Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH:22]=[O:23].O>O1CCCC1>[OH:23][CH:22]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)[CH2:21][C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)CC=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a −40° C. solution of methyl 4-iodobenzoate (1 g, 4 mmol) in tetrahydrofuran (10 mL) was added isopropylmagnesium chloride lithium chloride (3.82 mL, 1.3 M in THF, 4.98 mmol). The mixture was stirred at −40° C. for 30 minutes, 3,3-Dimethylbutanal (573 mg, 2.86 mmol) was added. The reaction was stirred at room temperature for 4 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/−)-methyl 4-(1-hydroxy-3,3-dimethylbutyl)benzoate (640 mg, 95%). 1H NMR (400 MHz, CDCl3, δ): 7.93 (d, 2H), 7.34 (d, 2H), 4.81-4.84 (m, 1H), 3.84 (s, 3H), 1.70-1.61 (m, 1H), 1.53-1.49 (m, 1H), 0.94 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[C:5]([C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:15]([NH:27][C:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[NH:3][C:2](=[O:1])[C:10]2=[O:11])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1Nc2c(C(=O)O)cccc2C1=O
Reactant: CCCCCCCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCNC(=O)c1cccc2c1NC(=O)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a solution of 2,3-dioxo-7-indolinecarboxylic acid (1000 mg, 5.23 mmol), 1-dodecanamine (1066 mg, 5.75 mmol), TEA (1.60 mL, 11.51 mmol), EDCI.HCl (1102 mg, 5.75 mmol) and HOBt (777 mg, 5.75 mmol) in DMF (60 mL). The resulting mixture was allowed to stir at rt for 24 hrs. The solvent was evaporated off and the residue was taken up in DCM to be purified by flash chromatography using DCM/MeOH (98/2) as eluant. A gummy orange solid was collected to be identified as the title compound (44%) in a 96.0% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:20][OH:21]>CCO>[NH2:2][C:1](=[N:20][OH:21])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)COCCc1cccc(C#N)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)COCCc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
tert-butyl [2-(3-cyanophenyl)ethoxy]acetate obtained in step 1 (1.42 g; 5.43 mmol) was dissolved in EtOH (28.40 mL) to which was added hydroxylamine (401.26 μL; 50%, 27.17 mmol). Reaction mixture was stirred at RT for 18 h after which solvents were removed under vacuum, solubilized in a water/ACN mixture (1:1) and lyophilized to give the desired compound as a sticky colorless oil (1.32 g; 82%). 1H NMR (DMSO-d6, 300 MHz) δ 9.56 (bs, 1H), 7.53-7.48 (m, 2H), 7.27-7.25 (m, 2H), 5.76 (bs, 2H), 3.96 (s, 2H), 3.67 (t, J=6.9 Hz, 2H), 2.83 (t, J=6.5 Hz, 2H). LC/MS (Method B): 295.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BrH:10].[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1cccnc1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a solution of 3-acetyl pyridine (2.71 ml, 24.74 mmol) in acetic acid (7.5 ml) was added 33% hydrobromic acid in acetic acid (7.5 ml) and then pyridinium tribromide (8.70 g, 27.21 mmol). The reaction mixture was stirred at room temperature for 12 hr to give a solid. The solid was filtered, washed with acetic acid and hexane and then dried under vacuum to give 2-bromo-1-pyridin-3-yl-ethanone 3.61 g (52%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[CH2:6]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCO
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
In a 2 L flask, a solution of 1,3-propane-diol (3) (38 g, 0.5 moles) and benzyl bromide (85.5 g, 0.5 moles) in dry tetrahydrofuran (500 mL) is cooled to 0° C. (internal temperature) using ice/salt mixture. Potassium-t-butoxide (56 g, 0.5 moles) is added in portions, maintaining the temperature below +20° C. The mixture is stirred at room temperature overnight, then poured into 2N HCl (1 L) and water (1 L). After saturating with NaCl, the mixture is extracted with ether (1.5 L). The organic phase is washed with water (3×), dried (Na2SO4) and evaporated to give an oil (81 g). This is distilled (oil pump) to give pure 14 as a colourless liquid: 58.5 g (70%), bp about 0.05 95°-105° C.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14]1([NH:20][N:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].CO>C(OCC)(=O)C>[C:14]1([N:20]2[CH:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:2]([C:1]([O:11][CH2:12][CH3:13])=[O:10])[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C(=NNc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1C(c2ccccc2)=NN(c2ccccc2)C1c1ccccc1

Procedure:
A mixture of ethyl cinnamate (7, 2.55 g), benzaldehyde phenylhydrazone (2, 4.21 g), chloramine-T trihydrate (6.45 g), and methanol (45 mL) were heated under refluxing for 22 hours. The reaction mixture was diluted with 50% ethyl acetate in n-hexanes (400 mL), filtered, and evaporated. The residue was purified by column chromatography (silica gel 200 g, eluent: 0 to 10% ethyl acetate gradient in hexanes) and evaporated to give FN1-1 (8, 1.25 g) as colorless crystal. 1H NMR (CDCl3, 400 MHz) δ 7.66-7.64 (m, 1H), 7.46-7.22 (m, 13H), 6.88 (t, J=7.2 Hz, 1H), 4.81 (d, J=4.0 Hz, 1H), 4.70 (d, J=4.0 Hz, 1H), 4.07 (quartet, J=7.2 Hz, 2H), 0.97 (t, J=7.2 Hz, 3H). MS: 371.9 (M+H), 325.5, 297.5.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:24](=[O:25])[C:23]([CH3:26])=[CH:22][N:11]([C@@H:12]3[O:18][C@H:15]([CH2:16][OH:17])[C@@H:14]([N:19]=[N+:20]=[N-:21])[CH2:13]3)[C:10]2=[O:27])C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:24](=[O:25])[C:23]([CH3:26])=[CH:22][N:11]([C@@H:12]2[O:18][C@H:15]([CH2:16][OH:17])[C@@H:14]([N:19]=[N+:20]=[N-:21])[CH2:13]2)[C:10]1=[O:27]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCCN)c1=O

Procedure:
A solution of approximately 0.5 mmole 3-PHT-P AZT (Example 26) in methanol was treated with 50 ul hydrazine hydrate and incubated overnight at room temperature. The resulting suspension was filtered through a 0.45 um PTFE membrane and the filtrate chromatographed by preparative TLC on silica gel-F 2000 um using the solvent system CHCl3 /MeOH/15M NH4OH (85+15+1). The major band (Rf =0.27; UV positive; ninhydrin positive)was well separated from 3-PHT-P-AZT (Rf =0.78; UV positive; ninhydrin negative) and from hydrazine (Rf =0.0; UV negative; ninhydrin postive). The product was eluted with MeOH. It was found to be immunologically active in an AZT assay by FPIA, was homogeneous on analytical TLC and its UV spectrum resembled that of a 3-alkylated AZT derivative.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].[Cl-].[Na+]>C1COCC1>[F:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At RT and with slight cooling, 99.23 g (394 mmol) of tert-butyl diethylphosphonoacetate were added dropwise to a suspension of 15.74 g (394 mmol) of sodium hydride (60% in mineral oil) in 540 ml of THF. After the addition had ended, the mixture was stirred at RT for 30 min and, after cooling to 0° C., a solution of 60.5 g (358 mmol) of 4-fluoro-3-nitrobenzaldehyde in 324 ml of THF was added. The reaction mixture was stirred at RT overnight and then added to a 10% strength aqueous sodium chloride solution. The mixture was extracted twice with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (twice) on silica gel (mobile phase petroleum ether/ethyl acetate 9:1). This gave 82.0 g (84.9% of theory) of the target product.
Reaction SMILES: CN1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19](O)[CH:20]=1.BrCCC=C>O.CC(C)=O>[CH:6]([O:7][C:20]1[CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=[CH:16][C:15]=1[F:14])=[CH:5][CH2:4][CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CN1CCCC1=O
Agent: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCC=COc1cc([N+](=O)[O-])ccc1F
Reaction time: 0.25 h

Procedure:
To a suspension of NMP (20 ml), acetone (20 ml) and potassium carbonate (8.85 g) was added 5-fluoro-2-nitro phenol (5.0 g, 30 mmol) in one portion. After 15 minutes, the suspension began to turn yellow. After stirring 30 minutes under nitrogen, 4-bromobutene (4.25 ml) was added and the suspension was refluxed for 18 hours. The suspension was poured into water and extracted with 3×200 ml of diethyl ether. The aqueous layer was acidified with 2N HCl and extracted with ether. The ether layers were combined, washed with 2N HCl and water and dried over anhydrous magnesium sulfate. Filtration and in vacuo concentration yielded 6.0 g of 2-(3-butenyloxy-4-fluoronitrobenzene, as an oil, which was used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)=O.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1>O1CCCC1.C(OCC)(=O)C.[Na].[Ti]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=[N:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: O=C(c1cc2ccccc2o1)c1nc2ccccc2s1
Reactant: CN1CCC(N)CC1
Agent: [Ti]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(N=C(c2cc3ccccc3o2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (benzofuran-2-yl)(benzothiazol-2-yl)methanone (1.4 g) and 4-amino-1-methylpiperidine (0.57 g) in tetrahydrofurane (8 mL) is added dropwise titanium tetraisopropoxyde (1.78 g). The suspension is stirred for 24 h at room temperature, diluted with ethyl acetate and 1N sodium hydroxyde. The precipitate is filtered over a clarcel pad and rinsed with ethyl acetate. The pooled filtrates are washed with saturated sodium chloride solution, dried and concentrated under reduced pressure. The residue is purified over silica gel (gradiant dichloromethane/methanol from 100/0 to 90/10) to afford [(benzofuran-2-yl)(benzothiazol-2-yl)methylene](1-methylpiperidin-4-yl)amine.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]1[CH:8]=[C:9]([CH2:12][NH:13][C:14]2C(C(O)=O)=[CH:18][C:17]([S:23]([NH2:26])(=[O:25])=[O:24])=[C:16]([Cl:27])[CH:15]=2)[O:10][CH:11]=1>ClCCl>[NH2:26][S:23]([C:17]1[C:16]([Cl:27])=[CH:15][C:14]([NH:13][CH2:12][C:9]2[O:10][CH:11]=[CH:7][CH:8]=2)=[C:1]([CH:18]=1)[C:2]([Cl:4])=[O:3])(=[O:24])=[O:25]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)Cl)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of oxalyl chloride (0.040 mole) in dichloromethane (20 mL) is added dropwise to an ice bath cooled solution of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid), (10) (Aldrich) (0.040 mole) in dichloromethane (50 mL). The reaction is stirred at ambient temperature for 5 hours. The reaction solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyl chloride (13). See eg., D. L. Musso, et. al., J. Med. Chem., (2003) 46: 409.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:18][CH2:19][F:20])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([Li])CCC.IC>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:21])([CH2:18][CH2:19][F:20])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(CCF)N=C(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)(CCF)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
19.94 g (63.64 mmol, 85% purity) of rac-2-[(diphenylmethylene)amino]-4-fluorobutanonitrile from Example 66A were initially charged in 421 ml of abs. THF, and 25.71 ml (64.28 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 10 min. Subsequently, 36.1 g (254.57 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 4.5 h. After complete depletion of the starting material, the reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=15/1). 17.2 g of the target compound were obtained (78% of theory, 81% purity).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:19][O:18][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.42 min.; [M+H]+: 403.73 g/mol.
Reaction SMILES: [S:1]1[CH:5]=[C:4]2[C:6]([O:8][C:9](=[O:10])[C:3]2=[CH:2]1)=[O:7].[CH2:11]([NH2:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1(C)C=CC=CC=1>[CH2:11]([NH:19][C:6]([C:4]1[C:3]([C:9]([OH:8])=[O:10])=[CH:2][S:1][CH:5]=1)=[O:7])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCN
Reactant: O=C1OC(=O)c2cscc21
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)c1cscc1C(=O)O

Procedure:
The anhydride was subsequently dissolved in toluene (320 mL) in a 500 mL flask, followed by the addition of n-octylamine (6.72 g, 52.02 mmol, 8.6 mL). The resulting reaction mixture was subsequently refluxed over a period of 24 h. The reaction mixture was allowed to cool and was subsequently concentrated affording 4-octylcarbamoylthiophene-3-carboxylic acid as a solid. The acid was dissolved in thionyl chloride (SOCl2) (270 mL) and refluxed over a period of 4 hours. The reaction mixture was cooled down and subsequently concentrated to dryness. The residue was purified by column chromatography using methylene dichloride:hexanes (2:1) as the eluant to afford the title compound as a pure white solid (5.2 g, yield 57%): mp: 120-122° C.; GC-Ms: 265; 1H NMR (400 MHz, CDCl3, ppm) δ:7.8(s, 2H), 3.62-3.59 (t, 2H), 1.64-1.62(m, 2H), 1.26(m, 10H), 0.87-0.85(m, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ: 162.4, 136.7, 125.2, 37.9, 31.7, 29.2 (2C), 28.4, 26.8, 22.4, 14.1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([C:26]4[CH2:27][CH2:28][O:29][CH2:30][CH:31]=4)=[CH:16][C:17]=3[C:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1.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.CN(C=O)C>[O:29]1[CH2:30][CH:31]=[C:26]([C:15]2[CH:14]=[C:13]([F:32])[C:12]3[O:11][C:10]4[C:19](=[CH:20][C:7]([C:39]5[CH:40]=[N:35][CH:36]=[N:37][CH:38]=5)=[CH:8][CH:9]=4)[C@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:17]=3[CH:16]=2)[CH2:27][CH2:28]1
Reactant: NC1=NC2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Reactant: OB(O)c1cncnc1
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: CN(C)C=O
Product: NC1=N[C@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 75 °C

Procedure:
A vial was charged with 2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (150 mg, 0.300 mmol), pyrimidin-5-ylboronic acid (111 mg, 0.899 mmol), and Pd(PPh3)4 (34.6 mg, 0.030 mmol). The vial was purged with Ar (g), then DMF (2 mL) and potassium carbonate (0.749 mL, 1.499 mmol) (as a 2.0 M aq. solution) were added in sequence. The vial was capped and heated in a Biotage Initiator microwave reactor for 1.5 h at 75° C. The product was purified via Gilson HPLC (gradient elution 20-90% MeCN/H2O, 0.1% TFA) to afford (R)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off white solid. Found MS: MH+=431.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[Br:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[C:18](N(C)C)=[O:19].O>C1COCC1.CCCCC>[Br:14][C:15]1[CH:16]=[C:17]([C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[O:19])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CN(C)C(=O)c1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCC
Product: Cc1ccc(C(=O)c2cccc(Br)c2)cc1
Temperature: -80 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 38.5 g (0.225 mol) of 4-bromotoluene in 450 mL of THF, 300 mL (0.450 mol) of 1.5 M tBuLi in pentane was added dropwise with vigorous stirring for 2 hr at −80° C. This mixture was slowly warmed to room temperature and additionally stirred at this temperature for 30 min. To this mixture 52.0 g (0.23 mol) of 3-bromo-N,N-dimethylbenzamide was added at 0° C., and then this mixture was stirred for 12 hr at room temperature. Later, 300 mL of water was added, organic solvent was evaporated using a rotary evaporator. The product was extracted with 2×200 mL of dichloromethane. The combined organic extracts were evaporated to dryness, and the residue was dried in vacuum. This procedure gave 51.3 g (83%) of 40 which was further used without additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:21]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CN1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
A solution of 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.131 g, 0.500 mmol) in methanol (2 mL) was added with 1H-indazole-3-carbaldehyde (0.0731 g, 0.500 mmol), and piperidine (0.00426 g, 0.0500 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (2 mL), and suspended in methanol and thereby washed to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.0731 g, 37%).
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]([CH2:7][CH2:8][OH:9])[CH2:5][OH:6].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.O>CN(C=O)C>[CH3:3][C@@H:4]([CH2:7][CH2:8][O:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:5][O:6][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: C[C@H](CO)CCO
Reactant: N#Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CCOc1ccc(C#N)cc1)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Sodium hydride (2.88 g, 120 mmol) was dispersed in 50 ml DMF and then added with (S)-2-methyl-1,4-butanediol (5.21 g, 50.0 mmol) while being iced with ice. The reaction mixture after being cooled with ice for another one hour was stirred at room temperature for 2 hours and then added with 4-chlorobenzonitrile (15.3 g, 120 mmol), followed by reaction for 20 hours. After completion of the reaction, the reaction mixture was added carefully with 5 ml water to inactivate excess sodium hydride, followed by vacuum-distillation of DMF. After addition of 200 ml water, a precipitate thus obtained was filtrated and recrystallized from 100 ml ethanol thereby providing the intended product (12.5 g, 40.8 mmol, 82%).