Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[N:9][S:10][C:6]=2[C:5]=1[C:13](OC)=[O:14].CC(C)=O.Cl>O.O1CCCC1>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[N:9][S:10][C:6]=2[C:5]=1[CH2:13][OH:14]
Reactant: COC(=O)c1c(Cl)ccc2nnsc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: OCc1c(Cl)ccc2nnsc12
Reaction time: 8 h

Procedure:
To a suspension of 4.5 g of sodium borohydride in 30 ml of water and 70 ml of tetrahydrofuran there are added dropwise with stirring and heating to 40°-50° C. in the course of haft an hour a solution of 1.9 g of 6-chloro-7-carbomethoxybenzo-1,2,3-thiadiazole in 30 ml of tetrahydrofuran (dissolved under hot conditions). Heating of the mixture is continued until the reaction is complete, and the mixture is then cooled to -20° to -30° C. using a CO2 cooling bath and treated dropwise with 15 ml of acetone, during which process gas is evolved vigorously. The reaction mixture is subsequently brought to pH 3 using 15% hydrochloric acid, with further vigorous cooling at -20° to -10° C. (evolution of gas), and stirring is continued overnight. Most of the tetrahydrofuran is then evaporated on a rotary evaporator, and the residue is extracted using ethyl acetate. The extracts are washed with water, dried over sodium sulfate and evaporated. The residue gives the title compound of m.p. 138°-140° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[NH:13]C(=O)C)([O-:3])=[O:2]>Cl.O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[NH2:13])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: Cl
Solvent: O
Product: Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 100 °C
Yield: 94.7 %

Procedure:
A suspension of N-(6-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (0.90 g, 4.09 mmol) in 5 M HCl was heated at 100° C. for 16 h. The suspension was cooled to 20° C., diluted with water (100 mL), filtered, washed with water (3×15 mL) and dried to give 6-nitro-5-indanamine 2 (0.69 g, 95%) as an orange solid: 1H NMR δ 7.93 (s, 1H, H-7), 6.64 (s, 1H, H-4), 5.99 (br s, 2H, NH2), 2.79-2.88 (m, 4H, H-1, H-3), 2.02-2.10 (m, 2H, H-2); 13C NMR δ 154.3, 144.2, 134.0, 131.3, 120.8, 113.5, 33.0, 31.4, 25.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:17][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Yield: 83.7 %

Procedure:
To a room temperature solution of piperidine-1,3-dicarboxylic acid-1-tert-butyl ester (5.00 g, 21.81 mmol) in 20% MeOH/toluene (100 ml) was added 14.18 ml of (trimethylsilyl)diazomethane (2.0 M, 28.35 mmol) dropwise and the reaction was monitored by TLC until completion and then concentrated under reduced pressure to yield 4.44 g (83.7%) of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester-3-methyl ester (Intermediate 53). 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (s, 9 H), 1.6 (d, J=3.4 Hz, 1 H), 1.6 (m, 1 H), 1.7 (m, 1 H), 2.0 (m, 1 H), 2.4 (m, 1 H), 2.8 (m, 1 H), 3.0 (s, 1 H), 3.7 (s, 3 H), 3.9 (d, J13.2 Hz, 1 H), 4.1 (s, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](I)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([C:42]#[N:43])(CCCC)CCCC)CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:42]#[N:43])[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Yield: 44.3 %

Procedure:
(1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine (3.58 g) in dioxane (30 ml) under N2 was treated with tributyltin cyanide (2.51 g) and catalytic quantities of 1.4-bis-(diphenylphosphino)-butane palladium (II) chloride and tetrakis (triphenylphosphine) palladium at reflux for 5 days. The mixture was absorbed onto silica and chromatographed to give the title compound (1.25 g); δH [2H6]DMSO 10.20(1H, s), 9.15(1H, s), 8.65(1H, s), 8.24(1H, s), 8.18(2H, m), 7.89(1H, s), 7.70(2H, m), 7.30(5H, m), 5.70(2H, s); m/z (M+1)+ 377.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[CH3:19][CH:20]([NH2:35])[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[O:22][N+:23]([O-:25])=[O:24].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:35][CH:20]([CH3:19])[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[O:22][N+:23]([O-:25])=[O:24])#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: CC(N)C(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: CC(N=C(NC#N)c1ccncc1)C(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
Isopropyl N cyano-4-pyridinecarboximidate (0.31 g, 1.6 mmol) was dissolved in methanol (15 ml), and 1-methyl- 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.50 g, 1.8 mmol) and sodium methoxide (0.09 g, 1.7 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (60:1). The eluted fractions were concentrated under reduced pressure and crystallized from diethyl ether to give the title compound (0.03 g, 0.08 mmol, yield 5%) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[CH2:12]([NH:15][CH2:16][CH:17]=[O:18])[C:13]#[CH:14]>C(OCC)(=O)C>[CH2:12]([N:15]([CH2:16][CH:17]=[O:18])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11])[C:13]#[CH:14]
Reactant: O=C=Nc1nnc(C2CC2)s1
Reactant: C#CCNCC=O
Solvent: CCOC(C)=O
Product: C#CCN(CC=O)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (7 grams), the dimethyl acetal of 2-propargylaminoacetaldehyde (5 grams) and ethyl acetate (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the mixture is stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:26])[CH2:5][CH2:4]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[O:26]=[C:6]1[CH2:5][CH2:4][C@@:3]2([CH:2]=[O:1])[C:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[O:21][C:22](=[O:25])[CH2:23][CH3:24])=[CH:7]1
Reactant: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@]12C

Procedure:
To a solution of 14 g of 19-hydroxy-17β-(1-oxopropoxy)androst-4-en-3-one in 1 liter of acetone cooled in an ice bath is added 13.3 ml of Jones reagent over 1 hour after which the reaction mixture is poured into a large volume of water and extracted with ether. The ether extract is dried over magnesium sulfate, filtered and the solvent removed. The residue is crystallized from acetone-hexane to give 3-oxo-17β(1-oxopropoxy)-androst-4-en-19-al, M.P. 119°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([C@H:16]([CH3:29])[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[N:19]([CH2:27][CH3:28])[CH:18]=1)[NH:5]C(OCC1C=CC=CC=1)=O>CO>[CH3:1][O:2][C:3](=[O:30])[C@@H:4]([C@H:16]([CH3:29])[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[N:19]([CH2:27][CH3:28])[CH:18]=1)[NH2:5]
Reactant: CCn1cc([C@@H](C)[C@@H](NC(=O)OCc2ccccc2)C(=O)OC)c2cc(Cl)ccc21
Solvent: CO
Product: CCn1cc([C@@H](C)[C@@H](N)C(=O)OC)c2cc(Cl)ccc21
Yield: 85.5 %

Procedure:
A solution of (αR,βR)-Nα -Benzyloxycarbonyl-5-chloro-1-ethyl-β-methyltryptophan methyl ester (4.17 g) in methanol (100 ml) containing 10% paradium on charcoal (0.5 g) was hydrogenated. After removal of the catalyst and evaporation of the solvent, (αR,βR)-5-chloro-1-ethyl-β-methyltryptophan methyl ester (2.45 g) was obtained as a yellow amorphous powder.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:23][O:24][CH2:25][CH2:26][OH:27].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:23][O:24][CH2:25][CH2:26][OH:27])=[O:7]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F

Procedure:
3,4-Difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]benzoic acid was dissolved in MeOH and prepared from reaction with 2(aminooxy)ethanol and DMT-MM by the general procedure of Example 6, Step B, affording a crude yellow oil after workup which was purified by filtration through a plug of silica gel (100% EtOAc as eluant). 3,4-Difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]-N-(2-hydroxyethoxy)benzamide was isolated as a viscous, transparent oil (57%). 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (v br s, 1 H), 8.77 (br s, 1 H), 7.44–7.37 (m, 1 H), 7.15–7.05 (m, 1 H), 7.06 (dd, J=12.5, 1.7 Hz, 1 H), 6.90 (dd, J=8.2, 1.7 Hz, 1 H), 6.81 (ddd, J=8.8, 8.8, 4.5 Hz, 1 H), 4.75 (br s, 1 H), 4.63 (t, J=5.2 Hz, 1H), 3.86 (t, J=5.0 Hz, 2 H), 3.61–3.52 (m, 4 H), 2.66 (t, J=6.9 Hz, 2 H). HRMS (EI+) calcd. for C20H16F2N2O3 370.1129 (M+), found 370.1133.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1.[N+:12]([O-])([OH:14])=[O:13].C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
A solution of 4-iodobenzoic acid methyl ester (5.24 g, 20.0 mmol) in sulfuric acid was treated with 1.43 mL of concentrated nitric acid in a dropwise fashion at 0° C. After 5 hours at room temperature, the reaction mixture was heated to 40° C. for 1 hour. The resulting orange solution was added to 100 g of ice, treated with 200 mL of ethyl acetate, shaken for 30 minutes, and filtered. The phases were separated and the aqueous layer was extracted with 200 mL of ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was passed through a column of silica gel (100% ethyl acetate) to give 2.0 g of 4-iodo-3-nitrobenzoic acid methyl ester as a yellow solid (33% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH3:24])[C:20]=1[C:21]([NH2:23])=[O:22]>>[CH3:24][C:19]1[C:20]([C:21]([NH2:23])=[O:22])=[C:16]([NH:15][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[N:4]=[CH:3][CH:2]=[N:1]3)[S:17][CH:18]=1
Reactant: Cc1csc(N)c1C(N)=O
Reactant: O=C(O)Cc1cccc2nccnc12
Product: Cc1csc(NC(=O)Cc2cccc3nccnc23)c1C(N)=O

Procedure:
The title compound was prepared from 2-(quinoxalin-5-yl)acetic acid and 2-amino-4-methylthiophene-3-carboxamide using protocol B. Method[1], MS(ESI) 327.0 [M+H], Retention time=1.644 min.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[O:8][C:7]([C:9]2[CH:14]=[C:13]([N:15]([CH3:21])[CH2:16][CH:17]3[CH2:19][CH:18]3[CH3:20])[N:12]=[C:11]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:10]=2)=[N:6][N:5]=1)[CH3:3].[C:28](=N)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.O.CCOC(C)=O>[C:29]1([C:28](=[N:1][CH:2]([C:4]2[O:8][C:7]([C:9]3[CH:14]=[C:13]([N:15]([CH3:21])[CH2:16][CH:17]4[CH2:19][CH:18]4[CH3:20])[N:12]=[C:11]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[CH:10]=3)=[N:6][N:5]=2)[CH3:3])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(N)c1nnc(-c2cc(N(C)CC3CC3C)nc(N(C)S(C)(=O)=O)c2)o1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(N=C(c1ccccc1)c1ccccc1)c1nnc(-c2cc(N(C)CC3CC3C)nc(N(C)S(C)(=O)=O)c2)o1
Reaction time: 15 h

Procedure:
To a solution of N-(4-[5-(1-aminoethyl)-1,3,4-oxadiazol-2-yl]-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide (0.544 g, 1.26 mmol, example 22) in 10 mL CH2Cl2 was added benzophenone imine (0.25 mL, 1.51 mmol). A white precipitate appeared gradually through the course of the reaction. The reaction was allowed to proceed for 15 h, when a further aliquot of benzophenone imine was added (0.160 mL, 0.894 mmol). After a further 24 h, the reaction was diluted with H2O and EtOAc, and the layers were separated. The aqueous layer was washed with EtOAc(2×), the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by normal phase chromatography (2->35% EtOAc/hexanes) to afford N-(4-(5-{1-[(diphenyl methylene)amino]ethyl}-1,3,4-oxadiazol-2-yl)-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N -methylmethanesulfonamide as a yellow foam. 1H NMR (CDCl3, 400 MHz) δ 7.63 (m, 4H), 7.54-7.50 (m, 4H), 7.48 (m, 2H), 7.05 (s, 1H), 6.99 (s, 1H), 4.95 (q, J=6.5 Hz, 1H), 3.52 (dd, J=14.3, 6.2 Hz, 1H), 3.38 (s, 3H), 3.34 (dd, J=14.3, 6.3 Hz, 1H), 3.14 (s, 3H), 3.12 (s, 3H), 1.67 (d, J=6.6 Hz, 3H), 1.01 (d, J=6.0 Hz, 3H), 0.74 (m, 1H), 0.65 (m, 1H), 0.40 (m, 1H), 0.25 (m, 1H); LCMS [M+H]+=559.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[Cl-].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26])[CH3:21]>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:25](=[O:26])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:28])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)CC(=O)O
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1ccc(N)c([N+](=O)[O-])c1

Procedure:
7.65 gm (0.05 mol) of 1,4-diamino-2-nitrobenzene were added to 80 ml of absolute tetrahydrofuran and 5.1 gm (0.05 mol) of triethylamine at room temperature to form a solution. While this mixture was being stirred, 7.5 gm (0.05 mol) of malonic acid monoethylester chloride were added dropwise thereto. After termination of the addition, the mixture was stirred at room temperature for another 6 hours. Then the solvent was evaporated in vacuo for the most part. The residue was suctioned off and recrystallized once from ethanol/activated charcoal and a second time from water. The product had a melting point of 133°-136°C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]=[C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: C1CCOC1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Nitro-1-tetralone (1.00 g, 5.23 mmol) was dissolved in dry THF (5 mL) and added to a solution of methyltriphenylphosphonium bromide (2.00 g, 5.60 mmol) and n-butyllithlum (2.5M in hexanes, 2.2 mL, 5.5 mmol) in THF (10 mL) cooled by an ice water bath. The mixture was allowed to warm to room temperature and stirred overnight. It was poured into ice water 45 mL) and extracted with EtOAc (3×20 mL). The extract was washed with NaCl solution, dried (MgSO4), filtered and concentrated to give a black solid (1.504 g). It was dissolved in CHCl3 and flash chromatographed over silica gel (65 g) eluting with EtOAc/hexane (1:20) to afford a white solid (263 mg, 27% yield): mp 45°-470° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[F:19].O.O.[Sn](Cl)Cl>CCO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]([F:19])=[CH:11][C:12]([NH2:16])=[C:13]([F:15])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccncc2Br)cc1F
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Temperature: 80 °C
Yield: 111.6 %

Procedure:
3-Bromo-4-(2,5-difluoro-4-nitrophenoxy)pyridine (0.414 g, 1.25 mmol) was dissolved in EtOH (30 mL). Tin (II) chloride dihydrate (1.129 g, 5.00 mmol) was added and the mixture was heated at 80° C. for 411. The solvent was removed under reduced pressure and the residue quenched with saturated aqueous NaHCO3. The mixture was diluted with EtOAc and filtered through Celite®. The Celite® bed was washed with water (2×) and EtOAc (2×), and the filtrate was extracted with EtOAc (2×). The combined organic extracts were dried and evaporated to yield 4-(3-bromopyridin-4-yloxy)-2,5-difluorobenzenamine (0.42 g, 112% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.33 (d, 1H), 7.28-7.23 (m, 1H), 6.76-6.71 (m, 2H), 5.56 (br s, 2H); MS (ESI) m/z: 301.0 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO>[NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: NCC(=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.5 %

Procedure:
To a solution consisting of 2-amino-1-(4-fluoro-phenyl)-ethanone (150 mg, 0.9 mmol) and MeOH (5 mL) was added NaBH4 (97 mg, 2.6 mmol). The mixture was stirred at rt for 45 min and then concentrated to dryness. The residue was diluted with EtOAc and washed with a satd. NH4Cl solution before drying (Na2SO4), and concentrating to give 2-amino-1-(4-fluoro-phenyl)-ethanol (139 mg, 100%) which was used without further purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)[N:12]=1.C(#N)C>O>[CH3:22][O:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:12]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2ccc(N)nc2n1
Reactant: O=C(O)c1ccccc1
Solvent: CC#N
Solvent: O
Product: COc1ccc2ccc(NC(=O)c3ccccc3)nc2n1
Temperature: 4 °C
Yield: 39.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with benzoic acid (13.4 g), N,N'carbonyldiimidazole (17.8 g) and 2-amino-7-methoxy-1,8naphthyridine (12.3 g). The product produced by precipitation in water (20 g; m.p. 80° C.) is dissolved in boiling acetonitrile (200 cc). After 1 hour's cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-methoxy-1,8-naphthyridin-2-yl)benzamide (7.8 g) is produced, m.p. 134° C. EXAMPLE 10
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][OH:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>CCO.O1CCOCC1>[ClH:21].[ClH:21].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][OH:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H]2CO)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: OC[C@@H]1CCCN1C1CCNCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A solution of 3.00 g (10.5 mmol) of 4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (intermediate 3A) in 70 ml of EtOH was treated at RT with 5.27 ml (21.1 mmol) of hydrochloric acid in 1,4-dioxane (4 molar) and the mixture was heated up to 100° C. After two hours, the solvents were evaporated and the residue was re-crystallized from MeOH/MeCN and Et2O to give 2.21 g (82%) of the title compound as colorless solid. MS: 185.2 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=4[CH3:25])[C:15]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+].Cl>CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][C:18]=4[CH3:25])[C:15]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(C#N)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(CN)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30B) (300 mg, 0.71 mmol) in methanol (10 mL) was added CoCl2′6H2O (337 mg, 1.41 mmol), then NaBH4 (137 mg, 3.53 mmol) was added in portions within 30 min. The reaction mixture was stirred at room temperature for 2 h. 10% hydrochloric acid was added to adjust pH=2. After methanol was distilled, conc. NH3.H2O was added to adjust pH=8 followed by extraction with ethyl acetate (80 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford crude ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30C) (300 mg), which was used for the next step without further purification. LC-MS: [M+H]+ 428.