Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:12]N1C(=O)CCC1=O>O1CCOCC1.COCCO>[CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[C:8]([Cl:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1ncc(CO)[nH]1
Solvent: C1COCCO1
Solvent: COCCO
Product: CCCCc1nc(Cl)c(CO)[nH]1
Temperature: 40 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
In a mixture of 70 ml of dioxane and 60 ml of methyl cellosolve was dissolved 4 g of 2-butyl-5-hydroxymethylimidazole, and 3.9 g of N-chlorosuccinimide was added to the solution, followed by stirring at 40° C. for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, and 100 ml each of water and ethyl acetate were added to the residue to shake for mixing. The ethyl acetate layer was evaporated to dryness under reduced pressure, and the residue was dissolved in 50 ml of ether. The solution was allowed to cool, thereby yielding 2.4 g of 2-butyl-4-chloro-5-hydroxymethylimidazole deposited as colorless prisms, m.p. 147°-148° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[F:20][C:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[C:30](O)=[O:31]>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:22]3[N:23]=[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]4[C:21]=3[F:20])=[O:31])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1nc2ccccn2c1F
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1nc2ccccn2c1F
Yield: 37.9 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol) and 3-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid (0.084 g, 0.466 mmol). The product was purified by recrystallization from acetonitrile. Yield 37.9%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.30 (dd, 1H), 4.46 (dd, 1H), 4.59-3.69 (m, 1H), 6.62 (d, 1H), 6.91-6.96 (m, 1H), 7.24-7.29 (m, 1H), 7.52-7.56 (m, 2H), 7.76-7.80 (m, 2H), 7.94-7.97 (m, 1H), 8.08 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Cc1cc(N)cc(F)c1
Agent: Br
Product: Cc1cc(F)cc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 58.4 %

Procedure:
3-fluoro-5-methylaniline (0.091 mL, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.1 g, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-fluoro-5-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.053 g, 57%) as a white solid. Mass Spectrum: M+H+ 454.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([F:19])=[C:8]([C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[C:9](O)=[O:10].[NH3:20]>C(N(CC)CC)C>[Cl:5][C:6]1[C:7]([F:19])=[C:8]([C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[C:9]([NH2:20])=[O:10]
Reactant: O=C(O)c1c(C(F)(F)F)ccc(Cl)c1F
Reactant: N
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: NC(=O)c1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 5 °C

Procedure:
420 g of thionyl chloride was added to 286 g of 3-chloro-2-fluoro-6-trifluoromethylbenzoic acid, and to the resultant mixture was further added 5 drops of triethylamine and the mixture then heated at reflux for 4 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and 3-chloro-2-fluoro-6-trifluoromethylbenzoyl chloride obtained was added into 1 liter of 28% aqueous ammonia solution, which has be cooled down to 5° C. over 10 minutes with stirring. Then. the solution was further stirred for 1 hour at room temperature. The reaction mixture was extracted with ether, and the extract was washed with water and with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the crude crystals obtained were washed with n-hexane and then filtered to obtain 266 g of the title compound(mp. 123-125° C.).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:27]3[O:26][C:25](=[O:28])[NH:24][C:23]=3[CH:22]=[C:21]([Cl:29])[CH:20]=2)[C:10]1=[O:30])[CH2:6][CH2:7][CH3:8].[OH-].[Li+].Cl>O1CCOCC1>[Cl:29][C:21]1[CH:20]=[C:19]([CH2:18][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH:5]([CH2:6][CH2:7][CH3:8])[CH2:4][C:3]([OH:31])=[O:2])[C:10]2=[O:30])[C:27]2[O:26][C:25](=[O:28])[NH:24][C:23]=2[CH:22]=1
Reactant: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Cl)cc3[nH]c(=O)oc23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Cl)cc3[nH]c(=O)oc23)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
3-[3-(5-Chloro-2-oxo-2,3-dihydro-benzooxazol-7-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid methyl ester (40 mg 0.08 mmol) is dissolved in 750 μL of 1,4 dioxane and then lithium hydroxide (5 mg in 750 μL of water) is added to the reaction. The reaction is stirred at room temperature for 1 hour and then acidified with 1N HCl. The product is extracted with ethyl acetate 3×1 mL) and the combined organic layers are dried, filtered and evaporated in vacuo. The crude material is purified by preparative reverse phase LC to give the title compound 20 mg (0.04 mmol, 54%). LCMS (ESMS): m/z 430.8 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:23]2[C:24]([CH3:26])=[CH:25][C:20]([O:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][C:22]=2[CH3:28])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(Cl)cc1

Procedure:
This compound is made in a manner substantially similar to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-chloro-phenylboronic acid as starting materials in step D. MS (ES): 492.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:14]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.ClS([N:26]=[C:27]=[O:28])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[C:27](=[O:28])([O:1][CH2:2][CH:3]([NH2:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)[NH2:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)OCC(N)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 59A, 93 mg (0.31 mmol) were introduced in 4 ml of acetonitrile under argon. At −15° C., 37 μl (0.43 mmol) of chlorosulphonyl isocyanate were added dropwise. After 30 min, the reaction solution was admixed with 8 ml of water and heated at 60° C. overnight. The reaction mixture was cooled and introduced into saturated sodium hydrogen carbonate solution. It was extracted with twice 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 66 mg (64% of theory) of the title compound in 73% purity.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)=[O:18]
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 ml dry DMF, p-chlorophenylisocyanate (15.36 g, 0.100 mole) is added dropwise with cooling. The mixture is stirred for 16 hours and then poured into about 500 ml of iced-water to yield the crystalline product which is filtered off, washed with water and recrystallized twice from acetone-methanol, once from tetrahydrofuran (THF) and then from DMF-methanol. The resultant pure 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-p-chlorophenylurea is dried in vacuo for 24 hours; m.p. 190°-2°C dec.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:18])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccccc1)c1cccc[n+]1[O-]
Product: O=C(c1ccccc1)c1cccc(Cl)n1

Procedure:
1.5 g 2-benzoyl-pyridine N-oxide (T. Kato et. al., see reference in Ex. 11) and 3.6 ml POCl3 are refluxed for 25 minutes. The cooled mixture is added to slightly alkaline ice:water, extracted with chloroform, the organic extract dried and solvent removed in vacuo. Yield: 1.1 g of title product, which by thin layer and gas chromatography is identical with that described in Ex. 7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([O:14][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.[Cl-].[Na+].O>[F:19][CH:10]1[C:11](=[O:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Trimethylsilyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (13.2 g, 48.6 mmol) was dissolved in acetonitrile (250 mL). 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (19.0 g, 53.5 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. Brine was added to the reaction mixture and the aqueous phase extracted ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, 100 g, 0% to 100% EtOAc in heptane). The title compound was obtained as white solid (5.66 g, 53%).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)O
Reactant: CN(C)CCN
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)NCCN(C)C
Yield: 90 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid (0.2 g, 0.66 mmol), prepared from the step 4 of the example 5, and N,N-dimethylethane-1,2-diamine (0.058 g, 0.66 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-methylphenoxy)-N-(2-(dimethylamino)ethyl)acetamide as a white solid (0.22 g, 89.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: C1CCNCC1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: N=C(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1)N1CCCCC1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (17.5 ml of a 0.0155 M solution, 0.27 mmol) was treated with piperidine (1.0 ml, 10.0 mmol) for 3 days. The ethanol was evaporated, and the residue purified by reverse phase HPLC to afford 26 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(piperidin-1-yl)methyl)benzamide. MS (Q1) 419 (M)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[Cl:13].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].O>CS(C)=O>[Cl:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)c(Cl)c1
Reactant: NCc1cccc(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(CCNCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of 1-(2-bromoethyl)-2-chloro-4-nitrobenzene (0.6 g, 1.84 mmol) in DMSO (20 mL), 3-chlorobenzylamine (1.21 g, 4.61 mmol) was added at room temperature. The reaction mixture was stirred for 3 hours at room temperature. After the completion of reaction, water (80 mL) was added and reaction mass was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and the solvents removed under reduced pressure. The product was purified by column chromatography on neutral silica gel using 5-15% EtOAc in hexane to give the title compound (0.43 g, 55%) as a solid.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)(=O)C.[NH2:23][CH2:24][C:25]1[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:23][CH2:24][C:25]2[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)COc1ccc(CN)cc1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynylbenzaldehyde, methyl [4-(aminomethyl)phenoxy]acetate, acetate salt and DIEA (1 eq.) (purification by flash chromatography on SiO2, DCM/MeOH 95:5) as a pale yellow oil (63%). M+ (ESI): 422.2. HPLC, Rt: 4.3 min (purity: 96.4%). 1H NMR (CDCl3) δ: 7.37 (d, J=8.3 Hz, 2H), 7.28 (m, 4H), 6.88 (d, J=8.6 Hz, 2H), 4.63 (s, 2H), 3.78 (m, 7H), 2.40 (t, J=7.0 Hz, 2H), 1.61 (m, 2H), 1.44 (m, 2H), 1.30 (brs, 8H), 0.90 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[OH-].[NH4+:14].C(O)C>C(OCC)(=O)C>[NH2:14][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: COc1cc([N+](=O)[O-])cnc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])cnc1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Into a 250 mL sealed tube were combined 2-chloro-3-methoxy-5-nitropyridine (0.50 g, 0.00265 mol), concentrated ammonium hydroxide (5 mL, 0.1 mol) and ethanol (20 mL). The mixture was heated to 80° C. and stirred overnight. After allowing to cool to room temperature, the mixture was reduced in vacuo and the residue was taken up in ethyl acetate (50 mL), then washed with equal amounts of brine and water (1×50 mL each). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum to leave a solid (0.312 g, 69%) which was used directly in the next step without further purification. LC-MS 1.94 min. M/Z=171.0 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:33]([O:36][CH3:37])[O:34][CH3:35])=[N:9][C:10]2[N:11]([C:17](=[O:32])[NH:18][C:19]3[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]([C:30]#[N:31])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.[CH3:38][NH2:39]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:30]([C:22]1[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:24][C:19]([NH:18][C:17]([N:11]2[C:10]3[C:15](=[CH:16][C:7]([CH2:6][NH:39][CH3:38])=[C:8]([CH:33]([O:34][CH3:35])[O:36][CH3:37])[N:9]=3)[CH2:14][CH2:13][CH2:12]2)=[O:32])=[N:20][CH:21]=1)#[N:31]
Reactant: CN
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(COS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(NCCOC)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 170, 363 mg, 0.679 mmol) in THF (8 ml) was added methylamine 2 M in THF (5 ml, 10.00 mmol) at room temperature and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (3×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (including 3% NH3, 10-20%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a colorless solid. (UPLC-MS 3) tR 0.70 min, ESI-MS 470.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 13.60 (s, 1H), 8.27 (s, 1H), 7.74 (s, 1H), 7.53 (s, 1H), 6.92 (t, 1H), 5.50 (s, 1H), 3.96-3.91 (m, 2H), 3.73 (s, 2H), 3.53 (t, J=5.8 Hz, 2H), 3.42-3.34 (m, 8H), 3.30 (s, 3H), 2.84 (t, 2H), 2.28 (s, 3H), 1.95-1.87 (m, 2H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C@@H:34]([CH2:38][NH:39][C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[C:35]([OH:37])=O)[CH:29]=[CH:30][C:31]=1[F:32].NCC(CC1C=CC=CC=1)C([NH:55][C:56]1[S:57][C:58]([Cl:68])=[C:59]([C:61]2[N:65]([CH3:66])[N:64]=[CH:63][C:62]=2[Cl:67])[CH:60]=1)=O.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:68][C:58]1[S:57][C:56]([NH:55][C:35](=[O:37])[C@@H:34]([CH2:33][C:28]2[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=2)[CH2:38][NH:39][C:40](=[O:41])[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:60][C:59]=1[C:61]1[N:65]([CH3:66])[N:64]=[CH:63][C:62]=1[Cl:67]
Reactant: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)O)OCc1ccccc1
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)C(CN)Cc2ccccc2)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)[C@H](CNC(=O)OCc2ccccc2)Cc2ccc(F)c(F)c2)sc1Cl
Reaction time: 12 h
Yield: 20.1 %

Procedure:
Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (401 mg, 0.859 mmol) was added in one portion to a solution of (2S)-3-(3,4-difluorophenyl)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]propanoic acid (200 mg, 0.573 mmol)[prepared in Preparation 4] and [5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amine-HCl (163 mg, 0.573 mmol)[prepared in Example 3] in N,N-diisopropylethylamine (0.500 ml, 2.86 mmol) and dichloromethane (7.174 ml). After 12 h, the solution was dry loaded onto silica and purified by chromatography (0-50% EtOAc in hexanes) affording phenylmethyl {(2S)-3-{[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-2-[(3,4-difluorophenyl)methyl]-3-oxopropyl}carbamate (70 mg, 0.115 mmol, 20.05% yield) as an orange solid: LCMS (ES) m/e 579, 581 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) d ppm 11.61 (s, 1 H) 7.67 (s, 1 H) 7.53 (br. s., 1 H) 7.32 (s, 7 H) 7.03 (br. s., 1 H) 6.55 (s, 1 H) 5.01 (s, 2 H) 3.68 (s, 3 H) 3.19-3.28 (m, 2 H) 2.76-3.00 (m, 3 H).
Reaction SMILES: CCCCCC.[Na].[C:8]([CH2:10][C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:9].[CH3:19][OH:20]>>[CH3:19][O:20][C:8]1[CH:10]=[C:11]2[C:12](=[C:17]([NH2:18])[N:9]=1)[N:13]=[CH:14][CH:15]=[CH:16]2
Reactant: CO
Reactant: N#CCc1cccnc1C#N
Agent: [Na]
Solvent: CCCCCC
Product: COc1cc2cccnc2c(N)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To an oven-dried 250 mL flask under a nitrogen atmosphere was added anhydrous MeOH (200 mL). Na metal (1.07 g, 44 mmol) was weighed to a small beaker containing hexane and then transferred to the reaction vessel. After dissolution of the sodium, 3-cyanomethyl-pyridine-2-carbonitrile (5.3 g, 37 mmol) dissolved in anhydrous MeOH (10 mL) was added to the reaction. The resulting solution was heated at 80° C. for 3 hours, then stirred at room temperature overnight. The reaction mixture was concentrated to remove MeOH and extracted into CH2Cl2 (2×200 mL). The organic phases were combined, dried over Na2SO4, filtered, concentrated and unsuccessfully chromatographed (2% MeOH/CH2Cl2). The mixed fractions were combined and recrystalized from EtOAc/hexane affording 1.16 g (18%) of the title compound as a yellow solid. The mother liquor was rechromatographed (50% EtOAc/hexanes) to afford an additional 560 mg (9%) of product: mp decomposes above 110° C.; MS(+)APCI m/z 176 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:25]1([CH2:24][NH:1][C:2]2[N:10]=[C:9]3[C:5]([C:6]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[C:7]([C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)[NH:8]3)=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1ccc(-c2[nH]c3nc(NCc4ccccc4)ccc3c2-c2ccncc2)cc1
Reaction time: 0.25 h

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (100 mg, 0.329 mmol), benzaldehyde (100 ml, 0.987 mmol), and 1,2-dichloroethane (20 mL) were allowed to stir for 15 min followed by the addition of sodium triacetoxyborohydride (139 mg, 0.658 mmol) as a solid. After 16 h at 23° C., the reaction was partitioned between ethyl acetate (200 mL) and satd bicarbonate (80 mL). The organic layer was washed with brine (80 mL), and dried (Na2SO4). After concentration in vacuo, a portion of the residue was purified by preparative chromatography to afford 6-(phenylmethylamino)-3-(4-pyridyl)-2-(4-fluoro phenyl)-7-aza-indole (144):Mass Spectrum (CI) 395 (MH+).