Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[Na+].[Cl-]>O1CCOCC1.C(Cl)(Cl)Cl>[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)N1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 88.4 %

Procedure:
N-(3-Bromopropyl)phthalimide (16.7 g, 62.4 mmol) is added to a stirred solution of 1-isopropyl-piperazine (8.00 g, 62.4 mmol) and diisopropylethylamine (8.06 g, 62.4 mmol) in anhydrous 1,4-dioxane (300 mL). The resultant mixture is heated in an oil bath at 90° C. for 20 hours. At ambient temperature, chloroform (300 mL) and half-saturated aqueous NaCl (200 mL) are added to the mixture. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated. The crude oil is subjected to chromatography on silica gel and eluted with 2 M NH3/CH3OH in dichloromethane 0-5% to provide the title compound as a tan oil (17.4 g, 87% yield).
Reaction SMILES: [Cl-].[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.CN(C)[CH:15]=[O:16]>>[CH:15]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[NH:2][CH:3]=1)=[O:16]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [Cl-]
Product: N#Cc1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Phophoyl chloride (4.24 ml, 45.48 mmol) was added dropwise to dimethylformamide (3.52 ml, 45.48 mmol) and stirred for 30 mins at room temperature. A solution of 1H-indole-5-carbonitrile (5.39 g, 37.9 mmol) in dimethylformamide (10 ml) was added dropwise. A solid precipitated, further dimethylformamide (10 ml) was added to aid stirring and the reaction mixture was then stirred at room temperature for 3 hr. Water was s added to quench the reaction mixture which was then stirred for 18 hr. The stirring was stopped and the reaction mixture was left to stand, after 24 hr a pink solid had precipitated in the organic layer. The layers were separated and organic layer filtered, washed with water and dried to give the desired product (5.44 g, 84%). 1H NMR (DMSO) δ 7.60-7.80 (m, 2H), 8.20-8.30 (m, 2H), 10.00 (s, 1H), 12.20-12.35 (s, br, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([CH:15]([CH2:20][CH:21]=[CH2:22])[C:16](OC)=[O:17])=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]=1[CH3:29])#[N:2].[Li+].[B-](CC)(CC)CC.[Cl-].[NH4+]>O1CCCC1>[CH:12]1([C:10]2[O:11][C:7]3[C:8](=[C:3]([C:1]#[N:2])[C:4]([CH3:29])=[C:5]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:6]=3[CH:15]([CH2:16][OH:17])[CH2:20][CH:21]=[CH2:22])[N:9]=2)[CH2:13][CH2:14]1
Reactant: C=CCC(C(=O)OC)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Agent: CC[B-](CC)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(CO)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Methyl 2-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)pent-4-enate (I-296) (100 mg, 0.26 mmol) was dissolved in tetrahydrofuran (2 ml), then under nitrogen atmosphere at −78° C., Super Hydride (1.0 M tetrahydrofuran solution) (570 μl, 0.52 mmol) was dropwise added. After stirring at the same temperature for 2 hours, aqueous saturated ammonium chloride solution was added, followed by further stirring at room, temperature for 10 minutes. The solution was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (88 mg, 95%) as a colorless gel.
Reaction SMILES: [C:1]([S@:5](/[N:7]=[C:8](/[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)\[CH2:9][CH2:10][N:11]([C@H:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:20])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br-].[CH2:33]1[CH2:37]OC[CH2:34]1>>[CH3:22][C:21]([CH3:24])([CH3:23])[C@@H:19]([N:11]([CH2:10][CH2:9][C@@:8]([NH:7][S@@:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[O:6])([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:37][CH:33]=[CH2:34])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH3:20]
Reactant: C[C@H](N(CC/C(=N\[S@](=O)C(C)(C)C)c1ccc(F)cc1)C(=O)OC(C)(C)C)C(C)(C)C
Reactant: C1CCOC1
Agent: [Br-]
Product: C=CC[C@](CCN(C(=O)OC(C)(C)C)[C@@H](C)C(C)(C)C)(N[S@](=O)C(C)(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (E)-3-((R)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl((S)-3,3-dimethylbutan-2-yl)carbamate (800 mg, 1.76 mmol) in THF (10 mL) was added allymagnesium bromide (1 M, 6 mL, 5.29 mmol) dropwise at −78° C. under N2. After adding completely, the reaction mixture was stirred at rt for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give tert-butyl (S)-3,3-dimethylbutan-2-yl((R)-3-((R)-1,1-dimethylethylsulfinamido)-3-(4-fluorophenyl)hex-5-enyl)carbamate (870 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][CH:12]([N:15]3[C:19]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:18]([CH3:28])[N:17]=[N:16]3)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:29][C:30]([O:32]CC)=[O:31].[Li+].[OH-]>C1COCC1.CO.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][CH:12]([N:15]3[C:19]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:18]([CH3:28])[N:17]=[N:16]3)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)Cc1c2n(c3c(F)cccc13)CC(n1nnc(C)c1Cc1ccc(F)cc1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnn(C2CCc3c(CC(=O)O)c4cccc(F)c4n3C2)c1Cc1ccc(F)cc1
Reaction time: 8 h

Procedure:
Each of the chiral resolved ethyl {4-fluoro-7-[5-(4-fluorobenzyl)-4-methyl-1H-1,2,3-triazol-1-yl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate was hydrolyzed to the final acid product by dissolving in 1:1:1 THF/MeOH/water (0.06 M), treating with LiOH (3.6 eq.) and stirring overnight. The reaction mixture was diluted with EtOAc, extracted with 2 N HCl, water, dried (Na2SO4), and concentrated to provide {4-fluoro-7-[5-(4-fluorobenzyl)-4-methyl-1H-1,2,3-triazol-1-yl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetic acid Examples 36.1 and 36.2: MS (EI) calc'd for C24H23F2N4O2 [M+1]+437.2. found 437.1.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]#[N:9])=[C:6]([NH2:10])[N:5](C(N)=O)[N:4]=1)#[N:2]>O>[C:1]([C:3]1[C:7]([C:8]#[N:9])=[C:6]([NH2:10])[NH:5][N:4]=1)#[N:2]
Reactant: N#Cc1nn(C(N)=O)c(N)c1C#N
Solvent: O
Product: N#Cc1n[nH]c(N)c1C#N
Yield: 87.8 %

Procedure:
3-cyano-4-cyano-5-amino-1H-pyrazole-1-carboxamide (15.6 g, 0.089 mol) was added in small protions to boiling water (150 ml). Upon completion of the addition, the reaction mixture was stirred at reflux for 5 minutes, cooled and a solid was collected by filtration. The solid was washed with water and air dried to afford 10.4 g (88%) of 3-cyano-5-amino-1H-pyrazole-4-carbonitrile, m.p. 260° C. (dec.).
Reaction SMILES: C[NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Cl:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40]([OH:42])=O)[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl.C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40](=[O:42])[NH:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=3[CH2:18][C:19]([O:21][CH3:22])=[O:20])[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23
Reactant: CNc1ccc(CNC(=O)OC(C)(C)C)cc1CC(=O)OC
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Reaction time: 4.5 h
Yield: 74.6 %

Procedure:
A mixture of methyl 4-tert-butoxycarbonylaminomethyl-2-methoxycarbonylmethylaniline (1.20 g, 4.27 mmol), (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (1.26 g, 4.27 mmol), triethylamine (1.49 mL, 10.7 mmol), and Bop-Cl (1.19 g, 4.69 mmol) in dichloromethane (26 mL) was stirred for 4.5 h at 0° C. to room temperature and diluted with ethyl acetate. The mixture was washed successively with 5% potassium hydrogen sulfate, water, 1/15 phosphate buffer (pH 7.5), water, and brine, dried over magnesium sulfate, and concentrated. The residual solid was washed with a 1:1 mixture of diethyl ether and dichloromethane, and dried to give 1.82 g of the title compound (74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]2.[CH3:15][O:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][CH:11]=2)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][CH2:5]3)[CH:20]=[N:19][CH:18]=1
Reactant: NC(=O)N1CCCc2cc(Br)cnc21
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 100 °C
Yield: 36.1 %

Procedure:
6-Bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (30 mg, 0.12 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (43 mg, 0.18 mmol) and K2CO3 (32 mg, 0.23 mmol) are mixed in 1.0 mL of 1,4-dioxane and 0.10 mL of water. Argon gas is bubbled through the mixture for 10 min and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (8.3 mg, 0.01 mmol) is added. The mixture is heated at 100° C. for 2 hrs. Then solvents are removed and EtOAc (20 mL) is added. The mixture is filtered to remove any solid and the filtrate is concentrated to give the crude product. Purification by flash column chromatography affords 12.3 mg of the title product.
Reaction SMILES: [Cl:1]Cl.[C:3]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[OH:15])[CH:10]=[O:11])([CH3:6])([CH3:5])[CH3:4].O>C(O)(=O)C>[C:3]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([Cl:1])[C:14]=1[OH:15])[CH:10]=[O:11])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C=O)cc(Cl)c1O

Procedure:
Chlorine gas was passed into a solution of 3-tert-butyl-4-hydroxybenzaldehyde (2.5 gm) in acetic acid (20 ml) for 1 hour. The solution was poured into water and the product collected. Recrystallisation from aqueous ethanol gave 3-tert-butyl-5-chloro-4-hydroxybenzaldehyde m.p. 123° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[C:3]=1[C:13]#[N:14].[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.O>C1COCC1>[CH2:15]([NH:21][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[C:3]=1[C:13]#[N:14])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1nc2ccnn2c(Cl)c1C#N
Reactant: NCc1ccco1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1nc2ccnn2c(NCc2ccco2)c1C#N
Yield: 70.9 %

Procedure:
200 mg of 7-chloro-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 62) and 100 mg of furfurylamine were reacted in 5 ml of THF in the presence of 110 mg of triethylamine for about 30 minutes, then about 30 ml of water was added thereto, and the precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were washed with ether to obtain 180 mg of 7-furfurylamino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 78) having a melting point of 110° C.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:19](=[O:32])[C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[C:14]([CH:18]=1)[C:15](O)=[O:16])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O[N:35]1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:18]=[C:14]2[C:13]([C:19]([OH:32])([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[NH:35][C:15]2=[O:16])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)c2ccc(OC(=O)c3ccccc3)cc2C(=O)O)cc(OC)c1OC
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2(O)NC(=O)c3cc(OCc4ccccc4)ccc32)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of 5-benzoyloxy-2-(3,4,5-trimethoxybenzoyl)benzoic acid 50 mg, 14.8M aqueous ammonia 50 μl, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimido.hydrochloride 68 mg and 1-hydroxybenzotriazole 15.9 mg is dissolved under ice cooling in N,N-dimethylformamide 2 ml and the mixture is stirred overnight at room temperature. To the reaction mixture is added water. The mixture is extracted with ethyl acetate and the extract is washed with water and dried, followed by removal of the solvent. The residue is purified with silica gel chromatography (solvent: chloroform:ethyl acetate=1:1) and left to be crystallized. The crystals are triturated with diisopropyl ether-ethyl acetate to give 6-benzyloxy-3-hydroxy-3-(3,4,5-trimethoxyphenyl)-2,3-dihydroisoindol-1-one 46.7 mg. mp 187-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[N:27]1([C:37]([NH2:39])=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C:28]1=[O:36]>CN(C)C=O.CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([CH:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([C:37]([NH2:39])=[O:38])[C:28]2=[O:36])=[O:9])[S:5][CH:6]=1
Reactant: NC(=O)N1C(=O)Cc2ccccc21
Reactant: O=C(O)c1cc(Cl)cs1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: NC(=O)N1C(=O)C(C(=O)c2cc(Cl)cs2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure of Example 55. An 831 mg (5.11 mmole) portion of 4-chloro-2-thiophenecarboxylic acid (prepared according to Iriarte, J., et al., J. Het. Chem., 13, 393 (1976)) was combined with 897 mg (5.53 mmole) of 1,1'-carbonyldiimidazole in 5 ml of N,N-dimethylformamide and the intermediate imidazolide coupled directly with 750 mg (4.26 mmole) of 2-oxindole-1-carboxamide in the presence of 1.40 g (11.49 mmole) of 4-(N,N-dimethylamino)pyridine. The resulting crude yellow solid (803 mg, 59% yield) was recrystallized from acetic acid to furnish 376 mg (1.17 mmole, 27% yield) of fluffy yellow crystals, m.p. 221°-3° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)C(=O)OC(C)(C)C)=O)(C)(C)C.Cl>CCO>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:20][CH2:21][CH2:22][NH:23][CH:24]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)NCCCN(CCCNC1CCCCCCCCCCCCCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: NCCCNCCCNC1CCCCCCCCCCCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 134.3 %

Procedure:
Compound 50a (450 mg, 0.8 mmol) was first dissolved in EtOH (60 mL) and stirred at 0° C. for 10 min A 4 M HCl solution (35 mL, 140 mmol) was then added dropwise and stirred for 30 min at 0° C. under N2. The reaction was then slowly warmed to room temperature and stirred under N2 for 4 h. Upon completion, the solvent was removed in vacuo to give 46a as a white solid (365 mg, 98%)1H NMR (D2O) δ 3.25 (m, 1H), 3.15 (t, 6H), 3.10 (t, 2H), 2.09 (m, 4H), 1.72 (m, 4H), 1.39-1.35 (m, 26H); 13C (D2O) δ. HRMS (FAB) m/z calc for C21H45N3 (M+H)+ 340.3613. found 340.3693. Elemental Analysis: C21H48Cl3N3.0.05 H2O theory C, 55.57; H, 10.68; N, 9.26. found C, 55.77; H, 10.65; N, 8.98.
Reaction SMILES: O[N:2]=[CH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([C:32]4[C:23](=[CH:24][C:25]5[O:30][CH2:29][CH2:28][O:27][C:26]=5[CH:31]=4)[O:22][CH2:21]3)[C:13]2=[O:33])=[CH:7][N:6]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.C(=O)(O)[O-].[Na+]>[N:4]1[CH:3]=[N:2][N:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]4([C:32]5[C:23](=[CH:24][C:25]6[O:30][CH2:29][CH2:28][O:27][C:26]=6[CH:31]=5)[O:22][CH2:21]4)[C:13]3=[O:33])[CH:9]=[CH:10][C:5]=12
Reactant: O=C1N(Cc2ccc(NC=NO)nc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc3ncnn3c2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a cooled (0° C.) suspension of N′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide (0.22 g, 0.5 mmol) in tetrahydrofuran (7 mL) was slowly added trifluoroacetic anhydride (0.08 mL, 0.54 mmol). The mixture was stirred at ambient temperature for 3 h, diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers was washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 50% to 65% gradient of ethyl acetate in hexanes to afford 1′-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.11 g, 54%) as a colorless solid: mp 207-209° C.; 1H NMR (300 MHz, DMSO-d6) δ8.65 (s, 1H), 8.37 (s, 1H), 7.82-7.77 (m, 1H), 7.61-7.55 (m, 1H), 7.30-7.17 (m, 2H), 7.11-7.04 (m, 1H), 6.90-6.85 (m, 1H), 6.52 (s, 1H), 6.18 (s, 1H), 5.03 (ABq, J=40.9, 15.6 Hz, 2H), 4.80 (ABq, J=79.6, 9.0 Hz, 2H), 4.23-4.09 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.7, 155.2, 154.2, 149.9, 144.8, 141.2, 138.4, 132.1, 129.8, 129.0, 127.0, 124.4, 124.0, 123.0, 120.5, 117.4, 111.4, 108.6, 99.5, 80.0, 64.5, 63.9, 58.0, 41.2; MS (ES+) m/z 426.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](O)=O)=[CH:8][CH:7]=2.[Cl:17][C:18]1[CH:19]=[C:20]([F:26])[C:21]([NH:24][NH2:25])=[N:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C#N>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([F:26])[C:21]2[N:22]([C:14]([CH2:13][C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]4)=[N:25][N:24]=2)[CH:23]=1
Reactant: NNc1ncc(Cl)cc1F
Reactant: COc1cnc2ccc(CC(=O)O)cc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cnc2ccc(Cc3nnc4c(F)cc(Cl)cn34)cc2c1
Temperature: 150 °C

Procedure:
To a mixture of 2-(3-methoxyquinolin-6-yl)acetic acid (0.22 g, 1.0 mmol), 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine (0.11 g, 0.68 mmol) and triphenylphosphine (0.97 g, 2.0 mmol) (on solid support) in DCM (5 mL) was added DIEA (0.24 ml, 1.4 mmol) followed by 2,2,2-trichloroacetonitrile (0.14 ml, 1.4 mmol) via a syringe. The mixture was then heated to 150° C. for 15 minutes in an appropriately sealed vial. The mixture was filtered and the filtrate was diluted with 50 mL of EtOAc. The solution was washed with 30 mL of satd. NaHCO3 followed by 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a silica gel column chromatography (EtOAc to 10% MeOH/EtOAc) to give light yellow solid as desired product. MS (ESI pos. ion) m/z: 343 (MH+). Calc'd exact mass for C11H12ClFN4O: 342.
Reaction SMILES: C(S[C:4]1[C:13]2[C:8](=[C:9]([CH2:24][CH2:25][CH3:26])[C:10]3[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:14](=[O:23])[C:11]=3[CH:12]=2)[N:7]=[C:6]([C:27]([O-:29])=[O:28])[CH:5]=1)C.[CH2:30](O)[CH3:31]>>[O:23]=[C:14]1[C:11]2[CH:12]=[C:13]3[C:8](=[C:9]([CH2:24][CH2:25][CH3:26])[C:10]=2[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15]1)[N:7]=[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:5]=[CH:4]3
Reactant: CCO
Reactant: CCCc1c2nc(C(=O)[O-])cc(SCC)c2cc2c(=O)cc(C(=O)OCC)oc12
Product: CCCc1c2nc(C(=O)OCC)ccc2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
Ethyl 6-ethylthio-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline 2,8-dicarboxylate (2.85 g) was dissolved in ethanol (200 ml), and ethanol washed Raney nickel (30 g wet) added carefully. The mixture was refluxed for 11/2 hours, filtered to remove the catalyst, and concentrated, to give on cooling the title compound, (1.76 g) mp 168°-171° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([OH:26])[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([OH:26])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)C2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1ccc(NC(=O)C2(O)CCNCC2)cc1

Procedure:
A mixture of 33 mg (0.09 mmol) 1-benzyl-4-hydroxy-piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide in 15 mL ethanol and 10 uL acetic acid was hydrogenated over Pd/C with 1 bar H2 for 2 h at room temperature. The mixture was filtered, the catalyst washed with ethanol and the filtrate evaporated to dryness yielding 33 mg (70% purity) of the title compound. MS (m/e): 263.1 [(M+H)+].
Reaction SMILES: O1CCCCC1[N:7]1[O:14][CH2:13][CH:12]2[CH:8]1[CH2:9][N:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2.Cl(O)(=O)(=O)=O.C[O-].[Na+]>C(O)C>[CH:8]12[CH2:9][N:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:12]1[CH2:13][O:14][NH:7]2
Reactant: CCOC(=O)N1CC2CON(C3CCCCO3)C2C1
Agent: C[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: CCOC(=O)N1CC2CONC2C1

Procedure:
15 g (55.5 mmol) of ethyl 2-(tetrahydropyran-2-yl)-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 8.25 g (56 mmol) of 70% strength perchloric acid in 100 ml of ethanol for 30 minutes. 10.5 g (58 mmol) of 30 strength sodium methylate solution are added, the mixture is concentrated, the residue is taken up in water and the solution is saturated with K2CO3 and extracted with CHCl3. The extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].C(N(C(C)C)C(C)C)C.Br.[C:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH:24](Br)[CH2:23]1)(=[O:21])[CH3:20]>C(#N)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:8][C:24]2[CH2:23][N:22]([C:19](=[O:21])[CH3:20])[CH2:27][CH2:26][C:25]=2[N:7]=1
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Reactant: NC(=S)c1cccs1
Agent: Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2nc(-c3cccs3)sc2C1
Temperature: 50 °C

Procedure:
2.8 mmol of thiophene-2-thiocarboxamide was dissolved in 10 ml acetonitrile. 5.6 mmol of N-ethyl-diisopropylamine was added, followed by 3.4 mmol 1-acetyl-3-bromo-piperidin-4-one hydrobromide (prepared according to patent U.S. Pat No. 4,122,083). The reaction mixture was heated to 50° C. for 4 hours, cooled and concentrated. Chromatography of the residue (SiO2; ethyl acetate) yields the title compound as a yellowish gum. MS (m/e): 265.0 (M+H+).