Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:9].ClCl>O>[NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cl
Reactant: Cc1ccncc1N
Agent: ClCl
Solvent: O
Product: Cc1ccnc(Cl)c1N
Temperature: 20 °C
Reaction time: 0.42 h

Procedure:
3-Amino-4-methylpyridine (21.6g, 0.2 mole) was suspended in 75 ml of water at room temperature. The mixture was dissolved by the addition of 25 ml conc. hydrochloric acid. The solution was cooled to 20° C. and 15.6 g (0.22 mole) of chlorine gas was introduced through an inlet tube reaching below the surface of the reaction mixture over 25 minutes. The mixture was stirred under a nitrogen purge for an additional 30 minutes, then cooled to 10° C. and basified by the addition of 70 mL of a 12.5 N. sodium hydroxide solution. Additional water (100 mL) was added to maintain efficient agitation of the mixture. The precipitate was collected, washed with water and dried to give 14.5g of the title product. The aqueous phase was extracted with 3 times 100 mL of methylene chloride. The organic phases were washed with water, dried over magnesium sulfate, and concentrated to give an additional 9.4g, mp 62-64° C. Total yield, 23.9g (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[CH2:31][CH2:32]2)=[O:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Reactant: c1ccc(CN2CCNCC2)nc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(Cc3ccccn3)CC2)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.100 g (0.29 mmol) of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolved in 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 51 mg (0.29 mmol) of 1-Pyridin-2-ylmethyl-piperazine and 0.098 g (0.3 mmol) of TOTU. The solution was stirred for 1 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in DCM and the solution was washed three times with saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1), ethyl acetate, and ethyl acetate/MeOH (10/1).
Reaction SMILES: [Cl:1][C:2]1[C:9](Cl)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C)C=O>[Cl:1][C:2]1[C:9]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5]
Reactant: C1CCNC1
Reactant: N#Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c([N+](=O)[O-])ccc(N2CCCC2)c1Cl
Yield: 88.2 %

Procedure:
13.0 g of 2,3-dichloro-6-nitrobenzonitrile was dissolved in 50 ml of dimethylformamide, and 11.0 g of pyrrolidine was added to the solution, followed by stirring while externally cooling because of heat generation. After continuing the stirring for 30 minutes, the reaction mixture was poured into water. The precipitate thus formed was filtered, washed with water and then with methanol to obtain 13.3 g of 2-chloro-6-nitro-3-pyrrolidinobenzonitrile (melting point: 170°-173° C.).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20](/[C:23](=[CH:28]\[CH:29]=[CH:30]\[C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)/[C:24]([O:26][CH3:27])=[O:25])=[N+]=[N-]>C(OCC)C>[CH3:27][O:26][C:24]([C:23](=[CH:28][CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)[N:20]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:25]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)/C(=C/C=C/c1ccc(C(C)C)cc1)N=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(=CC=Cc1ccc(C(C)C)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following General Procedure J, triphenylphosphine (1.4 g, 5.2 mmol), methyl (2Z,4E)-2-azido-5-(4-isopropylphenyl)penta-2,4-dienoate (Compound 111, 1.4 g, 5.2 mmol) in diethyl ether (50 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]([CH3:35])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:36][N:37]1[C:41]([CH3:42])=[C:40](B(O)O)[CH:39]=[N:38]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([O:30][C@@H:24]([C:15]1[C:14]([CH3:35])=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:40]4[CH:39]=[N:38][N:37]([CH3:36])[C:41]=4[CH3:42])=[CH:3][CH:4]=3)[S:9][C:10]=2[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(Br)cc3)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1c(B(O)O)cnn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(-c4cnn(C)c4C)cc3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
(S)-ethyl 2-(2-(4-bromophenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50.0 mg, 0.087 mmol), 1,5-Dimethyl-1H-pyrazole-4-boronic acid, pinacol ester (24.7 mg, 0.105 mmol), tetrakis(triphenylphosphine)palladium(0) (15.1 mg, 0.013 mmol), and K2CO3 (36.2 mg, 0.262 mmol) were taken in a microwave vial, and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (0.8 mL) and degassed water (0.2 mL). The reaction mixture was stirred at 100° C. for 2.5 h, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+ calc'd for C33H35ClN3O3S (M+H+): 588.2; Found: 588.3 (M+H+).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][CH3:3].C([N-]C(C)C)(C)C.[Li+].CS(O[CH2:20][CH2:21][CH2:22][C:23]1([CH3:34])[CH:29]2[O:30][C:26]([CH2:31][CH2:32][OH:33])([CH2:27][CH2:28]2)[CH2:25][O:24]1)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[C:1]([CH:2]([CH3:3])[CH2:20][CH2:21][CH2:22][C:23]1([CH3:34])[CH:29]2[O:30][C:26]([CH2:31][CH2:32][OH:33])([CH2:27][CH2:28]2)[CH2:25][O:24]1)([O:5][CH3:6])=[O:4]
Reactant: CC1(CCCOS(C)(=O)=O)OCC2(CCO)CCC1O2
Reactant: CCC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CCCC1(C)OCC2(CCO)CCC1O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
Methyl-2-lithio propionate is generated from methyl propionate (176 mg, 2 mM) and lithium diisopropylamide (2 mM) in tetrahydrofuran (5 ml) under nitrogen in the usual manner. To this reagent, (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (258 mg, 0.84 mM) in tetrahydrofuran (5 ml) is slowly added at -78° C. and stirred for two hours. The resulting mixture is allowed to warm to room temperature and stirred for an additional hour. This mixture is then poured into saturated aqueous ammonium chloride solution (5 ml) and extracted with ether (5×10 ml). The combined organic layers are dried (Na2SO4), the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel (30 g) with ether-petroleum ether (4:1) to give (1RS,4SR,5RS)-4-(4-carbomethoxypentyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (71 mg, 30%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[C:20]([C@H:22]4[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]4)[CH:19]=[CH:18][C:17]=3[Cl:33])[CH:13]=[CH:14][C:7]=2[O:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[Cl:33][C:17]1[CH:18]=[CH:19][C:20]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]2)=[CH:21][C:16]=1[CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[O:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][NH:9][C:8]=2[CH:11]=1
Reactant: COC(=O)C1CNc2cc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)ccc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CNc2cc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
To a stirred solution of 6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid methyl ester (190 mg) in THF: Methanol:water (1:1:1 mixture, 1.5 mL) was added lithium hydroxide (17 mg). After stirring at room temperature overnight, the reaction mixture was concentrated, and the resulting residue was taken up in 50% methanol in ethyl acetate. The solution was filtered through a celite bed, and the filtrate was concentrated to a residue which was purified by preparative HPLC to furnish 6-[2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid (23 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH3:28][O:29][CH2:30][CH2:31][CH2:32][NH2:33].CCCP(=O)=O>O1CCCC1>[CH3:28][O:29][CH2:30][CH2:31][CH2:32][NH:33][C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: COCCCN
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: COCCCNC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 3-methoxypropan-1-amine (169 μl, 1.66 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4-(3-Methoxypropyl)-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (113 mg, 94.3%) as a white solid. mp.: 191-3° C. MS: m/z=434.4 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>C(C(C)=O)C>[OH:1][C:2]1[C:3]([C:12]([NH:14][N:15]=[C:2]([CH3:3])[CH2:11][CH3:10])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NNC(=O)c1cc2ccccc2cc1O
Solvent: CCC(C)=O
Product: CCC(C)=NNC(=O)c1cc2ccccc2cc1O
Temperature: 20 °C

Procedure:
A four neck flask (3 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 121.2 g (0.6 mol) of 3-hydroxy-2-naphthohydrazide and 2 liters of methyl ethyl ketone and then heated under refluxing for 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby the intended compound (slightly yellow crystal) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:16]C.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[OH:16][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COc1cc(C(=O)c2ccccc2)ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)c2ccccc2)cc1O
Temperature: 25 °C
Yield: 66.1 %

Procedure:
Compound 39 (5 g, 22.1 mmol) was combined with AlCl3 (9 g, 66.3 mmol) and anhydrous toluene (50 mL) in a 200 mL round bottom flask. The stirring mixture was refluxed for 1 h under nitrogen then cooled to ambient temperature and quenched with 1 N aqueous HCl (50 mL). The reaction was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (MgSO4), filtered, and the solvents removed in vacuuo. The resulting residue was treated with 10% EtOAc/hexanes at which time a solid precipitated from the solvent. The solid was filtered and dried in vacuuo for 4 h to give 3.1 g (70%) of compound 40 as an ash solid. 1H NMR (400 MHz, CDCl3): δ 2.13 (s, 3H), 7.10-7.62 (m, 6H), 7.64-7.72 (m, 2H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:43])([F:42])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1.Cl>CO>[F:42][C:4]([F:3])([F:43])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 63.9 %

Procedure:
1N Sodium hydroxide (13 ml) was added to a solution of ethyl 3-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]propionate (3.69 g) in methanol (50 ml), and the mixture was refluxed for 5.5 hr. The reaction mixture was neutralized with 1N hydrochloric acid and concentrated. The precipitated crystals were filtered, washed with water and recrystallized from ethyl acetate-methanol-hexane to give the titled compound (2.24 g) as a colorless crystal powder.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([OH:15])[CH:9]=[N+:8]2[O-].[OH-].[K+]>>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([OH:15])[CH:9]=[N:8]2
Reactant: [O-][n+]1cc(O)nc2ccc(Cl)cc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1cnc2cc(Cl)ccc2n1
Reaction time: 5 h
Yield: 95.6 %

Procedure:
The treated catalyst (I) (containing 0.3 g of metallic nickel) and 4.0 g of a 80% aqueous hydrazine hydrate solution were added dropwise to 240 g of an aqueous solution containing 19.7 g of 6-chloro-2-quinoxalinol-4-oxide and 28 g of potassium hydroxide at 40° to 50° C., and the reaction was carried out at 40° to 80° C. for 5 hr. After the catalyst was removed, the filtrate was acidified to give 17.3 g (yield 96%) of 6-chloro-2-quinoxalinol.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of ethyl 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate (0.90 g) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.06 g) at 0° C. and the mixture was stirred at room temperature for 3 hrs. Sodium sulfate decahydrate (0.51 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, the precipitate was filtered off and the filtrate was concentrated. The obtained crystals were collected by filtration to give [1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazol-4-yl]methanol (0.63 g, yield 77%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 90-91° C.
Reaction SMILES: ClC1C=C(CC(=O)CC2C=CC=C(Cl)C=2)C=CC=1.C(OCC)=O.Cl.CN.[Cl:27][C:28]1[CH:29]=[C:30]([C:34]2[C:39](=[O:40])[C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=3)=[CH:37][N:36]([CH3:48])[CH:35]=2)[CH:31]=[CH:32][CH:33]=1.N1C=CC=CC1=O>>[Cl:47][C:43]1[CH:42]=[C:41]([CH:38]2[C:39](=[O:40])[CH:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)[CH2:35][N:36]([CH3:48])[CH2:37]2)[CH:46]=[CH:45][CH:44]=1
Reactant: Cn1cc(-c2cccc(Cl)c2)c(=O)c(-c2cccc(Cl)c2)c1
Agent: CN
Agent: Cl
Agent: O=C(Cc1cccc(Cl)c1)Cc1cccc(Cl)c1
Solvent: CCOC=O
Product: CN1CC(c2cccc(Cl)c2)C(=O)C(c2cccc(Cl)c2)C1

Procedure:
A 10 g. portion of 1,3-bis(3-chlorophenyl)-2-propanone was reacted with ethyl formate and methylamine hydrochloride to produce 7 g. of 3,5-bis(3-chlorophenyl)-1-methyl-4(1H)-pyridinone. A 6.4 g. portion of the pyridinone was reduced with 2 g. of lithium aluminum hydride and the products were separated by chromatography as described in the examples above. The yields were about 0.8 g. of Example 11, and 1.5 g. of Example 12. Example 11, m.p. 140°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[C:30]([CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[CH:27]=[CH:28][CH:29]=[C:30]([CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(C=O)cccc1CN1CCOCC1
Product: COc1c(CN2CCOCC2)cccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 70 %

Procedure:
In a similar fashion as for the synthesis of III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-methoxy-3-morpholin-4-ylmethylbenzaldehyde were reacted to produce the title compound (70%). Mp. 133-7° C. 1H NMR (d-chloroform): 12.03 (br s, 1H), 8.18 (d, J=7 Hz, 1H), 8.13 (s, 1H), 7.56 (d, J=7 Hz, 1H), 7.29 (t, J=8 Hz, 1H), 6.37 (m, 2H), 6.29 (s, 1H), 5.82 (d, J=7 Hz, 1H), 5.41 (s, 1H), 5.25 (t, J=7 Hz, 1H), 3.83 (s, 3H), 3.75 (m, 4H), 3.67 (s, 2H), 3.17 (s, 1H), 2.94 (s, 1H), 2.83 (d, J=7 Hz, 1H), 2.58 (m, 4H), 2.36 (d, J=7 Hz, 1H). MS: 509.2 (M+H). HPLC retention time: 1.71 minutes (G Method).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17](I)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([O:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[O:15][CH3:16])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Reactant: CCCCI
Product: CCCCOc1ccc(/C=C/C(=O)OCC)cc1OC
Yield: 83.9 %

Procedure:
Following a procedure similar to that described in Preparation 116, but using 6.66 g of ethyl (E)-4-hydroxy-3-methoxycinnamate and 6.62 g of butyl iodide, 7.00 g of the title compound were obtained as a solid material.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[S:22](Cl)(=[O:24])=[O:23])[C:18](=[O:26])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:16]=[C:15]3[Cl:36])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[NH3:37]>C1COCC1>[Cl:36][C:15]1[C:14]2[C:19](=[CH:20][C:21]([S:22](=[O:24])(=[O:23])[NH2:37])=[C:12]([O:11][C@@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]3)[CH:13]=2)[C:18](=[O:26])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:16]=1
Reactant: N
Reactant: COc1ccc(Cn2cc(Cl)c3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(S(=O)(=O)Cl)cc3c2=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(Cl)c3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(S(N)(=O)=O)cc3c2=O)cc1

Procedure:
To a solution of 29 mg of 6-(4-acetylamino-cis-cyclohexyloxy)-4-chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinoline-7-sulfonyl chloride (129, crude product) in 2 ml of THF 2 ml of 33% aqueous ammonia solution were added. After 1 h at room temperature the solvent was removed under reduced pressure and the crude product was used without further purification. Rt=1.22 min (Method C). Detected mass: 534.5 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17]Cl)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][SH:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17][S:29][CH2:28][CH2:27][NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: CC(C)(C)OC(=O)NCCNc1nc(CCl)cs1
Product: CC(C)(C)OC(=O)NCCNc1nc(CSCCNC(=O)OC(C)(C)C)cs1

Procedure:
2-(2-t-butyloxycarbonylaminoethylamino)-4-chloromethyl-1,3-thiazole was reacted with 2-t-butyloxycarbonylaminoethanethiol in a manner similar to that described in Example 42. 1H NMR (CDCl3) δ 1.50 (s, 18H), 2.80 (m, 2H), 3.30-3.60 (m, 6H), 3.72 (s, 2H), 5.10 (br s, 1H), 5.40 (br s, 1H), 6.38 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH2:15])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[C:19]2[S:26][CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1.CCN(C(C)C)C(C)C>CN(C)C=O.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][C:18]2[C:19]3[S:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCN)s1
Reactant: Clc1ncnc2ccsc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(CCNc2ncnc3ccsc23)s1

Procedure:
[5-(2-Amino-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (compound 14.1; 20.5 mmol), compound 6.2 (0.94 equivalent) and DIEA (1.0 equivalent) was heated in N,N-dimethylformamide (“DMF”; 75 mL) at 90° C. for 1.5 hours. The reaction mixture was cooled and diluted with EtOAc and water. The organic layer was separated, washed with brine, dried, concentrated and purified by flash column chromatography on silica gel to provide {5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (compound 14.2) in 75% yield.