Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:20]2OC3[C:13](=CC=CC=3)[NH:12][C:11]=2C=C[CH:8]=1.NCCC1CCCN1C.[Cl-].[Al+3].[Cl-].[Cl-].CO>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:8][N:12]([CH3:13])[CH2:11][CH2:20]1
Reactant: c1ccc(-c2cccc3c2Oc2ccccc2N3)nc1
Agent: CN1CCCC1CCN
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2ccccn2)C1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
4-Pyridinyl phenoxazine (13 mg, 0.1181 mmol), 2-(2-aminoethyl)-1-methylpyrrolidine (22 ul, 0.1518 mmol) and aluminum chloride (27 mg, 0.2025 mmol) were mixed in anhydrous dichloromethane (1 ml) and stirred for 1 h. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3×10 ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the 4-pyridinyl methylpyrrolidine (11 mg) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH3:3][N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12]([S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH:11]=2)[CH2:8][CH2:9]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
NaH (330 mg, 8.25 mmol) was added in several batches, to a solution of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (1.4 g, 5.42 mmol) in DMF (25 mL) while cooling to 0-5° C. The resulting solution was stirred at room temperature for 0.5 hours, and then benzenesulfonyl chloride (1.5 g, 8.41 mmol) was added dropwise. The reaction was stirred for an additional 4 hours at room temperature, and then filtered. The filter cake was washed with ethanol (3×50 mL) and dried to afford 1.2 g (55%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(phenylsulfonyl)-1H-indole as a light yellow solid. 1H NMR (DMSO) δ 8.62 (s, 1H), 8.17-8.27 (3H), 8.10 (d, 2H), 7.74 (1H), 7.61 (2H), 6.32 (s, 1H), 3.84 (s, 2H), 3.38 (2H), 2.83-2.87 (5H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.[C:15](#[N:18])[CH:16]=[CH2:17].C1N2CCN(CC2)C1>CCOCC>[F:12][C:11]([F:14])([F:13])[O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][CH2:17][C:16]([C:15]#[N:18])=[CH:4]2
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: N#CC1=Cc2cc(OC(F)(F)F)ccc2OC1
Temperature: 130 °C
Yield: 49.8 %

Procedure:
To a microwave tube was added 2-hydroxy-5-trifluoromethoxybenzaldehyde (1 g, 5.0 mmol), 2-propenenitrile (1.6 mL, 24.3 mmol) and triethylenediamine (136 mg, 1.2 mmol). The reaction was heated in the microwave at 130° C. for 1 hour. After cooling, the resulting solution was diluted with ether (100 mL) and washed with 1N NaOH (50 mL), 1N HCl (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (0 to 15% EtOAc in hexanes over 1 hour) gave the product (600 mg) as a solid. m/z=242.4 (M+1), r.t.=3.72 mins. 1H NMR (400 MHz; CDCl3) δ 7.14-7.12 (2H, m), 7.00 (1H, s), 6.89 (1H, d), 4.85 (2H, s).
Reaction SMILES: [CH3:1][Li].C[Si](Cl)(C)C.[Br:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16]([CH:25]=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]2[CH3:32])=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC.C1COCC1>[Br:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16]([CH:25]([CH3:1])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]2[CH3:32])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C=Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Reactant: [Li]C
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 73.1 %

Procedure:
To a 0° C. suspension of cuprous iodide (12.7 g, 67.0 mmol) in 150 mL ether was added CH3Li (1.4M in ether, 96 mL, 134 mmol). The solution was cooled to -78° C. and treated with TMSCl (8.5 mL, 67 mmol) and a solution of the unsaturated ester from Step 3 (6.79 g, 15.8 mmol) in 30 mL of THF. The yellow suspension was allowed to warm to room temperature and was stirred 2.5 h. The reaction mixture was poured into saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with water and brine and dried over Na2SO4. Purification by flash chromatography (20% ethyl acetate/hexanes) provided 5.13 g of the title product as a crystaline solid.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)[N:12]=[C:11]([NH:24][CH:25]([CH3:27])[CH3:26])[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2>CC(O)C.ClCCl.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:12]=[C:11]([NH:24][CH:25]([CH3:27])[CH3:26])[CH:10]=[C:9]([N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH2:2][O:3][CH2:4]4)[N:14]=2)=[CH:20][CH:19]=1
Reactant: CC(C)Nc1cc(N2C3CCC2COC3)nc(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Nc1cc(N2C3CCC2COC3)nc(-c2ccc(N)cc2)n1
Reaction time: 16 h
Yield: 98.1 %

Procedure:
In a 250 mL round-bottomed flask was placed 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-isopropyl-2-(4-nitrophenyl)pyrimidin-4-amine (60, 196 mg, 0.53 mmol) in 2-propanol (5 mL) and dichloromethane (5 mL) to give a yellow solution. A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered over Celite™, rinsed with dichloromethane and concentrated to give the title compound (176 mg, 0.52 mmol, 98%) as a yellow solid. HRMS: For [M+H]+ mass error=0.5 mDa or 1.46 ppm.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].O>CO>[CH3:22][S:19]([C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:10][C:14]2=[N:15][CH:16]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ccccn1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ccccn3)cc2c1
Yield: 95.5 %

Procedure:
To a solution of the compound obtained in Example 5 (3) (3.8 mg) in methanol (0.5 ml), a 1N aqueous potassium hydroxide solution (2 ml) was added and the mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction solution was poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was poured into a phosphorate buffer (pH 7.0), extracted with dichloromethane, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform:methanol 50:1) to obtain 2.4 mg of the desired product as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@:5]([CH3:9])([CH:7]=O)[CH2:4][O:3]1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[CH3:1][C:2]1([CH3:10])[O:6][C@:5]([CH3:9])([CH:7]=[N:12][OH:13])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@](C)(C=O)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@@](C)(C=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
(S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde (5.8 g, 40 mmol) was dissolved in 1:1 methanol water (100 mL) and hydroxylamine hydrochloride (2.8 g, 40 mmol) and Na2CO3 (2.4 g, 20 mmol). The reaction was stirred at ambient temperature overnight, then concentrated in vacuo. The aqueous layer was extracted with CH2Cl2, and the organic layer was dried over sodium sulfate, filtered and concentrated to afford (R)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde oxime (4.8 g, 30 mmol, 75% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][NH:6][N:7]([CH3:18])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:5][N:6]1[C:1](=[S:2])[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8](=[O:9])[N:7]1[CH3:18]
Reactant: S=C(Cl)Cl
Reactant: CNN(C)C(=O)Nc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(-c2ccc(Cl)cc2)c(=S)n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.5 %

Procedure:
A solution of 3.8 g (0.33 mol) thiophosgene in 10 ml chloroform was added dropwise to a stirred solution of 7 g (0.033 mol) 1,2-dimethyl-4-(4-chlorophenyl)semicarbazide and 6.67 g (0.066 mol) triethylamine in 200 ml chloroform. After completion of the addition, the reaction mixture was heated under reflux for 2 hours and stirred at about 25° C. for 3 days. The reaction mixture was then washed with water, dilute hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 10 g of a semi-solid residue. The residue was diluted with 100 ml dichloromethane and filtered. The filtrate was chromatographed on 200 g of silica gel. Elution with 1% methanol in dichloromethane gave the product, 3.9 g, as light tan crystals, m.p. 143°-144° C. Infrared analysis showed strong carbonyl absorption at 5.8 micron. The product is tabulated in Table I as Compound No. 2.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH3:31])=[O:29])[C:10]([S:13]([CH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])([CH3:12])[CH3:11])=[O:7])(C)(C)C.Cl.ClC(O[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=O>O1CCOCC1>[CH2:37]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH3:31])=[O:29])[C:10]([S:13]([CH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])([CH3:11])[CH3:12])=[O:7])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Reaction time: 12 h
Yield: 39.9 %

Procedure:
A solution of 1.0g (2.19mmol) of (RS)-α-[[[(R)-2-(1-tert-butoxyformamido)-2-(methoxycarbonyl)-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamic acid was added dropwise at room temperature to 10 ml of 1.4 M hydrogen chloride in dioxan and stirred for a further 12 hours. After evaporation of the solvent under reduced pressure there was obtained a colourless foam which, without further purification and characterization, was dissolved in 8.5 ml of 1N sodium hydrogen carbonate solution and treated with 0.44 ml (3.07 mmol) of benzyl chloroformate. The thus-obtained suspension was stirred at room temperature for 12 hours. Subsequently, it was extracted twice with 250 ml of ether each time, the combined ether extracts were dried over magnesium sulphate and evaporated under reduced pressure. For purification, the oily crude product (1.05 g) was chromatographed on 50 g of silica gel firstly with methylene chloride then with a 95:5 mixture of methylene chloride and methanol as the eluent. There were obtained 430 mg of (RS)-α-[[[(R)- 2-(1-benzyloxyformamido)-2-(methoxycarbonyl)-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamic acid as a colourless foam, MS: 493 (M+H)+.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:4]=[C:3]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:2]=1.[CH:33](=O)[CH:34]([CH3:36])[CH3:35].[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:4]=[C:3]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:2][CH:1]([CH3:27])[CH3:6])[CH:2]=1
Reactant: NCCCNCCCNCc1cc(CNCCCNCCCN)cc(-c2ccccc2)c1
Reactant: CC(C)C=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)CNCCCNCCCNCc1cc(CNCCCNCCCNCC(C)C)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round-bottom flask was added the crude N1,N1′-([1,1′-biphenyl]-3,5-diylbis(methylene))bis(N3-(3-aminopropyl)propane-1,3-diamine) (3.5 g, 8.0 mmol) and MeOH (50 mL). To the solution was added isobutyraldehyde (1.15 g, 15.9 mmol) and the reaction mixture was stirred at rt for 24 h. Sodium borohydride (1.2 g, 31.9 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aq. NaOH (10%, 200 mL) and EtOAc (200 mL) were added, and the mixture was stirred for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (200 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as a clear oil which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:5]2.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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.O.COCCOC>[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][N:14]=[C:7]1[C:6]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:5]2
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: OCCCNc1nc2cc(Br)ccc2n2ccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: OCCCNc1nc2cc(-c3ccccc3C(F)(F)F)ccc2n2ccnc12
Yield: 38.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium (11 mg, 0.009 mmol, 0.1 eq), 3-(7-Bromo-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (30 mg, 0.093 mmol, 1 eq), 2-(trifluoromethyl)phenylboronic acid (19 mg, 0.102 mmol, 1.1 eq), potassium carbonate (51 mg, 0.372 mmol, 4 eq) are stirred under argon in a mixture of degassed water/1,2-dimethoxyethane (1 mL/1 mL) at 80° C. for 3 days. Evaporation of 1,2-dimethoxyethane, partition (water/ethyl acetate), extraction of the aqueous phase (two times ethyl acetate), reunion of the organic phases, drying over magnesium sulfate and purification over silicagel on prep TLC (eluent: dichloromethane/methanol 90:10) affords the title compound as an off-white solid (14 mg, 0.036 mmol, 39%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:15]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]2)[CH:3]=1.COC1C(C)=C2C(C(O[CH:41]3[CH2:58][CH:57]4[CH:43]([C:44](=[O:64])[N:45]([CH3:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:51][CH:52]5[C:54]([C:60]([OH:62])=[O:61])([NH:55][C:56]4=[O:59])[CH2:53]5)[CH2:42]3)=CC(C3SC=CN=3)=N2)=CC=1>>[CH3:21][C:17]1[CH:18]=[C:19]([CH3:20])[N:15]([C:4]2[CH:3]=[C:2]([O:1][CH:41]3[CH2:58][CH:57]4[CH:43]([C:44](=[O:64])[N:45]([CH3:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:51][CH:52]5[C:54]([C:60]([OH:62])=[O:61])([NH:55][C:56]4=[O:59])[CH2:53]5)[CH2:42]3)[C:11]3[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[N:16]=1
Reactant: COc1ccc2c(O)cc(-n3nc(C)cc3C)nc2c1C
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3nc(C)cc3C)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(3,5-dimethylpyrazol-1-yl)-7-methoxy-8-methylquinoline (129) and intermediate 26 following the procedure (Step D-F) reported for the preparation of 17-[7-methoxy-8-methyl-2-(thiazol-2-yl)quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (29): m/z=616 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16][NH2:17]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)-benzene sulphonyl chloride (200 mg) in 1,4-dioxane (1 mL) was added methylamine (40% aqueous solution, 96 mg). The mixture was stirred at room temperature for three hours then diluted with ethyl acetate (20 mL) and washed with HCl (1M, 2×20 mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield 3-bromo-N-methyl-5-trifluoromethyl-benzenesulphonamide (181 mg) as a yellow solid. 1H NMR (MeOD): δ 8.19 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 4.58 (m, 1H), 2.74 (d, 3H). MS m/z 319.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][CH:8]=[N:7][C:6]2=O.P(Cl)(Cl)([Cl:17])=O.O.C(=O)([O-])O.[Na+]>C(N(CC)C(C)C)(C)C>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:12]([CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)nc[nH]c2cc1C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2c(Cl)ncnc2cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
6-Methoxy-7-methyl-1H-quinazolin-4-one (275 mg) was suspended in N,N-diisopropylethylamine (3.78 ml), phosphorus oxychloride (0.3 ml) was added to the suspension, and the mixture was stirred at 100° C. for 6 hr. The reaction solution was added in small portions to water of 0° C., an aqueous sodium hydrogencarbonate solution was further added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 4-chloro-6-methoxy-7-methyl-quinazoline (199 mg, yield 66%).
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1)=[O:5])=[N-].FC(F)(F)C(O)=[O:15].O>C(OCC)C>[OH:15][CH2:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1)=[O:5]
Reactant: Cc1cc(C(=O)C=[N+]=[N-])no1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C(=O)CO)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
2-Diazo-1-(5-methylisoxazol-3-yl)ethanone (7.0 g, 46 mmol) was dissolved in diethyl ether (100 ml) and trifluoroacetic acid (25 ml) and water (100 ml) were added. The solution was stirred at room temperature for 2 hours, then the diethyl ether was removed in vacuo and the aqueous solution was stirred at room temperature for 18 hours. Further water (100 ml) was added and the aqueous solution was extracted twice with ethyl acetate. The organic extracts were washed successively with water, 10% aqueous potassium carbonate solution and brine, and dried (Na2SO4). Evaporation of the solvent yielded the title-compound as a pale solid (4.0 g, 61%), 1H NMR (360 MHz, CDCl3) 2.52 (3H, s), 4.90 (2H, s), 6.44 (1H, s).
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:27][CH:26]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][Br:19])[CH:32]=2)=[CH:27][CH:26]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1ccc(-c2cccc(C)c2)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2cccc(CBr)c2)cc1
Yield: 96 %

Procedure:
3′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 3′-Methyl-biphenyl-4-carboxylic acid ethyl ester (3.80 g, 15.81 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.1 g, 17.39 mmol, 1.1 eq.) and 2,2′-azobisisobutyronitrile (0.13 g, 0.79 mmol, 5 mol %). When complete, the reaction was worked up as described leaving 3′-bromomethyl-biphenyl-4-carboxylic acid ethyl ester (4.83 g, 96%) as a yellow oil that crystallized on standing.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([NH2:16])[CH:6]=1)=[O:4].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:27](O)=[O:28])=[CH:21]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([NH:16][C:27]([C:22]2[NH:23][C:24]3[C:20]([CH:21]=2)=[CH:19][C:18]([Cl:17])=[CH:26][CH:25]=3)=[O:28])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)cc2c1OCCCO2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2cc3cc(Cl)ccc3[nH]2)cc2c1OCCCO2
Reaction time: 4 h
Yield: 22.6 %

Procedure:
8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (0.300 g), 5-Chloro-1H-Indole-2-carboxylic acid (0.263 g), BOP (0.594), TEA (0.377 mL) and DMF (3.0 mL) were mixed together and stirred for 4 hours. The reaction was diluted with water and the resulting filtrate filtered. The resulting solid was tritriated with EtOAc, rinished with the same and purified by flash chromatography (silica gel; 25% EtOAc/hexane) to yield 122 mg of the product. MS PDS: M+ 401/403
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[CH:14]([O:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21])([CH3:16])[CH3:15]>>[CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:26][C:18]=3[O:17][CH:14]([CH3:16])[CH3:15])=[O:21])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CN(C)c1ccc2c(c1)CNCC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(N(C)C)cc2C1

Procedure:
Prepared in analogy to example 1.1 from dimethyl-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-amine (CA [138276-84-3]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:11](CC)CC)C.[Si](C#N)(C)(C)C>C(#N)C.C(OCC)C>[Cl:1][C:2]1[C:3]([C:9]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cccc(Cl)c1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1ncccc1Cl
Yield: 97.8 %

Procedure:
To a solution of compound 145-B, (22.37 g, 172.7 mmol) in acetonitrile (175 mL) was added triethylamine (48 mL, 346 mmol) and TMS-CN (56 mL, 420 mmol). The solution was heated at reflux for 20 h then evaporated in vacuo. The residue was partitioned between EtOAc (250 mL), 10% aqueous Na2CO3 (50 mL), and filtered over celite. The organic portion of the filtrate was washed with 10% aqueous Na2CO3 (2×50 mL), brine (50 mL), and the organics dried over Na2SO4, filtered, and evaporated in vacuo to afford a dark crystalline residue, which was dissolved in warm diethyl ether (200 mL), filtered, and evaporated in vacuo to afford compound 145-C as a tan-orange powder (23.41 g, 98%). 1H-NMR (DMSO-d6): δ 7.78-7.84 (m, 1H), 8.30 (d, 1H), 8.73 (d, 1H); MS: m/z 139.1 (MH+).