Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:25][N:26](C)CCN(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CS(C)=O.CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)#[N:26]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Br)cc3cccnc23)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccnc23)C1
Temperature: 160 °C
Yield: 74.9 %

Procedure:
A solution of (S)-tert-butyl 3-((6-bromo-1,7-naphthyridin-8-yl)oxy)pyrrolidine-1-carboxylate (1400 mg, 3.55 mmol), zinc cyanide (834 mg, 7.1 mmol) and N1,N1,N2,N2-tetramethylethane-1,2-diamine (0.106 mL, 0.71 mmol) in DMSO (9 mL) was degassed with nitrogen for 5 minutes. Xantphos (206 mg, 0.355 mmol) and Pd2(dba)3 (325 mg, 0.355 mmol) were added and the mixture was heated in a microwave reactor at 160° C. for 15 minutes. The reaction mixture was diluted with EtOAc and washed with water (2×). The organic layer was separated and concentrated in vacuo. The crude product was purified by silica column chromatography to give the title compound as a yellow solid (181 mg, 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1C.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1COCC1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccccc1N=C=O
Reactant: CCOC(=O)Cc1ccc(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2OC)cc1
Reaction time: 23 h
Yield: 100.8 %

Procedure:
To a stirred solution of ethyl 4-amino-3-methylphenylacetate (1.32 g, 7.37 mmol) and triethylamine (205 ml, 1.47 mmol) in THF (20 ml) was added 2-methoxyphenyl isocyanate (980 ml, 7.37 mmol), and the resulting mixture was stirred for 23 h. The mixture was concentrated to a small volume in vacuo and hexane was added to the residue to give precipitate, which was collected to give ethyl 4-[N′-(2-methoxyphenyl)ureido]phenylacetate (2.44 g, quant.) as a white crystalline material. mp 107–109° C.; 1H-NMR (CDCl3) δ 1.26 (t, J=7.1 Hz, 3 H), 3.56 (s, 3 H), 3.79 (s, 3 H), 4.15 (q, J=7.1 Hz, 2 H), 6.82–6.85 (m, 1 H), 6.91–7.00 (m, 2 H), 7.08 (s, 1 H), 7.17 (d, J=8.5 Hz, 2 H), 7.27 (d, J=8.6 Hz, 2 H), 7.33 (s, 1 H), 8.07–8.10 (m, 1 H); MS (ESI) m/z 329 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: BrCCOc1ccccc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCOc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 4-nitro-1H-pyrazole (220 mg, 1.95 mmol) in acetonitrile (10 mL), Cs2CO3 (697 mg, 2.14 mmol) and (2-bromoethoxy)benzene (439 mg, 2.14 mmol) was added. The resulting mixture was refluxed (80° C.) for 40 min and then let stir at rt overnight. The reaction mixture was filtered, the filter cake washed with DCM and the filtrate concentrated in vacuo to obtain 4-nitro-1-(2-phenoxyethyl)-1H-pyrazole as a crude solid which was used without further purification. LC-MS conditions A: tR=0.85 min, [M+H]+=no ionization.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:14]2[CH:19]=[C:18]([CH:20]=O)[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:14]2[CH:19]=[C:18]([CH2:20][N:8]([CH3:9])[CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[S:17][C:15]=2[N:16]=1
Reactant: CNC1CCN(C)CC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
1-Methyl-4-(methylamino)-piperidine was reacted with 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde via General Procedure B-3. Purification on silica yielded (2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-yl)-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:29].N>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=[O:29]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN1CCCC1
Agent: N
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCCC1
Yield: 61.1 %

Procedure:
A solution of 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (524 mg, 1.3 mmol) in methanol saturated with ammonia (10 ml) was stirred for 20 hours at ambient temperature. The volatiles were removed by evaporation and the solid residue was triturated with ether, collected by filtration and dried under vacuum to give 6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (230 mg, 61%).
Reaction SMILES: [C:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:9]([O:13][C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]1([CH2:7][N:19]2[CH2:20][CH2:21][C@H:17]([NH:16][C:14](=[O:15])[O:13][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:18]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=CC1=CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CC2=CCCCC2)C1
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
1-Cyclohexene-1-carboxaldehyde (1.48 ml, 13 mmol) was added to a mixture of (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (2.0 g, 10.8 mmol), acetic acid (1.24 ml, 21.6 mmol) and tetrahydrofuran (dehydrated) (27 ml), followed by stirring at mom temperature for 15 minutes, and sodium triacetoxyborohydride (4.58 g, 21.6 mmol) was then added and the reaction mixture was stirred at mom temperature for 17 hours and 45 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (1.3 g, yield: 42.9%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:24]([O:28][C:29]([C:30]1[O:17][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=[CH:15][C:12]=2[CH:13]=1)=[O:32])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 140 °C
Yield: 71.8 %

Procedure:
To a solution of 4-benzyloxy-2-hydroxy-benzaldehyde (5.56 g, 24.4 mmol) in DMF (20 mL) is added K2CO3 (6.73 g, 48.8 mmol), bromo-acetic acid tert-butyl ester (4.75 g, 24.4 mmol), and DBU (1.0 mL). The mixture is heated to 140° C. for 2 hours and cooled to room temperature. The mixture is quenched with water (200 mL) and extracted with EtOAc (100 mL). The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography cluting with 15% EtOAc/Hexanes to provide the title compound (5.68 g, 72%). LC-ES/MS m/e 269.0 (acid, M+1)
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21]CC)=[O:20])=[CH:11][N:12]3CCC#N)=[CH:7][C:6]=2[Cl:25])[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([OH:21])=[O:20])=[CH:11][NH:12]3)=[CH:7][C:6]=2[Cl:25])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(Cl)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2nc(N3CCC3)c(Cl)cc2c1=O
Reaction time: 3 h

Procedure:
A suspension of EXAMPLE 81D (0.50 g) in methanol (100 mL) at reflux was treated with a 1M LiOH (50 mL), stirred for 3 hours then cooled, treated with 10% citric acid, and filtered. NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.13 (s, 1H), 4.28 (m, 4H), 2.28 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=3)[CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=3)[CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(CCc2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(-c3cccc(CCc4ccc(C(=O)O)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a stirred solution of methyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenethyl)benzoate (70 mg, 0.13 mmol) in 3 mL of 1,4-dioxane and 3 mL of H2O was added NaOH (140 mg, 3.5 mmol) at room temperature. Then the reaction was stirred at room temperature overnight and then treated with conc. HCl until pH=3-4. The solvent was removed under reduced pressure, the residue was triturated with H2O (3×10 mL) and ethyl acetate (3×10 mL) then dried to give 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenethyl)benzoic acid (35 mg, 51%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.13 (s, 1H), 9.39 (s, 1H), 8.32-8.24 (m, 2H), 7.89-7.84 (m, 3H), 7.52-7.40 (m, 5H), 7.03 (d, 1H, J=8.7 Hz), 3.84 (s, 3H), 3.79 (s, 3H), 3.37 (brs, 4H). LC-MS: 513 [M+H]+, tR=1.67 min. HPLC: 97.30% at 214 nm, 97.09% at 254 nm, tR=5.16 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[NH2:10])([O-])=O>CCO>[N:6]1[CH:7]=[C:8]([NH2:11])[C:9]([NH2:10])=[C:4]([NH2:1])[CH:5]=1
Reactant: Nc1c([N+](=O)[O-])cncc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1cncc(N)c1N
Reaction time: 18 h

Procedure:
3,5-Dinitro-pyridin-4-ylamine 2 (5.00 g, 27 mmol) was suspended in EtOH (80 ml). The flask was evacuated and then purged with a nitrogen atmosphere. To this flask, Pt/C (500 mg of 10%) was added. The flask was re-evacuated, and then placed under a hydrogen atmosphere (40 psi) on a Parr hydrogenator. It was allowed to shake for 18 hours, and was judged complete by TLC. The platinum catalyst was removed by CELITE filtration, and the solvent was removed by evaporation under a reduced atmosphere to yield the title product 3, a brown solid (3.24 g (97%), 27 mmol). 1H NMR (20): δ 7.51 (s, 2H). MS (ESI-POS): [M+H]+=125.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C@H:44]3[CH2:49][CH2:48][C@H:47]([CH2:50][CH2:51][CH:52]=O)[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)=[O:31].O>C1COCC1>[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:39][CH2:40][C@H:41]([C@H:44]3[CH2:45][CH2:46][C@H:47]([CH2:50][CH2:51][CH:52]=[CH2:2])[CH2:48][CH2:49]3)[CH2:42][CH2:43]2)[CH2:34][CH2:33]1)=[O:31]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](CCC=O)CC3)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](C(=O)OC)CC3)CC2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 130 g (322 mmol) of methyltriphenylphosphonium iodide and 1.3 liters of THF was cooled to -50° C. To this mixture was added 33.4 g (110 mmol) of t-BuOK and the resulting mixture was stirred for one hour. To this mixture was added dropwise, while maintaining a temperature at below -50° C., a solution of 90.0 g (248 mmol) of crude trans-4-(trans-4-(trans-4-(2-formylethyl)-cyclohexyl)cyclohexyl)cyclohexane carboxylic acid methyl ester in 900 ml of THF. After the dropwise addition, the temperature of the reaction solution was gradually allowed to rise up to room temperature and the mixture was stirred for further 5 hours. After the reaction was completed by adding 500 ml of water, the reaction mixture was filtered through Celite, the solvent was distilled off under reduced pressure and the filtrate was extracted with 1.0 liter of toluene. The organic layer was washed three times with 500 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to a silica gel column chromatography (a developing solvent: toluene) to give 40.0 g of crude trans-4-(trans-4-(trans-4-(3-butenyl)cyclohexyl)cyclohexyl)-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-].[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C(Cl)Cl.FC1C(F)=C(F)C=CC=1>[Br:1][C:2]1[N:3]=[C:4]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: Cc1ccc(Br)[n+]([O-])c1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Fc1cccc(F)c1F
Solvent: ClCCl
Product: Cc1ccc(Br)nc1NC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 19.4 %

Procedure:
To a solution of 2-bromo-5-methylpyridine 1-oxide (2.0 g, 10.6 mmol) in DCM (40 mL) and trifluorobenzene (17 mL) at 0° C. were added tert-butylamine (8.0 mL, 76.7 mmol) and p-toluenesulfonic anhydride (11.4 g, 35.0 mmol) portion-wise. The reaction mixture was stirred at 0° C. for 1.5 hours and then filtered. The filtrate was concentrated to give a residue that was purified by flash chromatography (Si—PPC, Et2O:pentane, gradient 0:100 to 100:0) to give (6-Bromo-3-methylpyridin-2-yl)-tert-butylamine as a colourless oil (500 mg, 19%). 1H NMR (400 MHz, CHCl3-d): δ 6.98 (d, J=7.5 Hz, 1 H); 6.59 (d, J=7.5 Hz, 1 H); 4.05 (s, 1 H); 1.96 (s, 3 H); 1.47 (s, 9 H).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]3[NH:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].CO>CN(C)C=O.O>[O:1]([C:8]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]3[NH:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: OCc1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of 2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (173 mg) in N,N-dimethylformamide (5 mL) was added 1,1′-carbonyldiimidazole (97 mg) and the mixture was stirred at room temperature for 1 hr. Sodium borohydride (38 mg) was added to the reaction mixture at room temperature, and methanol (1 mL) was added dropwise. After stirring overnight at room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→20:80) and crystallized from methanol-ethyl acetate, to give the title compound (44 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([C:11](=O)[NH2:12])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:27][C:28]1[CH:29]=[C:30]([NH:35][C:36]2[CH:37]=[N:38][CH:39]=[C:40]([F:42])[CH:41]=2)[C:31](N)=[CH:32][CH:33]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([C:11]1[N:35]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([F:42])[CH:41]=2)[C:30]2[CH:29]=[C:28]([F:27])[CH:33]=[CH:32][C:31]=2[N:12]=1)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cc1Nc1cncc(F)c1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
To a suspension of ((S)-1-carbamoylpropyl)carbamic acid tert-butyl ester (250 mg, 1.24 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (228 mg, 1.20 mmol) and the reaction mixture stirred at RT for 1.5 h under argon. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (3 mL). 4-Fluoro-N2-(5-fluoropyridin-3-yl)benzene-1,2-diamine (88 mg, 0.40 mmol) was added and the reaction mixture heated at 60° C. for 20 min. The reaction mixture was concentrated in vacuo, and the residue partitioned between DCM and sat. NaHCO3. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a white foam (128 mg, 82%). LCMS (Method J): RT=3.42 min, [M+H]+=389.
Reaction SMILES: C[Si]([CH2:5][C:6]([O:8]CC)=[O:7])(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:41]=[CH:40][C:26]([CH2:27][O:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[C:35](=O)[CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=1>C1COCC1>[CH3:21][O:22][C:23]1[CH:41]=[CH:40][C:26]([CH2:27][O:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)/[C:35](=[CH:5]/[C:6]([OH:8])=[O:7])/[CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: COc1ccc(COc2ccc3c(c2)CCCC3=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc3c(c2)CCC/C3=C\C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl (trimethylsilyl)acetate (12.07 g, 75 mmol) in anhydrous THF (60 mL) at −78° C. was treated dropwise with LiHMDS (1M in THF, 66 mL). The resulting mixture was stirred at −78° C. for 30 minutes. A solution of 52.3 (14.0 g, 50 mmol) in THF (10 mL) was added to the mixture over 20 minutes. The resulting mixture was stirred at −78° C. for 2 hours before warming to 0° C. The reaction mixture was quenched with NH4Cl (sat. 200 mL) and extracted with ethyl acetate (70 mL×4). The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate in Hexane). [6-(4-Methoxy-benzyloxy)-3,4-dihydro-2H-naphthalen-(1E)-ylidene]-acetic acid (52.4) was obtained as a light yellow oil (12.2 g, 69% yield). MS ESI (pos.) m/e: 353 (M+1)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35](=[N:37]O)[NH2:36]>>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35]1[N:37]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([N:4]3[CH2:5][CH:2]([OH:1])[CH2:3]3)=[O:7])[CH2:9]2)[O:26][N:36]=1
Reactant: NC(=NO)c1ccc(F)cc1F
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3F)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 47.3 (0.266 mmol) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 35.2 mg (27% of theory).
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[O:41][CH:40]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([N+:51]([O-])=O)[CH:46]=2)[CH2:39][CH2:38]3)=[N:32][CH:33]=1)([O-])=O>[Zn]>[NH2:51][C:47]1[CH:46]=[C:45]([CH:40]2[CH2:39][CH2:38][C:37]3[C:42](=[CH:43][CH:44]=[C:35]([O:34][C:31]4[N:32]=[CH:33][C:28]([NH2:25])=[CH:29][CH:30]=4)[CH:36]=3)[O:41]2)[CH:50]=[CH:49][CH:48]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc([N+](=O)[O-])c2)O3)nc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: [Zn]
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(N)c2)O3)nc1

Procedure:
6-[2-(3-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 using 150 mg 5-nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine (Example 92(d)) and 997 mg of Zn. 1H NMR (300 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 2.8 Hz), 7.05 (dd, 1H, J 8.6, 2.8 Hz), 7.01 (t, 1H, J 15.4, 7.7 Hz), 6.70-6.78 (m, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.63 (s, 1H), 6.54 (d, 1H, J 7.7 Hz), 6.50 (d, 1H, J 8.6 Hz), 5.06 (s, 2H), 4.98 (s, 2H), 4.90 (dd, 1H, J 10.0, 2.2 Hz), 2.85-2.96 (m, 1H), 2.62-2.74 (m, 1H), 2.05-2.11 (m, 1H), 1.89-1.95 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C@@H:9]([C:14]([OH:16])=O)[CH2:8][CH2:7]2)([O-:3])=[O:2].[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[OH:20].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:20][C@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][NH:17][C:14]([C@H:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[O:10]1)=[O:16]
Reactant: NC[C@H](O)c1cccnc1
Reactant: O=C(O)[C@H]1CCc2cc([N+](=O)[O-])ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC[C@H](O)c1cccnc1)[C@H]1CCc2cc([N+](=O)[O-])ccc2O1
Reaction time: 18 h

Procedure:
(2R)-6-Nitro-3,4-dihydro-2H-chromene-2-carboxylic acid (4.1 g, 18 mmol) and (1R)-2-amino-1-(3-pyridinyl)ethanol (5.0 g, 24 mmol) (both described in U.S. Pat. No. 6,051,586) were suspended in CH2Cl2 and stirred vigorously. Triethylamine (9.2 mL, 66 mmol) was added followed by hydroxybenzotriazole (4.9 g, 36 mmol) and EDCI (6.9 g, 36 mmol), and the reaction was stirred overnight. After 18 hours, TLC showed no remaining acid starting material, so the reaction was partitioned between water and CH2Cl2 and the organic layer was washed 3×100 mL of water. The organic layer was washed with 1N HCl, which removed the product into the aqueous layer. This aqueous layer was washed with CH2Cl2 and the organic was discarded. The aqueous solution was then basified and became cloudy with a white precipitate. The basified mixture was extracted with 3×100 mL of CH2Cl2.