Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4](F)[C:3]=1[F:14].[OH-:15].[K+]>CS(C)=O.O>[N+:8]([C:7]1[C:2]([F:1])=[C:3]([F:14])[C:4]([OH:15])=[C:5]([F:12])[C:6]=1[F:11])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(F)c(F)c(O)c(F)c1F
Reaction time: 24 h
Yield: 95 %

Procedure:
21.3 g of pentafluoronitrobenzene (0.1 mol) are dissolved in 400 ml of dimethyl sulfoxide; a solution of 11.2 g of potassium hydroxide (0.2 mol) in 100 ml of water is added drop wise to this solution with vigorous stirring. After 24 hours at room temperature, the crude product is washed by shaking with 200 ml of ethyl acetate and 400 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The reaction product is then recrystallized from a mixture of ethyl acetate and n-hexane (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 95%).
Reaction SMILES: C([O:8][CH2:9][C:10]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:22]=[C:23]([NH:30][CH:31]3[CH2:33][CH2:32]3)[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=2)=[CH:16][CH:15]=1)[CH3:13])=[O:11])C1C=CC=CC=1>CCO.[Pd]>[CH:31]1([NH:30][C:23]2[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([N:12]([CH3:13])[C:10](=[O:11])[CH2:9][OH:8])=[CH:19][CH:18]=3)[N:22]=2)[CH2:32][CH2:33]1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc(Nc2nc(NC3CC3)c3cc[nH]c3n2)cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C(=O)CO)c1ccc(Nc2nc(NC3CC3)c3cc[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-benzyloxy N-(4-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (0.015 g, 0.034 mmol) in EtOH (0.4 mL) was added Pd/C (10 mg), and was charged with H2 (1 atm). After stirring for 15 h at room temperature, it was purified by preparative HPLC to give N-(4-(4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-2-hydroxy-N-methylacetamide (MS calcd for C18H20N6O2 352.2, found [MH] 352.8; UV 206.3, 228.7, 297.3 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethynyl]piperidine-1-carboxylate (0.103 g, 0.277 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0386 g, 0.264 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethynyl)piperidine-1-carboxylate (0.105 g, 80%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=O)[NH:9][N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[S:29])[NH:9][N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]n(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc2c(=S)[nH]n(-c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed 6-nitro-1-phenyl-1,2-dihydroindazol-3-one (15 g, 58.82 mmol, 1.00 equiv), xylene (150 mL), P2S5 (52.2 g, 235.14 mmol). The resulting solution was heated to reflux for 40 min in an oil bath. The resulting mixture was then cooled to 25° C. The resulting solution was diluted with ethyl acetate (50 mL). The solids were filtered out to yield 6-nitro-1-phenyl-1,2-dihydroindazole-3-thione as a yellow solid. MS: 272 (MH+).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>ClCCl>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.71 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 19.4 ml of triethylamine in 150 ml of dichloromethane under argon is added in small portions 4-nitrobenzoyl chloride (exothermic). The mixture is stirred for 3 hours at 25° C. and then washed with water, sodium bicarbonate solution, brine and dried (Na2SO4). The solvent is removed, the residue dried under vacuum and recrystallized by dissolving in hot ethyl acetate and diluting with hexane. Chilling overnight and filtering gives 16 g of light brown crystals, m.p. 141°-142° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:15][CH3:16])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.N.[H][H]>O.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:15][CH3:16])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: O
Product: COC(Cc1cccc(N)c1)C(=O)O
Yield: 88.7 %

Procedure:
50 g (223 mmol) of 3-(3-nitrophenyl)-2-methoxyacrylic acid is suspended in 785 ml of water and brought into solution by the addition of 30 ml of concentrated ammonia. After addition of 3 g of Raney nickel, the mixture is hydrogenated at 80 bar until uptake of hydrogen ceases. The solution is filtered, 325 g of salt are added, and the resultant solution is thoroughly extracted with tetrahydrofuran. The combined tetrahydrofuran extracts are dried over sodium sulfate, filtered over active carbon and concentrated, thus producing 38.6 g (88% of theory) of 3-(3-aminophenyl)-2-methoxypropionic acid. This product is dissolved in 1 liter of water by the addition of 110 ml of 2N ammonia. The resultant solution is treated first with 160 ml of glacial acetic acid, and then with 36 ml of bromine in 160 ml of glacial acetic acid added dropwise at room temperature over the course of 2 hours. The reaction mixture is stirred for several hours in an ice bath, the resultant precipitate is vacuum-filtered, washed with water and dried at 50° C., thus producing 66 g (73% of theory) of 3-(3-amino-2,4,6-tribromophenyl)-2-methoxypropionic acid, as a white powder, mp 173°-175° C. 32 g (74 mmol) of this compound is added portionwise at +5° C. to 80 ml of nitrosylsulfuric acid. Then, 40 ml of glacial acetic acid is added, and the mixture is stirred for 2 hours at +5° C. The mixture is poured onto 360 g of ice, and the resultant mixture is added to a solution of 33 g of copper(I) cyanide, 62 g of potassium cyanide and 464 ml of concentrated ammonia in 297 ml of water, resulting in discharge of gas. The reaction mixture is stirred overnight at room temperature, treated with 1 liter of ethyl acetate, and brought to pH 2 by addition of concentrated hydrochloric acid. After pressure filtration, the ethyl acetate phase is separated and the aqueous phase is again thoroughly extracted with ehtyl acetate. The combined ethyl acetate extracts are drid over sodium sulfate, filtered over active carbon and vacuum-concentrated to dryness, thus producing 24 g of crude 3-(3-cyano-2,4,6-tribromophenyl)-2-methoxypropionic acid. This product is hydrolyzed to the amide by stirring at 60° C. in 100 ml of water containing 3 g of caustic soda for 3 hours. The resultant solution is filtered over active carbon and the filtrate is brought to pH 2 with concentrated hydrochloric acid. The resultant mixture containing a precipitate is stirred for several hours in an ice bath, vacuum-filtered, washed with water and dried at 50° C., thus producing 27.5 g (81% of theory) of 3-(3-carbamoyl-2,4,6-tribromophenyl)-2-methoxypropionic acid, as a white powder, mp 138°-139° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:16]=2[CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][N:22]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:21][C:20]=3[C:16]=2[CH:15]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
4-Cyanobenzenesulfonyl chloride (53 mg, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 41 (55 mg, 62% yield) as a yellow solid. LC-MS (M+H=373, obsd.=373).
Reaction SMILES: [OH:1][C@@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25]Cl)=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9].[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O>[OH:1][C@@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]([CH2:25][N:29]=[N+:30]=[N-:31])=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(nc(CCl)n2Cc2ccccc2)n(C)c1=O
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](O)CCCCn1c(=O)c2c(nc(CN=[N+]=[N-])n2Cc2ccccc2)n(C)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A suspension of (S)-1-(5-hydroxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (2.0 g, 5.0 mmol) and sodium azide (1.62 g, 25 mmol) in methyl sulfoxide (15 ml) was stirred at 60° C. overnight. The reaction mixture was quenched by addition of water (30 ml) and extracted with ethyl acetate (3×25 ml). The combined extracts were washed with water (2×10 ml), with saturated aqueous sodium chloride solution (25 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (S)-1-(5-hydroxyhexyl)-7-benzyl-8-azidomethyl-3-methylxanthine (1.7 g, 83% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11](=[CH2:23])[CH:12](O)[CH:13]([NH:19][CH:20]=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].S(Br)([Br:26])=O.O>C(Cl)Cl>[Br:26][CH2:23][C:11]([CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:13]([NH:19][CH:20]=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=S(Br)Br
Reactant: C=C(CCCOCC(=O)OCC)C(O)C(NC=O)C(=O)OCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COCCCC(=CC(NC=O)C(=O)OCC)CBr
Reaction time: 0.17 h

Procedure:
5 g (15.1 mmol) of ethyl 7-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-4-methylene-heptanoate are dissolved in 50 ml of CH2Cl2 and 1.4 ml (18.1 mmol) of thionyl bromide are added dropwise at room temperature. After 2 hours 50 ml of water are added and the batch is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and twice with water. The aqueous phases are extracted once with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered, and the filtrate is concentrated by evaporation giving ethyl 4-bromomethyl-7-ethoxycarbonyhnethoxy-2-formylamino-hept-3-enoate as a yellow oil which is further reacted without purification.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:24]CC)[C:6]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)([PH2:10]=[O:11])[CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+].CO>C1COCC1>[OH:24][C:5]([CH3:27])([C:6]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)([PH2:10]=[O:11])[CH:7]([CH3:9])[CH3:8])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)C(C)(OCC)C(CSc1ccc2ccccc2n1)([PH2]=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(CSc1ccc2ccccc2n1)([PH2]=O)C(C)(O)C(=O)O
Yield: 97.3 %

Procedure:
2-(Ethoxy) (quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid ethyl ester (4.5 g) was dissolved in 100 mL THF and 12.5 mL of 2N NaOH was added together with enough methanol to make the solution homogeneous. After 18 hours the THF was removed by evaporation, the residue diluted with 50 mL H2O and washed with 50 mL ethyl acetate. The aqueous phase was then acidified to pH 4, and the product extracted with 50 mL ethyl acetate (2×). The ethyl acetate was washed with 20 mL brine, dried with MgSO4 and evaporated to yield 3.8 g of 2-(hydroxy) (quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid as a yellow oil, MS: 368 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)=[O:6]
Reactant: COC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: COC(=O)C1CCNCC1
Agent: Cl
Product: COC(=O)c1ccc(O)c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate is prepared in analogy to the process described in Example IX, method 1, from 2-hydroxy-5-carbomethoxybenzoic acid [CAS No. 79128-78-2] and methyl piperidine-4-carboxylate hydrochloride.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([NH2:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:26]([NH:12][C:4]12[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:11][C:2]([OH:1])([CH2:9]3)[CH2:3]1)[CH2:5]2)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC12CC3CC(C1)CC(NC(c1ccccc1)(c1ccccc1)c1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 3-hydroxytricyclo[3.3.1.13,7 ]decan- 1-amine (5 g; 0.03 mole) dissolved in dichloromethane (140 ml) with gentle heating is added triethylamine (6 g; 0.06 mole) and cooled in an ice bath. Triphenylmethyl chloride (8.30 g; 0.03 mole) in CH2Cl2 (10 ml) is added all at once. The reaction is stirred in an ice bath for 10 minutes, warmed to room temperature and then refluxed for 3 hours. The reaction is then filtered and the filtrate evaporated to dryness. The reaction products are separated on HPLC, using 15% ethyl acetate/hexane and the product is then recrystallized from ethyl acetate/pet. ether to give N-trityl-3-hydroxytricyclo-[3.3.1.13,7 ]decan-1-amine (m.p. 184°-186° C.) which is used directly in step C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[N:34]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][NH2:47])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([NH:47][CH2:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[N:3]=1
Reactant: NCc1ccccc1N1CCCCC1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(Cl)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(NCc4ccccc4N4CCCCC4)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 120 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-chloropyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.6 mmol) and [2-(1-piperidinyl)phenyl]methanamine (CAS#: 72752-54-6) (105 mg, 0.8 mmol) in i-PrOH (2 mL) was added diisopropylethyl amine (0.5 mL). The reaction was heated to 120° C. for 2 h followed by heating to 140° C. for 1 h under microwave conditions, then cooled to RT and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-(piperidin-1-yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:17])([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH2:4]([O:3][C:1]([NH:11][C:12]([CH3:13])([CH3:17])[C:14]([NH:18][C@@H:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:33])=[O:16])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N[C@@H]1CCc2cc([N+](=O)[O-])ccc2NC1=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
Prepared from N-carbobenzyloxy-2-methylalanine and 3(R)-amino-7-nitro-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step A) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1H NMR (400 MHz, CDCl3): δ 1.48 (s, 3H), 1.49 (s, 3H), 2.00 (m, 1H), 2.73 (m, 2H), 2.92 (m, 1H), 4.45 (m, 1H), 5.07 (s, 2H), 5.30 (s, 1H), 7.05 (d, 8 Hz, 1H), 7.30 (m, 6H), 8.06 (dd; 8, 6 Hz; 1H), 8.13 (d, 2.5 Hz, 1H), 8.35 (s, 1H). FAB-MS: calculated for C22 H24N4O6 424; found 425 (M+H, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].Cl[C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40]>N1C=CC=CC=1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[O:40])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[O:37])(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: COCCOC(=O)Cl
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCCOC(=O)N1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 18 h

Procedure:
A solution of Example 173A (54.1 mg, 0.1 mmol) in pyridine (2 mL) and triethylamine (1 mL) at room temperature was treated with 2-methoxyethyl chloroformate (0.2 mmol), stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 0-5% methanol/dichloromethane) to provide the desired product. MS (ESI(−)) m/e 642 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.66 (t, 1H), 8.55 (d, 1H), 7.89 (dd, 1H), 7.75 (d, 2H), 7.30-7.40 (m, 2H), 7.31-7.25 (m, 2H), 7.21-7.07 (m, 2H), 6.90 (d, 2H), 4.16-4.12 (m, 2H), 3.63 (q, 2H), 3.54-3.43 (m, 4H), 3.31-3.20 (m, 8H), 3.23 (s, 3H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N>CC(=O)CC>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=Cc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCC(C)=O
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1

Procedure:
of styrene (2 mol) and 196 gs. of maleic acid anhydride were dissolved in 1600 gs. of 2-butanone, whereafter as catalyst 0.5 gs. of azo-bis-isobutyronitrile was added. The mixture was completely polymerized in a nitrogen atmosphere in a period of approx. 4 hours, while being stirred and heated at approx. 70°-80°C. The dry, solid polymer could be obtained from the solution as a white powdery substance with a melting-point above 200°C by precipitating with methanol, filtering off, rinsing out with methanol and drying.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(N3C(=O)c4ccccc4C3=O)n[nH]c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2cc(O)ccc12
Temperature: 200 °C
Yield: 69 %

Procedure:
A mixture of 24.2 g (82.5 mmol) of 2-({6-methoxy}-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione and 73.4 g (0.635 mol) of piridine hydrochloride was heated at 200° C. for 4 hours. The resulting brown solution was cooled to 140° C. and slowly poured in a well stirred mixture of 250 ml of 0.2 N HCl and 350 ml of ethyl acetate. The organic layer was separated and the aqueous layer was salted (45 g of NaCl) and extracted twice with 350 ml of ethyl acetate. Organic extracts were dried over sodium sulfate and concentrated under vacuum to small volume. The precipitate was filtered off and dried: 15.89 g of product as yellow solid were obtained. Yield=68.9%. mp=265-270° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.C(O)(=O)C.[N-:17]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[NH:17][C:6]=2[CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCSc2ccc(F)cc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCSc2ccc(F)cc2N1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (100 mg, 0.54 mmol ) was dissolved in acetic acid (0.5 mL, 1.1 eq), sodium azide (71.2 mg, 1.1 mmol) was added and mixture was heated to 50° C. Sulfuric acid (0.13 mL, 4.3 eq) was added slowly and stirred at 50° C. for 1.5 hours. Ice chips (150 mg) were added and a green solid precipitated, this was filtered, washed with water and dried to give 7-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (80 mg, 24%). 1H NMR (CDCl3, 300 MHz): δ 7.77 (s-broad, 1H), 7.69 (t, 1H, J=7.3 Hz), 6.94-6.82 (m, 2H), 3.42 (t, 2H, J=7 Hz), 2.63 (t, 2H, J=6.7 Hz) ppm.