Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][C:7](=[O:10])[CH2:8]Br)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[N-:17]=[N+:18]=[N-:19].[Na+]>>[C:1]1(=[O:16])[N:5]([CH2:6][C:7](=[O:10])[CH2:8][N:17]=[N+:18]=[N-:19])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)CN1C(=O)c2ccccc2C1=O
Yield: 95 %

Procedure:
A suspension of (3-phthalimidoacetonyl)bromide, ethylene ketal (70.0 g, 210mmole) and sodium azide (33.0 g, 504 mmole) in 25 ml. of dimethyl sulfoxideis heated on a steambath under nitrogen for 4 days. The above mixture is poured onto ice and extracted with chloroform (3×, 500 ml). The chloroform extract is washed with water (2×), saturated sodium chloride solution and dried over anhydrous sodium sulfate. Evaporation of chloroform in vacuo gives a white oil which on trituration with hexane crystallizes to afford 59 g, (95%) of (3-phthalimidoacetonyl)azide, ethylene ketal as white prisms of melting point 90.5°-92° C.An analytical sample recrystallized from ethyl acetate hexane has a meltingpoint 92.5°-93.5° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][S:7]([OH:10])(=O)=[O:8])=[N+:2]=[N-:3].[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C1C=CC=CC=1>[N:1]([CH2:4][CH2:5][CH2:6][S:7]([Cl:13])(=[O:10])=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCS(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: c1ccccc1
Product: [N-]=[N+]=NCCCS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Azidopropanesulfonic acid, sodium salt 5 (1.87 g, 10.0 mmol) was suspended in dry benzene (20 mL), and PCl5 (2.3 g, 10.5 mmol) was added to the suspension. The mixture was stirred at room temperature for 30 minutes, then at gentle reflux for about 1 hour. The benzene and P(O)Cl3 were removed by evaporation under reduced pressure. Benzene was added to the crude mixture and the solvent was removed again under reduced pressure. The residue was dried in vacuo. The dried residue was dissolved in dichloromethane (anhydrous, 15 mL) and cooled at −10° C. using an ice/acetone bath.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9](C2C=C3C(=CC=2)CN(S(C2C=CC(C)=CC=2)(=O)=O)CC3)[CH2:8]1.[CH3:32][O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[C:44](Br)[CH:45]=[CH:46][C:39]=2[CH2:38][CH2:37]1)=[O:35].C[C@H]1CCCN1[C@H]1CCNC1>>[CH3:32][O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[C:44]([N:9]3[CH2:10][CH2:11][C@H:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)[CH:45]=[CH:46][C:39]=2[CH2:38][CH2:37]1)=[O:35]
Reactant: COC(=O)N1CCc2ccc(Br)cc2CC1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)cc1
Agent: C[C@H]1CCCN1[C@H]1CCNC1
Product: COC(=O)N1CCc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)cc2CC1

Procedure:
This intermediate was synthesized in substantially the same way as intermediate (vi), 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline, by condensation of 7-bromo-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid methyl ester with (2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH2:14]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:21]([N:20]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:1](=[O:13])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: CCCCCCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Homovanillic acid (182 mg, 0.999 mmol) dissolved in DMF (3 ml) was cooled in an ice-bath. N-Hexylbenzylamine (201 mg, 1.049 mmol) was added and then TBTU (337 mg, 1.049 mmol) followed by DIPEA (407 mg, 3.147 mmol). The mixture was stirred at room temperature overnight and evaporated. Sodium hydrogencarbonate aqueous solution (sat.) was added into the residue. The mixture was then extracted with ethyl acetate (×2). The extracts were combined and washed with water and brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/15 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 264 mg the desired product, yield 74%.
Reaction SMILES: [CH2:1]1[C:14]2[CH:5]([CH2:6][CH:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH2:8]3)[CH2:4][CH2:3][CH2:2]1>[H][H]>[CH:4]1[C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: C1=CCC2CC3CCCCC3=CC2=C1
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 480 °C
Yield: 101 %

Procedure:
In the dehydrogenation apparatus described in Example 2 the preheating zone was heated to a temperature of 480° C. and the reaction and afterheat zone were heated to a temperature of 520° C. 400 ml molten sym.-octahydroanthracene (385 g) of Example 3 were added drop by drop per hour from a drip funnel heated to 95° C. At the same time about 4 liter hydrogen per hour were added as a carrier gas. 372 g of raw anthracene were obtained per hour, which contained as impurities 1.8 percent 9,10-dihydroanthracene, 2.5 percent 1,2,3,4-tetrahydroanthracene, 2.6 percent sym.-octahydroanthracene and 2.9 percent phenanthrene.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1)[CH2:6][CH2:7][CH3:8].[O:17]1[C:22]2=[C:23]([C:30](OC)=[O:31])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[N:21]2[CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:5]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:30]([C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[N:21]3[CH2:20][CH2:19][CH2:18][O:17][C:22]=23)=[O:31])[CH2:11][CH2:10]1)[CH2:6][CH2:7][CH3:8]
Reactant: COC(=O)c1c2n(c3ccccc13)CCCO2
Reactant: CCCCN1CCC(CN)CC1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCN1CCC(CNC(=O)c2c3n(c4ccccc24)CCCO3)CC1
Temperature: 10 °C
Yield: 93 %

Procedure:
Method A Toluene (85L) was azeotropically dried in an argon purged reactor, cooled to 10° C. and a solution of trimethylaluminum in toluene (18.57 kg, 16.7% w/w, 43 mole) added. To this at 20 to 24° C. was added a solution of 1-n-butyl-4-piperidinylmethylamine (7.39 kg, 99.4% pure, 42.7 mole) in toluene (22 L) over 43 minutes. Methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate (9.65 kg, 98.9% pure, 41.3 mole) was added in one portion and the reaction heated to reflux at 112° C. for 4 hours 10 minutes after which time the reaction was judged to be complete by HPLC analysis. 10% Sodium hydroxide solution (52.2 L), prepared from 32% ww sodium hydroxide (24 L) and water (80 L), was added cautiously over 16 minutes at about 60 to 70° C. The resulting mixture was heated to 70 to 80° C. and the aqueous layer separated. The toluene layer was washed with 10% sodium hydroxide (52.2 L) followed twice by water (29 L each wash). The toluene layer was cooled and diluted with hexane fraction (133 L) to crystallise the product. After cooling to about 2° C. overnight the product was collected by filtration, washed on the filter with hexane (21 L) and dried in vacuo at 40° C. overnight to give SB-207266 batch 207266-HP8 (12.26 kg, 94.5% pure, 75.9%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2].[F:18][C:19]([F:38])([F:37])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[C:28][CH2:29][CH2:30][CH2:31]OS(C)(=O)=O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:31][CH2:30][CH2:29][C:28]#[C:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][C:19]([F:18])([F:37])[F:38])=[CH:22][CH:23]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)n1ccc2ccc(O)cc21
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)C(C)n1ccc2ccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described in example 11 c], [rac]-2-(6-hydroxy-indol-1-yl)-propionic acid ethyl ester (GB 2253848 A1) was reacted with methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 9 a]) in the presence of cesium carbonate and potassium iodide to give the title compound as colorless liquid.
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:11][C:12]1[C:17]([F:18])=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[C:15]([NH2:28])=[C:14]([CH3:29])[CH:13]=1>>[CH2:1]([C:4]1([S:7]([NH:28][C:15]2[C:14]([CH3:29])=[CH:13][C:12]([F:11])=[C:17]([F:18])[C:16]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: Cc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Product: C=CCC1(S(=O)(=O)Nc2c(C)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Yield: 47.9 %

Procedure:
According to the general procedure B, 1-allyl-cyclopropanesulfonyl chloride (142 mg, 142 mg) was reacted with 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamine (150 mg, 0.4 mmol) to obtain the title product (100 mg, 47%); m/z=521 [M−1]−.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:28](=[O:32])/[CH:29]=[CH:30]/[CH3:31].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH:30]([CH3:31])[CH2:29][CH:28]=[O:32])=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: C/C=C/C=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)C(C)CC=O
Temperature: 0 °C
Yield: 92 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (15 ml) was added triethylamine (0.34 ml, 0.0024 mole), trimethyl silylchloride (0.30 ml, 0.0024 mole) and crotonaldehyde (0.20 ml, 0.0024 mole). The reaction mixture was stirred at reflux temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 5% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a yellow oil (0.60 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[CH:24]1([C:27]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:12]2)=[O:28])[CH2:26][CH2:25]1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: O=C(O)C1CC1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3CC3)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 19 mg (0.22 mmol, 1.1 eq.) of cyclopropanecarboxylic acid were reacted according to General Method 1. Yield: 38 mg (50% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(O)[C:4]=2[CH:3]=1.[I-].[K+].O.[PH2](=O)[O-].[Na+].[PH2](=O)O>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:6]3[C:11]([C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: OC1(c2ccccc2)c2ccccc2C(O)(c2ccccc2)c2cc(Br)ccc21
Agent: O=[PH2]O
Agent: O=[PH2][O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
7.55 g (16.95 mmol) of the obtained 2-bromo-9,10-diphenyl-9,10-dihydroanthracene-9,10-diol, 5.06 g (30.51 mmol) of potassium iodide, 9.70 g (91.52 mmol) of sodium phosphinate monohydrate, and 50 mL of glacial acetic acid were put into a 500 mL three-neck flask, and the mixture was heated at 120° C. for 2 hours. Thereafter, 30 mL of 50% phosphinic acid was added to the mixture, and the mixture was stirred for 1 hour at 120° C. After the reaction, the mixture was washed with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in toluene, and the solution was filtered through celite, Florisil, and then alumina. The filtrate was concentrated, and the residue was recrystallized with chloroform and hexane, giving 5.1 g of 2-bromo-9,10-diphenylanthracene as a light yellow solid in 74% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].C(C1C=C(O)C(=CC=1)O)(C)(C)C.C(Cl)(Cl)[Cl:25].C(Cl)(=O)C(Cl)=O>CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:25])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a reaction vessel fitted with a cooling pipe, a stirrer, a thermometer and a nitrogen feed pipe, 20 parts of formula-(21) 4-vinylbenzoic acid, 0.6 part of 4-tert-butylcatechol and 225 parts of chloroform were fed, and then cooled to 15° C. or below. While keeping the liquid temperature at 15° C. or below, 2.8 parts of dehydrated N,N-dimethylformamide was added, and then 87.4 parts of oxalyl chloride was dropwise added thereto. After its addition made dropwise, the liquid temperature was raised to room temperature, followed by stirring for 20 hours. After the reaction was completed, the solvent was evaporated off under reduced pressure, and then 340 parts of n-heptane was added. The organic layer formed was washed with ion-exchanged water, and this organic layer was dried with magnesium sulfuric anhydride, followed by evaporation of the solvent under reduced pressure to obtain a crude product of formula-(22) 4-vinylbenzoic acid chloride (21.8 parts).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][N:6]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:24][CH2:23]1)[CH3:21]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1

Procedure:
The title compound was prepared from 4-bromo-1-(benzenesulfonyl)-1H-indole and 4-ethylpiperazine according to Method 1 to afford 129 mg (48%) of a white solid: 1H NMR (CD3OD) δ 7.94–6.81 (m, 10 H), 3.69–3.62 (m, 4 H), 2.34–3.26 (partly hidden) (m, 4 H), 3.14–3.04 (m, 2 H), 1.40 (t, J=7 Hz, 3 H); MS (ESI) 370.1 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=3)[N:14]=1)[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:22]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH:8]=[C:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]1=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc(-c2cncc(Cl)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncc(Cl)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A mixture of 1-benzyl-8-(5-chloro-pyridin-3-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (38 mg, 0.076 mmol), β-alanine (681 mg, 7.6 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 12 mg of the title compound as an off-white solid. MS: (+) m/z 555.23 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][CH:4]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([C:22]2[CH:21]=[C:6]([O:7][C:8]3[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]4[C:9]=3[CH2:10][CH2:11][CH2:12]4)[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C(=O)c1ccc(F)cc1

Procedure:
4-(4-methoxyphenoxy)-5-methyl-7-nitroindane (197 mg) and 4-fluorobenzoyl chloride (194 μL) were dissolved in dichloromethane (3.9 mL). Titanium tetrachloride (360 μL) was added dropwise to the solution under ice-cooling with stirring. The mixture was stirred under an argon atmosphere at room temperature for 15 hours. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=9/1) to give (4-fluorophenyl)-[2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)phenyl]methanone (155 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:24][N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3.[CH3:30][O:31][CH2:32]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[CH:22][N:23]([CH2:30][O:31][CH3:32])[N:24]=1)=[CH:16][CH:15]=3
Reactant: COCBr
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: COCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 36 above, using 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-5-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one from Example 39 above and bromomethyl methyl ether.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O.O>CCCCCC>[OH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cccc(C(=O)OC)c1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(=O)OC)c1O
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Dimethyl 2-hydroxyisophthalate (1.5 g) was added to a mixture of 69% nitric acid (5 ml) and concentrated sulfuric acid (5 ml) and the mixture was stirred in an ice bath for 0.5 hours. After pouring into iced water, the reaction mixture was extracted with ethyl acetate. The extract was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford a yellow solid. To the solid was added hexane and the mixture was filtered to give the desired compound (1.6 g, yield 89%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Br[CH2:18][CH3:19]>>[CH2:18]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH2:13][CH2:12]1)[CH3:19]
Reactant: CCBr
Reactant: Cc1ccc(N2CCNCC2)cc1[N+](=O)[O-]
Product: CCN1CCN(c2ccc(C)c([N+](=O)[O-])c2)CC1

Procedure:
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and 1-bromoethane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 249 (M+, 53), 234 (47), 84 (36), 57 (bp), 56 (46).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[C:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=1.Cl[CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][NH:29][C:28]1=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH:6]=[C:5]2[C:18]1[CH2:19][CH2:20][N:21]([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[CH2:22][CH:23]=1
Reactant: Fc1ccc(-n2cc(C3=CCNCC3)c3cc(Cl)ccc32)cc1
Reactant: O=c1[nH]ccn1CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1NCCN1CCN1CC=C(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 92.5 °C

Procedure:
5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole (6.0 kg. 16.5 mol), 1-(2-chloroethyl)imidazolon (3.19 kg, 1.3 eq.), sodium carbonate (anhydrous) and methyl isobutyl ketone (60 L) were mixed. The reaction mixture was heated under N2-cover and stirring until 90-95° C., and was stirred over night at this temperature. The next day the reaction mixture was filtered while still hot. The apparatus and filter cake were washed with further 2.5 L of methyl isobutyl ketone. The combined filtrates were left over night for crystallisation. The product was isolated on a nutch, washed with 7.5 L n-Heptane and dried over night in vacuum at 60° C.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.CC1CCN(CCN2CCC(N)CC2)CC1>>[CH3:5][CH:4]1[CH2:3][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:7][CH2:6]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: CC1CCN(CCN2CCC(N)CC2)CC1
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(C)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 7.