]>C1COCC1>[N:5]1[C:4]2[CH:8]=[N:9][CH:10]=[CH:11][C:3]=2[C:2]([NH:12][NH2:13])=[N:7][CH:6]=1
Reactant: Clc1ncnc2cnccc12
Reactant: NN
Solvent: C1CCOC1
Product: NNc1ncnc2cnccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
To a suspension of 4-Chloro-pyrido[3,4-d]pyrimidine (34)(1.65 g, 10 mmol) in anhydrous THF (10 ml) was added hydrazine (1M in THF, 30 ml, 30 mmol). The reaction mixture was stirred at room temperature for 5 hours whereupon a yellow precipitate formed. The solid was removed by filtration, washed with cold THF (10 ml) and dried to give the title compound (1.56 g, 96.9%) as the sole product which required no further purification. m/z (LC-MS, ESP): 162 [M+H]+, R/T=0.85 mins.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[CH:22]=[CH:21][C:13]=2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccc(F)cc3)c2)c1
Reaction time: 1 h

Procedure:
0.056 mL of triethylamine and 0.036 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate at room temperature sequentially and stirred at the same temperature for 1 hour. 0.014 mL of triethylamine and 0.012 mL of 4-fluorobenzoyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(4-fluorobenzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([O-])=O>[Ni].CCO.N.C(Cl)Cl>[CH:9]1[C:8]2[C:13](=[C:14]([NH2:16])[N:15]=[C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]3=2)[N:12]=[CH:11][CH:10]=1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Agent: [Ni]
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc2c(c1)nc(N)c1ncccc12
Reaction time: 8 h

Procedure:
A mixture of 8-nitrobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Raney Nickel (wet, 10% wt) in EtOH/ammonia (2:1) was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The insoluble solid was filtered off through celite, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was washed with 10% MeOH/DCM and 70% EtOAc/Hexanes to give benzo[f][1,7]naphthyridine-5,8-diamine as an off white solid: 1H NMR (methanol-d4): δ 8.97 (dd, 1H), 8.90 (dd, 1H), 8.41 (d, 1H), 7.83 (dd, 1H), 7.57 (d, 1H), 7.39 (dd, 1H), 3.96 (s, 2). LRMS [M+H]=229.1.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]1[CH2:10][S:9][C:8]2([CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)[S:7]1)(=[O:3])[CH3:2].Cl[CH2:22]C1CSC2(CCCC(CC(OCC)=O)C2)S1.C([O-])(=S)C.[K+]>CN(C=O)C>[C:1]([S:4][CH2:5][CH:6]1[CH2:10][S:9][C:8]2([CH2:14][CH2:13][CH2:22][CH:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)[S:7]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC1CCCC2(C1)SCC(CCl)S2
Reactant: CCOC(=O)CC1CCC2(C1)SCC(CSC(C)=O)S2
Agent: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCC2(C1)SCC(CSC(C)=O)S2

Procedure:
The titled compound was synthesized according to the procedure used for the synthesis of the thioacetate of Example F using the chloride of Example H derived from the less polar pair of racemates (0.62 g, 0.002 mole) and potassium thioacetate (917 mg) in DMF (15 ml). The crude product was chromatographed on silica gel using 10% ethyl acetate/hexane to give 0.57 g of the titled product (Product A.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[Br:16][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:15]
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=O)C(Br)CC2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A mixture of 500 mg. (2.4 mmol) 6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one was dissolved in anhydrous ethanol (10 ml) and Chloroform (10 ml). To this solution was added pyridinium tribromide (0.768 g, 2.4 mmol). The reddish brown mixture was heated with stirring at 50° C. for 20 min. The reaction mixture was then cooled and the solvent was evaporated. Then water (20 ml) was added to the residue and it was then extracted with 50 ml of dichloromethane. The dichloromethane layer was then washed with 10% sodium bicarbonate solution (50 ml) followed by water (50 ml). The organic layer was then dried and the solvent was evaporated in vacuum to yield the crude product, 2-bromo-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one which was purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:11]([NH2:25])=[N:12][CH:13]=[C:14]([B:16]4[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]4)[CH:15]=3)=[CH:7][C:6]=2[CH:26]=1.[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>C1COCC1>[NH2:25][C:11]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([CH3:36])[CH:28]=4)=[O:35])=[CH:26][C:6]=3[CH:7]=2)=[CH:15][C:14]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)=[CH:13][N:12]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4cc(N)ccc4s3)c2)OC1(C)C
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(B5OC(C)(C)C(C)(C)O5)cnc4N)cc3c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of 3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (734.6 mg, 2 mmol. 1 eq) in anhydrous THF (10 mL) at room temperature was added dropwise m-tolylisocyanate (0.251 mL, 1 eq). After the reaction was stirred at room temperature for 4 hours, it was partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium sulfate. The upper solution layer was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (DCM to MeOH-DCM 1:5). The products' fractions were collected, concentrated, the solid was triturated with EtOAc-Hex (1:7) yielding 1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-(3-methylphenyl)urea as a white powder upon filtration in amount of 407 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]#[N:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N+:9]2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.C(O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]#[N:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2[n+]([O-])n1-c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: ClP(Cl)Cl
Product: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Br)cc1
Temperature: 60 °C
Yield: 86.1 %

Procedure:
To a stirred solution of compound (v) (4.1 g, 0.010 mol) in chloroform (40 mL) was added phosphorus trichloride (4.1 mL, 0.047 mol) and the reaction mixture was heated to 60° C. for 1 h (monitored by TLC and LCMS). The reaction mixture was quenched in ice water and the product was extracted into DCM (2×80 mL). Concentration of solvent gave the crude product, to which was added ethanol and filtered to give 2-(4-bromophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carbonitrile (vi) (3.3 g, 84%).