Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.[N:10]([O-])=O.[Na+]>>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:10])=[C:5]([CH3:9])[CH:4]=1
Reactant: CNc1cccc(C)c1
Reactant: O=N[O-]
Agent: [Na+]
Product: CNc1ccc(N)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A mixture of 12.1 g N-methyl-m-toluidine (I) 14.5 g conc. HCl and 40 g of ice were stirred while 7 g NaNO2 were added over a period of 5 minutes. The mixture was cooled externally and small portions of ice were added when needed to keep the temperature below 10°C. The mixture was allowed to stand at 0°C for 1 hour after the addition was complete and the oily top layer formed was separated. The lower aqueous layer was then extracted twice with 10 ml portions of benzene and the combined organic layers were distilled under reduced pressure. The material which boiled at 132°-138°C/8mm Hg was collected and dissolved in ethanol. Dry HCl gas was passed through this solution which heated up and deposited a precipitate of N,2-dimethyl-4-nitrosaniline (III) as the hydrochloride salt. The 16 g of product were suspended in isopropanol and reduced over Pt/C on a Parr hydrogenator. The reduction mixture was filtered and the catalyst was extracted with water. The combined filtrates were evaporated to dryness to yield 8 g of the product N,3-dimethyl-p-phenylenediamine hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:12][PH:13](=[O:15])[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:1]([O:8][C:9]([CH:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:12][P:13]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:14])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Yield: 48.5 %

Procedure:
To a solution of 2,4-di-(benzyloxycarbonyl)butyl phosphinic acid (6) (19.3 g, 49.4 mmol) in tetrahydrofuran was added benzyl alcohol (5.3 g, 49.3 mmol) and dimethylamino in tetrahydrofuran was added benzyl alcohol (5.3 g, 49.3 mmol) and dimethylamino pyridine (0.5 g). Dicylcohexylcarbodiimide (DCC, 12 g, 58 mmol) was added and a white precipitate formed. After 30 minutes the white suspension was filtered and the filtrate evaporated under reduced pressure. The clear and colorless oil was purified by flash chromatography and eluted with 1:1 Hex./EtOAc to give 2,4-di(benzyloxycarbonyl)butylbenzylphosphinic acid (7) (11.5 g, 47%) as a clear and colorless oil. Rf. 0.16 (1:1 Hex./EtOAc);
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: COC(OC)c1cccc(N)c1
Solvent: c1ccccc1
Product: COC(OC)c1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
334 mg of 3-aminobenzaldehyde dimethyl acetal was dissolved in 10 ml of anhydrous benzene, and 212 mg of benzaldehyde and 2 g of molecular sieve 4A (a product of Nippon Chromato Kogyo Co., Ltd.) were added. The mixture was stirred at room temperature for 4 hours. The molecular sieve was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was dissolved in 20 ml of methanol, and 100 mg of sodium borohydride was added. The mixture was stirred for 2 hours. The reaction mixture was diluted with water, and extracted with ethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was recrystallized from hexane to give 451 mg (yield 87.7%) of 3-benzylaminobenzaldehyde dimethyl acetal having a melting point of 55° to 56° C.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(O)C.[Ni]>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[C:4]([F:11])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccncc2)c1F
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(F)c(-c2ccncc2)c1F
Yield: 68 %

Procedure:
A solution of 4-(2,6-difluoro-3-nitrophenyl)pyridine (10.9 g) in ethanol (500 ml) was hydrogenated (at 50 p.s.i.) for 1 hour over 15 g of Raney Nickel The reaction mixture was then filtered through Supercel and the filtrate was evaporated in vacuo to give the product as a white solid of m.p. 190°-192° C. (6.6 g, 68% yield).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.[Li].C(O)C>CCOCC>[N:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:18]3[CH2:17][CH:16]=[CH:15][CH2:14][C:13]=3[CH2:12][CH:11]2[OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC1Cc2ccccc2C1CCCN1CCCCC1
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: OC1CC2=C(CC=CC2)C1CCCN1CCCCC1

Procedure:
The crude 1-(3-piperidinopropyl)-2-indanol (~ 0.2 M) is dissolved in 300 ml ether and added to 2 liters liquid ammonia. Lithium ribbon (50 g) is added in small portions over a period of 30 minutes. After stirring 11/2 hours, absolute ethanol is added dropwise until the color is discharged (~ 1 liter added over a period of 4 hours). The ammonia is allowed to evaporate and the residue is then diluted to 4 liters with water; two ether extracts yield 62 g of crude diene which becomes partially crystalline on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O:12][C:13](=O)[CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:15](=O)[CH3:16])C>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:14]2[C:13](=[O:12])[NH:1][C:2]3[C:3]([C:15]=2[CH3:16])=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=3)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: Cc1cc(N)cc(O)c1
Product: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Temperature: 150 °C

Procedure:
A mixture of 3-amino-5-methylphenol (0.25 g) and 2-(4-chlorobenzyl)-3-oxobutyric acid ethyl ester (0.52 g) was heated at 150° C. under nitrogen for 7 hours. The mixture was cooled to room temperature and the residue triturated with methanol to afford the title compound as an off-white solid, 0.32 g.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([NH:36][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopropylamine (20 mg, 0.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford the title compound.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14](Br)[C:15]2[N:16]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:17]=1>CN(C)C=O>[CH2:1]([O:8][C:14]1[C:15]2[N:16]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:17]=[C:12]([Br:11])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2c(Br)cc(Br)cn2c1C
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3ccccc3)cc(Br)cn2c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
34.8 ml of benzyl alcohol are added dropwise with ice-cooling to a suspension of 13.5 g of sodium hydride (60% strength suspension in paraffin) in 510 ml of dimethylformamide and the mixture is stirred for 1 h until the evolution of gas is complete. 51.2 g of 6,8-dibromo-2,3-dimethylimidazo[1,2-a]pyridine are then introduced in small portions and the mixture is stirred at room temperature for 40 h. It is then poured onto 1 l of ice water and extracted three times with 100 ml of dichloromethane each time. The combined organic extracts are washed with saturated ammonium chloride solution and twice with water, and concentrated to dryness in vacuo and the residue is stirred with a little ethyl acetate. The precipitate obtained here is filtered off and dried in vacuo. 43.2 g of the title compound of melting point 151–3° C. (ethyl acetate) are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
A mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (300 mg), 4-chlorobenzyl chloride (210 mg), potassium carbonate (214 mg) and DMF (10 ml) was stirred at room temperature for 13 hours and at 50° C. for 3 hours. The reaction mixture was mixed with water and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (272 mg) as colorless crystals.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][N:29]([CH3:37])[C:30](=[O:36])[CH2:31][CH2:32][C:33](O)=[O:34]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH2:31][C:30]([N:29]([CH3:37])[CH3:28])=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CN(C)C(=O)CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CN(C)C(=O)CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (48 mg, 52%), MS (ISP) m/z=458.6 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 4-(dimethylamino)-4-oxobutanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[Cl:7][C:8]1[CH:33]=[CH:32][C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[CH2:15][CH2:16][N:17](CC3C=CC=CC=3)[CH2:18][CH2:19][O:20][C:10]=2[CH:9]=1.Cl>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:33]=[CH:32][C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[CH2:15][CH2:16][N:17]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:19][O:20][C:10]=2[CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc2c(c1)OCCN(Cc1ccccc1)CCc1ccccc1O2
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCOc2cc(Cl)ccc2Oc2ccccc2CC1
Yield: 95 %

Procedure:
4.47 ml of chloroformic acid ethyl ester were added at room temperature to a solution of 4.17 g of 3-chloro-7,8,9,10-tetrahydro-8-phenylmethyl-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine in 390 ml of toluene. The mixture was heated to reflux overnight, and after cooling shaken with excess of 1N hydrochloric acid. The toluene layer was separated and the acid aqueous layer extracted with diethyl ether. The combined organic extracts were shaken with 1N hydrochloric acid and water, after which the organic layer was concentrated in vacuo and dried azeotropically to yield 3.78 g (95%) of ethyl 3-chloro-7,8,9,10-tetrahydro-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine-8-carboxylate. Rf 0.6 (silica; hexane-acetone 8:2).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=O)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CSc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ccc(-c2cc3ccccc3c(Cl)n2)cc1

Procedure:
The resulting 3-(4-methylthiophenyl)isoquinolin-1-one (0.73 g) was reacted with phosphorus oxychioride (5 ml) according to the method of Example 10-2, to give 1-chloro-3-(4-methylthiophenyl)isoquinoline. Then, N-ethylpiperazine (10 ml) and potassium carbonate (0.36 g) were added to the resulting product as it was. The resulting mixture were reacted at 100° C. overnight. The reaction solution was evaporated, and the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.95 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[N:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].[H-].[Na+]>CN(C)C=O>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([C:25]3[C:26]([C:27]#[N:28])=[CH:29][CH:30]=[CH:31][N:32]=3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1-n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21

Procedure:
5-(4-Phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ylamine (906 mg) was reacted with 2-chloronicotinonitrile (510 mg) in the presence of sodium hydride (150 mg) in dimethylformamide (30 ml) at 100° C. for 5 hours to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-3-carbonitrile, m.p. 242-242.5° C., after workup.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[N:3]=1.CI.[C:19](=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][CH3:19])=[O:15])=[CH:11][CH:12]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(-c2ccc(CC(=O)O)cc2)no1
Agent: [K+]
Solvent: CI
Product: COC(=O)Cc1ccc(-c2noc(C)n2)cc1

Procedure:
Reaction of equimolar amounts of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylacetic acid, methyl iodide and potassium carbonate gives methyl 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylacetate (“D”).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[CH3:15]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 5-acetyl-2-hydroxybenzoate (95.3 g, 490.6 mmol) was added to DMF (381 mL) and potassium carbonate (82.2 g, 588.8 mmol) at RT under an atmosphere of nitrogen. To the resulting suspension was added methyl iodide (90.5 g, 637.8 mmol) whilst maintaining good agitation. After stirring at RT for 30 minutes, the crude reaction mixture was analysed by GC demonstrating complete reaction. Water (380 mL) was added followed by further water (380 mL) and the resulting white solid filtered off to afford 82.5 g of the desired, water wet product (7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:24])[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[K+].[K+].Br[C:37]1[CH:46]=[CH:45][C:44]2[N:43]([CH3:47])[C:42](=[O:48])[CH:41]=[C:40]3[C:49]4[C:54]([C:55](=[O:56])[C:38]=1[C:39]=23)=[CH:53][CH:52]=[CH:51][CH:50]=4>CO.ClC1C=CC=CC=1Cl>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:7]1[C:6](=[O:24])[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37]3[CH:46]=[CH:45][C:44]4[N:43]([CH3:47])[C:42](=[O:48])[CH:41]=[C:40]5[C:49]6[C:54]([C:55](=[O:56])[C:38]=3[C:39]=45)=[CH:53][CH:52]=[CH:51][CH:50]=6)=[C:13]3[C:14]=2[C:9](=[CH:10][CH:11]=[CH:12]3)[C:8]1=[O:15]
Reactant: Cc1ccc(N2C(=O)c3cccc4c(N)ccc(c34)C2=O)c(C)c1
Reactant: Cn1c(=O)cc2c3c(c(Br)ccc31)C(=O)c1ccccc1-2
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: Cc1ccc(N2C(=O)c3cccc4c(Nc5ccc6c7c(cc(=O)n6C)-c6ccccc6C(=O)c57)ccc(c34)C2=O)c(C)c1
Temperature: 120 °C

Procedure:
To a three-necked round-bottomed flask equipped with a thermometer and a Dean-Stark apparatus was charged 6-amino-2-(2,4-dimethylphenyl)benzo[de]isoquinoline-1,3-dione (4.69 g), potassium acetate (1.443 g), potassium carbonate (2.032 g), cupric acetate (0.1262 g), cupric iodide (0.120 g), and ortho-dichlorobenzene (45 ml) to obtain a mixture. The mixture was heated to 120° C. in about 10 minutes. After being maintained at 120° C. for about 30 minutes, 6-bromo-3-methyl-3H-naphtho[1,2,3-de]quinoline-2,7-dione (5 g) and ortho-dichlorobenzene (45 ml) were added to the mixture. Then the temperature of the resulting reaction mixture was raised to 165° C. over a period of about 1.5 hours. After being maintained at this temperature for about 4 hours, formation of a red solid was observed. A portion of the reaction mixture was spotted on a TLC plate and viewed under ultraviolet radiation to monitor the disappearance of the starting materials 6-amino-2-(2,4-dimethyl)phenyl-benzo[de]isoquinoline-1,3-dione and 6-bromo-3-methyl-3H-naphtho[1,2,3-de]quinoline-2,7-dione. After being heated for 2 more hours at the same temperature, TLC analysis of the reaction mixture indicated the absence of both the starting materials. The reaction mixture was then cooled, poured into 175 ml of methanol, filtered, and the filter cake was washed with 2 to 3 100 ml portions of methanol to give the desired product in a yield of 7.2 g.
Reaction SMILES: N[C@@H](CCC(N[C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=O)[CH2:12]S)=O)C(O)=O.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=[O:29])N2[C@H]1C(O)=O.N1CCC[C@H]1C(O)=O>>[NH:16]1[CH2:14][C@H:11]([OH:29])[CH2:12][C@H:17]1[C:18]([OH:20])=[O:19]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
A plasmid (pD4-α1, FIG. 67) encoding the gene for the carboxy terminal 219 amino acids of human Type I (α1) collagen with optimized E. coli codon usage fused to the 3′-end of the gene for glutathione S-transferase and under control of the tac promoter and containing the gene for ampicillin resistance was used to transform by electroporation proline auxotrophic E. coli strain JM109 (F-). Transformation cultures were plated on LB agar containing 100 μg/ml ampicillin. After overnight incubation at 37° C., a single colony from a fresh transformation plate was used to inoculate 100 ml of LB media containing 100 μg/ml ampicillin. This culture was grown to an OD600nm of 0.5 and 100 μl aliquots transferred to 1.5 ml tubes. The tubes were stored at −80° C. For expression, a tube was thawed on ice and used to inoculate 25 ml of LB media containing 400 μg/ml ampicillin. After overnight growth at 37° C., a four ml aliquot was withdrawn, centrifuged, the cell pellet washed once with 1 ml of 2×YT media containing 400 μg/ml ampicillin, and the washed cells used to inoculate 1 L of 2×YT medium containing 400 μg/ml ampicillin. This culture was grown at 37° C. to an OD600nm of 0.8. The culture was centrifuged and the cell pellet washed once with 100 ml of M9 medium (1× M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 400 μμg/ml ampicillin). The cells were resuspended in 910 ml of M9 medium (1× M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 400 μg/ml ampicillin) and allowed to grow at 37° C. for 30 minutes. NaCl (80 ml of 5 M), hydroxyproline (7.5 ml of 2M), and IPTG (500 μl of 1 M) were added and growth continued for 3 hours. Cells were harvested by centrifugation and stored at ˜20° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][NH:15][CH3:16]>CS(C)=O.CCOC(C)=O>[CH3:14][N:15]([CH3:16])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: CNC
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)c1ccc(C#N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Fluoro-3-(trifluoromethyl)benzonitrile (240 mg, 1.27 mmol) was dissolved in DMSO (1 ml) together with dimethylamine (1 ml, 40% aq). The mixture was stirred at r.t. for 18 hours followed by 4 hours at 50° C. The reaction was cooled, diluted with EtOAc (10 ml), washed with H2O (2*20 ml), dried over MgSO4 and evaporated to give 253 mg (93%) of the title substance as a greenish oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:35])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19](=[N:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:38]=[C:39]([C:44]([O:46]C)=O)[C:40]([O:42][CH3:43])=[O:41]>O(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:35])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=3[O:33][CH3:34])[C:44](=[O:46])[C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][C:20]=1[CH2:21][CH3:22])=[CH:14][CH:13]=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Temperature: 190 °C

Procedure:
N-(1-(2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-indol-5-yl)butylidene)-1-(2,4-dimethoxyphenyl)methanamine (5.94 g, 12.0 mmol), prepared according to procedure described in Example 164 Step 1, was suspended in Ph2O (20 mL) then dimethyl 2-(methoxymethylene)malonate (3.55 g, 20.4 mmol, 1.7 eq) was added. The reaction mixture was heated to 190° C. for 1 h before mixture was cooled to room temperature then purified by flash column chromatography (0-50% EtOAc in CH2Cl2) to give the title compound. LC-MS 605.5 [M+H]+, RT 1.75 min.