Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:33][OH:34])=[CH:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1>ClCCl.C(OCC)C>[F:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[CH:33]=[O:34])=[CH:20]\[C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)/C=C/c1ccc(C=C(CO)c2ccc(F)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C=Cc1ccc(/C=C(/C=O)c2ccc(F)cc2)cc1
Yield: 55.6 %

Procedure:
To a suspension of pyridinium chlorochromate (PCC, 0.75 g, 3.5 mmol) in dichloromethane (20 mL) a dropwise solution of methyl 3-(E)(4-(2-(4-fluorophenyl)-3-hydroxyprop-1-en-1-yl)phenyl)acrylate (0.9 g, 2.9 mmol) in dichloromethane (5 mL) was added under constant stirring and the reaction mixture was stirred at room temperature for 1 hour. The reaction mass was diluted with diethyl ether (200 mL) and filtered through a celite bed, the filtrate was successively washed with saturated aqueous NaHCO3 solution (3×100 mL) and water (1×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the pure title compound as a white solid (0.5 g, 56% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH2:21][CH3:22])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([F:43])=[CH:30][C:29]=1[N:44]1[CH2:55][CH2:54][C:53]2[C:52]3[CH2:51][C:50]([CH3:57])([CH3:56])[CH2:49][C:48]=3[S:47][C:46]=2[C:45]1=[O:58])(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:27][C:28]1[C:33]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:20][N:19]([CH2:21][CH3:22])[CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:32][C:31]([F:43])=[CH:30][C:29]=1[N:44]1[CH2:55][CH2:54][C:53]2[C:52]3[CH2:51][C:50]([CH3:57])([CH3:56])[CH2:49][C:48]=3[S:47][C:46]=2[C:45]1=[O:58])(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Reactant: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Product: CCN1CC(c2ccc(Nc3cc(-c4cc(F)cc(N5CCc6c(sc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)C1
Yield: 37 %

Procedure:
Following Example 136a, starting with 5-bromo-3-(5-(1-ethylazetidin-3-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 250a and (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 247b, compound 257a was obtained in 37% yield.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].CN(C)C=O>O.C(=O)([O-])[O-].[Na+].[Na+]>[NH:19]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]3[CH2:6][O:5][C:4]4[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=4[C:2](=[O:1])[C:8]=3[CH:9]=2)=[N:14][N:21]=[N:20]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)C(=O)c1ccccc1OC2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(-c3nnn[nH]3)ccc2COc2ccccc21

Procedure:
Heat a mixture of 800 mg. of the nitrile of Example 2, Step F, 293 mg. of sodium azide and 265 mg. of ammonium chloride in 25 ml. of dimethylformamide at 130°-135° C. for 6 hours. Dilute the mixture with water and excess sodium carbonate. Extract with ethyl acetate. Acidify the aqueous phase and separate and precipitate by filtration to obtain the title product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:35])[CH2:25][CH2:26][S:27][CH2:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:35])[CH2:25][CH2:26][S:27][CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[S:32][CH:33]=1)[CH3:22]
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CCSCc1csc(N)n1
Product: CCOC(=O)CCSCc1csc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)n1

Procedure:
3-[2-(3-Isopropoxy-5-phenoxy-benzoylamino)-thiazol-4-ylmethylsulfanyl]-propionic acid ethyl ester was prepared from 3-isopropoxy-5-phenoxy-benzoic acid and 3-(2-amino-thiazol-4-ylmethylsulfanyl)-propionic acid ethyl ester following general procedure A.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:23])([F:24])[F:22])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: COc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccncc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccncc2)c(O)c1)C(F)(F)F
Yield: 17.7 %

Procedure:
To a stirred suspension of N-[3-methoxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.05 g, 2.6 mmol) in dry methylene chloride (30 mL) was added boron tribromide (10.4 mL of a 1.0 M solution of boron tribromide in methylene chloride, 10.4 mmol). The resulting solution was stirred at reflux for 2 hours. An additional 5 mL of 1.0M boron tribromide solution in methylene chloride was added and the reaction stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride (50 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to yield an oil. Purification by flash column chromatography (20% v/v methanol in ethyl acetate) yielded the title propanamide as a white solid (0.18 g, 18%); mp 188°-189° C. 1H-NMR (250 MHz, d6-DMSO): 1.54 (s, 3H, CH3) 7.35 (d, 1H, J=9.0 Hz, aromatic) 7.51 (s, 1H, OH) 7.61 (s, 1H, aromatic) 7.77 (d, 2H, J=5.5 Hz, aromatic) 7.84 (d, 1H, J=8.9 Hz, aromatic) 8.83 (d, 2H, J=5.5 Hz, aromatic) 10.26 (s, 1H, NH) 11.04 (s, 1H, ArOH). MS (CI, CH4): 391 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([Br:16])[CH:10]=1)=S)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[C:1]([N:5]=[C:6]=[N:8][C:9]1[CH:10]=[C:11]([Br:16])[CH:12]=[C:13]([Br:15])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=S)Nc1cc(Br)cc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N=C=Nc1cc(Br)cc(Br)c1

Procedure:
To a solution of 3.5 g N-t-butyl-N'-(3,5-dibromophenyl)thiourea produced in Example A-9 in 80 ml of dichloromethane were added 5.0 g of triphenylphosphine, 3.0 g of carbon tetrachloride and 1.9 g of triethylamine. The mixture was refluxed for 4 hours and evaporated in vacuo. The residue was extracted with petroleum ether and the extract evaporated in vacuo to give N-t-butyl-N'-(3,5-dibromophenyl)carbodiimide as an oil. To a solution of this oil in 30 ml of DMF were added 1.9 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 4 hours, cooled to room temperature and poured into 700 ml of water. The resulting crystals were collected, washed with small amount of cyclohexane and recrystallized from benzene to give 2.0 g of the title compound as colorless needles melting at 189.0°-191.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:25])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][O:22][C:23]=3[CH3:24])=[CH:15][CH:14]=2)[CH3:9])=[N:6][CH:7]=1.[CH:26](B1OC(C)(C)C(C)(C)O1)=[CH2:27].CC1C(P(C2C(C)=CC(C)=C(S([O-])(=O)=O)C=2)C2C(C)=CC(C)=C(S([O-])(=O)=O)C=2)=CC(S([O-])(=O)=O)=C(C)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CC#N.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][C:23]1[O:22][N:21]=[CH:20][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:11]([NH:10][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([CH:26]=[CH2:27])=[CH:7][N:6]=2)[CH3:9])=[O:25])=[CH:14][CH:15]=1
Reactant: Cc1oncc1-c1ccc(CC(=O)N[C@H](C)c2ccc(Br)cn2)cc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])cc1P(c1cc(S(=O)(=O)[O-])c(C)cc1C)c1cc(S(=O)(=O)[O-])c(C)cc1C
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: C=Cc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3cnoc3C)cc2)nc1
Reaction time: 0.33 h

Procedure:
To a solution of 0.18 g (0.46 mmol) N-[(1R)-1-(5-bromopyridin-2-yl)ethyl]-2-[4-(5-methylisoxazol-4-yl)phenyl]acetamide in 0.50 ml CH3CN and 0.50 ml water was added 0.07 g (0.46 mmol) 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.02 g (0.03 mmol) TXPTS, 0.003 g (0.01 mmol) Palladium (II) acetate, and 0.13 mL (0.92 mmol) diisopropylamine. After 20 min in the microwave at 120° C., the reaction mixture was cooled, extracted with CH2Cl2, and washed with brine. The organic layer was dried over NaSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 40-85% EtOAc:hexane) afforded 2-[4-(5-methylisoxazol-4-yl)phenyl]-N-[(1R)-1-(5-vinylpyridin-2-yl)ethyl]acetamide. Electrospray mass spec M+H=348.1.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Cl[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:12]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:10]=1>CO.[OH-].[Na+].C(#N)C.O.O.O.O.O.[Cl-].[Mn+2].[Cl-]>[OH:4][CH2:3][CH2:2][N:1]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:12]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: OCCNCCO
Agent: [Mn+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: OCCN(CCO)c1cc(-c2ccccn2)nc(-c2ccccn2)c1

Procedure:
3.41 g (17.2 mmol) of manganese(II) chloride tetrahydrate and 98 g (0.93 mol) of diethanolamine are added in succession to a mixture of 2.14 g (8 mmol) of 4′-chloro-[2,2′;6′,2″]-terpyridine in 200 ml of methanol. The mixture is heated at reflux for 14 hours, cooled and concentrated. The residue so obtained is stirred in 250 ml of sodium hydroxide solution in acetonitrile/water 1:1 (v/v, pH>12) for 20 hours in air. Acetonitrile is removed using a rotary evaporator and the aqueous portion is extracted three times with chloroform. The organic extract is filtered over sodium sulfate and concentrated. Diethyl ether is added to the residue and the mixture is stirred and filtered, yielding 2-[(2-hydroxy-ethyl)-[2,2′;6′,2″]-terpyridin-4′-yl-amino]-ethanol in the form of a white solid. 1H-NMR (360 MHz, CD3OD): 3.76 (t, J=5.4 Hz, 4H); 3.85 (t, J=5.4 Hz, 4H); 7.38-7.47 (tm, 2H); 7.69 (s, 2H); 7.94 (dt, J=8.1, 1.8 Hz, 2H); 8.53 (d, J=8.1 Hz, 2H); 8.58-8.65 (dm, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:24])[CH:4]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:24])[CH:4]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(C=Cc1ccccc1)CCl

Procedure:
A mixture of 1-chloro-3-(triphenylphosphanylidene)-propane-2-one (2.8 g, 7.9 mmol) and freshly distilled benzaldehyde (0.7 g, 6.6 mmol) in toluene (10 ml) is heated at reflux for 20 hours. Evaporation to dryness yields a mixture containing the title compound that is used in the subsequent step without purification.
Reaction SMILES: C1(C)C=CC=C[C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19](C3C=CC=CC=3C)=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[Br:30]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:2][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccccc1-c1ccc(S(=O)(=O)c2ccc(-c3ccccc3C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(c1ccccc1)c1ccc(CBr)cc1
Yield: 171.6 %

Procedure:
A solution of p-tolyl phenylsulphone (20 g) in refluxing CCl4 (400 ml) containing dibenzoyl peroxide (0.4 g) was treated with N-bromosuccinimide (15.3 g) in portions rapidly. The mixture was heated under reflux for 30 min., filtered whilst hot and the filtrate allowed to cool. Evaporation gave the title compound (26.8 g), m.p. (103°-104°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)=[O:6]
Reactant: NCC(c1ccccc1)c1ccnnc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: O=C(NCC(c1ccccc1)c1ccnnc1)c1ccc(Cl)cc1Cl

Procedure:
From 2,4-dichlorobenzoic acid and 2-phenyl-2-(pridazin-4-yl)ethanamine. LCMS (MH+): m/z=372.1, tR (minutes, Method G)=2.09
Reaction SMILES: [Na].FC(F)(F)S(O[C:8]1[C:13]([Br:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[C:16](=[O:18])[CH3:17])(=O)=O.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:14][C:13]1[C:8]([C:24]2[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=2)=[C:9]([C:16](=[O:18])[CH3:17])[CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: CC(=O)c1cc(Cl)cc(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)cc(Br)c1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 89.2 %

Procedure:
A solution of sodium hydrogenecarbonate (2.0 g, 23 mmol) in water (50 mL) was treated with a solution of 2-acetyl-6-bromo-4-chlorophenyl trifluoromethanesulfonate (4.5 g, 12 mmol) in toluene (50 mL) followed by (3,5-difluorophenyl)boronic acid (2.0 g, 13 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.67 g, 0.58 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated at 80° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with sodium bicarbonate, water, and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0%-10%) gave the desired product (3.7 g, 82%). LCMS for C14H9BrClF2O (M+H)+: m/z=344.9, 346.9. Found: 344.9, 346.8.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>O1CCCC1>[O:1]=[C:2]1[CH2:6][S:5][CH2:4][N:3]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CSCN1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CSCC1=O

Procedure:
A solution of 4-oxothiazolidine (50 g) in tetrahydrofuran (900 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil) (22.6 g) in tetrahydrofuran (850 ml) at room temperature and the mixture was allowed to warm up to reflux temperature. After the mixture was refluxed for an additional 30 minutes, ethyl bromoacetate (60 ml) was added dropwise under that condition. The mixture was refluxed further 1 hour and then cooled. Insoluble materials were removed by filtration. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography by eluting with chloroform to give ethyl 4-oxo-3-thiazolidinylacetate (78.5 g) as light brown powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].Cl>[OH-].[Na+]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([C:27](=[O:29])[CH3:28])[CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C)CC1C
Reaction time: 0.5 h

Procedure:
1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.3 g) is dissolved in 10% aqueous sodium hydroxide (5 ml), and thereto is added acetic anhydride (0.3 ml) at room temperature, and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is acidified with conc. hydrochloric acid and is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is purified by silica gel column chromatography (solvent, dichoromethane) and then recrystallized from methanol to give 1-cyclopropyl-7-(4-acetyl-3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 g), as white powder, m.p. 219°-221° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1)[CH3:2].Cl>[Pd].CO>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([C:9]2[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(C(N)=O)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCC(c2cccc(C(N)=O)c2F)CC1

Procedure:
Preparation according to preparation 18: 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzamide (0.75 g, 3.0 mmol), methanol (20 ml), palladium on carbon (0.2 g) and hydrochloric acid (0.2 ml, conc.). Yield: 0.57 g. MS m/z (relative intensity, 70 eV) 250 (M+, 48), 249 (26), 236 (34), 235 (bp), 109 (30).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>CN(C)C=O>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[CH2:16][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: ClCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCc3ccc4ccccc4n3)cc21
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a slurry of NaH (0.29 g, 12.25 mmol) in 25 mL dimethylformamide under nitrogen at 0° C. is added portionwise 7-hydroxy-1-tetralone (2.0 g, 12.33 mmol) over 5 minutes. After half an hour, 2-(chloromethyl)quinoline (2.2 g, 12.43 mmol) is added in 10 mL dimethylformamide. The ice bath is removed and the reaction mixture is stirred overnight. The solvent is then removed in vacuo and the residue is partitioned between 1N sodium hydroxide and methylene chloride. The organic layer is separated, dried over magnesium sulfate, evaporated down to an oil, and chromatographed on silica gel. Elution with 9-1 methylene chloride/ethyl acetate gives 2.0 g (54%). This material is recrystallized from acetonitrile to afford 1.3 g (35%) of yellow crystals, m.p. 98.5°-101.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:19])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[CH2:14][CH2:13]2)[CH3:11])=[CH:6][CH:7]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](O)CC1
Reactant: BrCCCCCBr
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](OCCCCCBr)CC1

Procedure:
In analogy to example 11.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester and 1,5-dibromopentane were reacted to yield trans-[4-(5-Bromo-pentyloxy)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester as yellow oil, MS: 433 (MH+, 1Br, 1Cl).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].O.C(OCC)(=O)C>C1COCC1.C(OCC)C>[Cl:6][C:7]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:8]=1[CH:9]([CH:1]1[CH2:3][CH2:2]1)[OH:10]
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc(C(F)(F)F)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
84 ml (41.9 mmol) of 0.5N cyclopropylmagnesium bromide solution in THF were added to 5.83 g (30.0 mmol) of 2-chloro-4-(trifluoromethyl)benzaldehyde in 117 ml of diethyl ether at 0° C., and the mixture was warmed to RT and stirred at RT overnight. The reaction mixture was added to water and ethyl acetate, the phases were separated, the aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 95/5) to result in 5.00 g (61% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]([OH:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][N:17]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]([O:25][C:44](=[O:46])[CH3:45])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][N:17]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1cc2c(C(O)CC(C)C)cn(-c3ccc(C(C)C)cc3)c2cn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc2c(C(CC(C)C)OC(C)=O)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3-methyl-butan-1-ol (20 mg, 0.044 mmol) in DCM (2 mL), N,N-diisopropylethylamine (15 μL, 0.08 mmol), acetic anhydride (6.6 μL, 0.06 mmol), and DMAP (1 mg) were added. The mixture is stirred at room temperature for 4 h. All volatiles are removed under reduced pressure and the residue is purified by chromatography to afford acetic acid 1-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3-methyl-butyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36]C)[N:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[N:6][CH:7]=1.Br.C(O)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[CH:27]=[CH:28][N:29]=[C:30]5[C:35]=4[NH:34][C:33](=[O:36])[CH:32]=[CH:31]5)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[N:6][CH:7]=1
Reactant: COc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cn5)c5ccccc45)cc3)c2n1
Agent: Br
Solvent: CC(=O)O
Product: O=c1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cn5)c5ccccc45)cc3)c2[nH]1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A small reaction vial was charged with 4-(5-chloropyridin-2-yl)-N-(4-(6-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (50 mg, 0.096 mmol), HBr (1.04 mL, 19.12 mmol), and acetic acid (1.1 mL, 19.12 mmol). The mixture was stirred at 85° C. for 2 hrs. LC/MS showed completion of the reaction. The reaction mixture was poured onto an aqueous sodium bicarbonate solution ice bath and the product was extracted with DCM. The organic layer was dried over sodium sulfate and concentrated to afford 8-(4-(4-(5-chloropyridin-2-yl)phthalazin-1-ylamino)phenylthio)-1,5-naphthyridin-2(1H)-one as yellow solid. MS: [M+H]=509.1; Calc'd for C27H17ClN6OS: 509.