Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].[CH2:10]([SH:14])[CH2:11][CH2:12][CH3:13].[OH-].[K+]>>[CH2:10]([S:14][CH2:7][CH:6]([CH3:8])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[O:9])[CH2:11][CH2:12][CH3:13]
Reactant: C=C(C)C(=O)OCCO
Reactant: CCCCS
Agent: [K+]
Agent: [OH-]
Product: CCCCSCC(C)C(=O)OCCO

Procedure:
To the reactor described in Example I was charged 55 grams of 2-hydroxyethylmethacrylate, 37 grams of n-butanethiol, 1.5 grams of Triton™ B and 3 pellets of KOH. The flask contents were reacted at 40° to 50° C. until the reaction was complete by gas chromatography analysis. The yield was theoretical.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(=O)CC>[CH3:12][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A stirred solution of 2-hydroxybenzotrifluoride (23.0 g, 142 mmol) in 2-butanone (107 mL) was treated with potassium carbonate (25.51 g, 185 mmol) and iodomethane (13.3 mL, 213 mmol). The mixture was heated at reflux overnight under argon until the thin-layer chromatography showed a completed reaction. The mixture was cooled to room temperature and filtered through diatomaceous earth. The filtered solid was washed with acetone and the filtrate concentrated carefully in vacuo without heating. The resulting crude liquid was purified by vacuum distillation to yield the title compound (21.79 g, 0.124 mol, 87%) as a colorless liquid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([B:23]2[O:27][C:26]([CH3:29])(C)C(C)(C)[O:24]2)=[C:17]([CH:20]=[CH:21][CH:22]=1)C=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N+:33]([O-:35])=[O:34].Cl>O.C1COCC1>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]2[B:23]([OH:24])[O:27][CH:26]([CH2:29][N+:33]([O-:35])=[O:34])[C:17]=2[CH:20]=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: CC1(C)OB(c2c(C=O)cccc2OCCCOCc2ccccc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.9 %

Procedure:
NaOH aq. (NaOH (3.64 g, 83 mmol) was added to 3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (36 g, 91 mmol) in H2O (180 mL), and THF (50 mL) at rt, and the reaction mixture was stirred at rt for 5 min. MeNO2 (16.6 g, 273 mmol) was added dropwise and the mixture was stirred at rt for 16 h. The reaction mixture was acidified with 2 N HCl and extracted with EtOAc. The organic fraction was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo. Purification was accomplished by flash chromatography (1:1 hexane/EtOAc) to give 15.9 g of the title compound as a light yellow oil (yield 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.05 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.35-7.20 (m, 5H), 7.06 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.70 (dd, J=9.4, 2.3 Hz, 1H), 5.29 (dd, J=13.7, 2.7 Hz, 1H), 4.53 (dd, J=13.3, 9.4 Hz, 1H), 4.45 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.60 (t, J=6.3 Hz, 2H), 2.04-1.91 (m, 2H); MS (ESI): m/z=356 (M−1, negative); HPLC purity: 99.35% (MaxPlot 200-400 nm), 97.32% (220 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C2(CO)CCCC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=CC1(c2ccc(Cl)cc2)CCCC1
Agent: OCC1(c2ccccc2)CCCC1
Product: OCC1(c2ccc(Cl)cc2)CCCC1
Yield: 37.4 %

Procedure:
[1-(4-chlorophenyl)-cyclopentyl]-methanol (23-02) (25 g, 37.52%) was synthesized from 1-(4-chlorophenyl)-cyclopentanecarbaldehyde (22-02) (66 g, 317.3 mmol) as a colourless liquid following the procedure as described for (1-phenyl-cyclopentyl)-methanol (23-01).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([NH:7][C@H:8]([CH2:16][CH3:17])[C:9]([O:11][C:12](C)(C)C)=[O:10])[CH2:3]1.Cl>CO>[F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([NH:7][C@H:8]([CH2:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10])[CH2:3]1
Reactant: CC[C@@H](N[C@@H]1CCC(F)(F)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC[C@@H](N[C@@H]1CCC(F)(F)C1)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
(R)-tert-butyl 2-((R)-3,3-difluorocyclopentyl amino)butanoate (1.0 g, 3.798 mmol) was dissolved in methanol (70 mL) and cooled down to 0° C. The resultant mixture was saturated with HCl gas, then stirred at room temperature for 3 hours. The reaction mixture was warmed to 40° C. for 90 minutes then concentrated under reduced pressure. The residue was partitioned between DCM and an aqueous solution of NaHCO3. The aqueous phase was extracted with DCM three times, dried over magnesium sulfate and concentrated under reduced pressure to afford the desired product as colourless oil (645 mg, 78% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:28])([CH3:27])[C:10]([NH:12][C@H:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:28])([CH3:27])[C:10]([NH:12][C@H:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14]([NH:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])=[CH:35][CH:36]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
The acid (338 mg, 0.87 mmol) from Step D and 4-aminomethyl-2'-nitro-1,1'-biphenyl (200 mg, 0.87 mmol) and triethylamine (0.245 mL, 1.76 mmol) were dissolved in methylene chloride (8 mL) and stirred at room temperature. Benzotriazolyl-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (388 mg, 0.87 mmol) was added in a single portion. The reaction mixture was stirred together for 3.5 hours then the reaction was quenched by adding saturated aqueous sodium chloride (10 mL) and extracted with methylene chloride (3×20 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated under vacuum. The resulting thick gum was chromatographed on silica gel using ethyl acetate/hexanes (1:2 v/v) to give 297 mg (50%) of an orange semi-solid.
Reaction SMILES: [CH:1]1[C:9]2[CH:8]=[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]3=[CH:5][C:4]=2[CH2:3][CH:2]=1.Br[C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25]([C:17]1[CH:16]=[C:15]([C:2]2[CH2:3][C:4]3[CH:5]=[C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]4=[CH:8][C:9]=3[CH:1]=2)[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: C1=Cc2cc3ccccc3cc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C2=Cc3cc4ccccc4cc3C2)cc(C(C)(C)C)c1
Temperature: 60 °C
Yield: 31.5 %

Procedure:
Benz[f]indene (10.8 g, 0.065 mole) was dissolved in 100 mL of dimethylformamide. 1-Bromo-3,5-di-t-butylbenzene (14 g, 0.052 mole) was added along with palladium acetate (0.3 g), tri-o-tolylphosphine (0.8 g), and triethyl amine (11.0 g). The solution was heated to 60° C. for 3 days. The solution was cooled and washed with 1 N HCl and by saturated sodium bicarbonate. The product was found to be difficult to separate from the residual tri-o-tolylphosphine. After purifying by passing through silica with hexanes three times, and recrystallization from ethanol, followed by three recrystallizations from hexanes, it yielded 5.8 g of 2-(3,5-di-t-butylphenyl)benz[f]indene (26% yield). 1HNMR (CDCl3, 300 MHz δ7.95-7.77 (m, 4H); 7.52-7.37 (m, 5H); 7.23 (s, 1H); 3.99 (s, 2H); 1.43 (s, 18H).
Reaction SMILES: [C:1](#N)C.[NH2:4][C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]([OH:17])=[O:16])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O1CCCC1>[CH3:1][O:16][C:15]([C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:18])[CH:12]=2)[N:7]=[C:6]([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[C:5]=1[NH2:4])=[O:17]
Reactant: CC#N
Reactant: Nc1c(-c2ccc(I)cc2)nc2ccc(F)cc2c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1c(N)c(-c2ccc(I)cc2)nc2ccc(F)cc12
Reaction time: 1 h

Procedure:
To a solution of 400 ml of acetonitrile and 40 ml of tetrahydrofuran was added 4.0 g of 3-amino-6-fluoro-2-(4-iodophenyl)-4-quinolinecarboxylic acid and 2.0 g of cesium carbonate. The solution was stirred for 1 hour and 0.84 ml of methyl iodide was added. After stirring for an additional 12 hours, the volatiles were removed in vacuo and the residue dissolved in methylene chloride and ethyl acetate. The insoluble solids were removed by filtration and the volatiles removed from the filtrate in vacuo. The yellow solid obtained was recrystallized from methylene chloride, giving 3.45 g of the desired compound as yellow crystals, mp 223°-225° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:29]#[N:30])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH:14]=2)=[O:9])C.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:32])([CH3:31])[C:4]([OH:33])=[O:3])=[O:9])[N:11]=[C:12]2[C:29]#[N:30])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{[7-(3-Chloro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (26 mg, 0.06 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 18 mg. MS: (−) m/z 437.93 (M−1).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=1[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16])(=[O:9])=[O:8].[H-].[Na+].[CH3:25]I>CN(C)C=O>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=1[CH:6]([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16])(=[O:8])=[O:9])[CH3:25]
Reactant: O=S(=O)(Cc1cc(Cl)ccc1OC(F)F)c1cccc[n+]1[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1cc(Cl)ccc1OC(F)F)S(=O)(=O)c1cccc[n+]1[O-]

Procedure:
In the same manner as in Example 1, 8.86 g of 2-(2-difluoromethoxy-5-chlorobenzylsulfonyl)pyridine-N-oxide, 1.11 g of 55% sodium hydride and 3.60 g of methyl iodide were mixed with 150 ml of dimethylformamide and the mixture was reacted followed by the same after-treatment as in Example 1, whereby 7.00 g of Compound No. 15 of the present invention was obtained. The product was white crystals having a melting point of from 145°-147° C.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:8]([C:10]1([C:16]2[N:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)#[N:9].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:10]1([C:16]2[N:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:18][CH:17]=2)[CH2:11][CH2:12][N:13]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:14][CH2:15]1)#[N:9]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(S(=O)(=O)C(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Isopropylsulfonyl chloride (72 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (227 mg) described in Reference Example 169 and potassium carbonate (138 mg) in N,N-dimethylformamide (1.7 ml) and stirred at room temperature for six hours. Then, potassium carbonate (276 mg) and isopropylsulfonyl chloride (144 μl) were added and stirred at room temperature for 0.5 hours. Water was added to the reaction solution and the precipitated solid was washed with water, ethanol and ethyl acetate to give the titled compound (151 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][O:29][C:30](=[O:45])[C@@H:31]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:32][NH2:33].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:28][O:29][C:30](=[O:45])[C@@H:31]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[CH2:32][NH:33][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25]
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
To a mixture of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidinecarboxylic acid (20.0 g), 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (17.2 g) and 1-hydroxybenzotriazole (8.07 g) in N,N-dimethylformamide (200 ml) was added dropwise 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (10.9 ml) at 0° C. The mixture was stirred at 4° C. for 15 hours, then poured into ice water (500 ml), and extracted with ethyl acetate (500 ml×2). The combined organic layer was successively washed with water, saturated aqueous NaHCO3 and brine, dried over Na2SO4, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with n-hexane-ethyl acetate (from 1:1 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester (30.5 g) as a colorless oil.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].[Cl:10][C:11]1[CH:12]=[C:13]([CH:24](O)[CH3:25])[C:14]2[O:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[C:15]=2[C:22]=1[CH3:23].CN(C)C=O>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:24]([Cl:3])[CH3:25])[C:14]2[O:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[C:15]=2[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)cc(C(C)O)c2c1C(=O)NCCO2
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C(C)Cl)c2c1C(=O)NCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A mixture of cyanuric chloride (15 mg, 0.079 mmol), 7-chloro-9-(1-hydroxyethyl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (14 mg, 0.053 mmol) and N,N-dimethylformamide (20 μL) in methylene chloride (0.4 mL) was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired compound (10 mg, 70%).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9]>CN(C=O)C.CCOC(C)=O>[C:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])#[N:3]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(C#N)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 61.2 %

Procedure:
A mixture of copper (I) cyanide (510 mg, 5.69 mmol) and DMF (16 mL) was heated to 140 ° C. The reaction was added methyl 3-bromo-4-methylbenzoate (505 mg, 2.2 mmol) in DMF (10 mL) and heating was continued for 12 h. The reaction was cooled, diluted with EtOAc (125 mL) and washed with H2O (5×25 mL). The EtOAc layer was dried over MgSO4 and concentrated. The residue was chromatographed (40 g silica, 10% EtOAc/hexanes) to give the title compound as a solid (236 mg, 61%); IR(CHCl3): 1128, 1269, 1300, 1725, 2231, 3024 cm−1; NMR(300 MHz, CDCl3): 2.63 (s, 3H); 3.95 (s, 3H); 7.43 (d, 1H, J=8.1 Hz); 8.14 (d, 1H, J=8.1 Hz); 8.28 (s, 1H); MS(FD): 175.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[C:4]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:1][C:2]1[C:3]([Cl:20])=[C:4]2[C:10]([C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OCc1ccccc1B(O)O
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)c(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OCc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(Cl)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 11.8 %

Procedure:
5-Bromo-4-chloro-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.02 mmol), 2-(tert-Butoxymethyl)phenylboronic acid (224 mg, 1.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (42 mg, 0.05 mmol), and 1 mL of sodium carbonate solution (2M, 2 mmol) were dissolved in 5 mL of acetonitrile and 5 mL of THF under an atmosphere of nitrogen. The mixture was heated at 60° C. with rapid stirring under N2 for 2 h. Sodium sulfate was added to the reaction mixture and the slurry was filtered over Celite and concentrated. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford the title compound (66 mg, 0.12 mmol, 12% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:15](=[O:16])[CH2:14][C:13](=[O:17])[N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C:11]1=[O:27].C(N(C(C)C)CC)(C)C.[N:37]([CH2:40][C:41]([O:43]CC)=[O:42])=[C:38]=[O:39]>ClCCl>[OH:17][C:13]1[N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[C:11](=[O:27])[N:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:15](=[O:16])[C:14]=1[C:38]([NH:37][CH2:40][C:41]([OH:43])=[O:42])=[O:39]
Reactant: CCOC(=O)CN=C=O
Reactant: COc1ccccc1CN1C(=O)CC(=O)N(Cc2ccccc2OC)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Cn1c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc2ccccc2OC)c1=O
Reaction time: 5 h

Procedure:
N-[(6-hydroxy-1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4-dioxo-1,2,34-tetrahydro-5-pyrimidinyl)carbonyl]glycine. A mixture of 1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione (1.64 g, 4.45 mmoles) and diisopropylethylamine (1.56 mL, 8.94 mmoles) was stirred in dichloromethane (30 mL) and treated with ethyl isocyanatoacetate (500 uL, 4.45 mmoles). The mixture was stirred for 5 hours, washed with 1 molar hydrochloric acid (×2), evaporated, taken up in ethanol-6 molar sodium hydroxide and stirred overnight. The mixture was acidified and extracted into ethyl acetate (×2). The extracts were washed with 1 molar hydrochloric acid evaporated, dried and evaporated. The title compound was recrystallized from acetic acid (1.0 g, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s., 1 H), 10.11 (t, J=4.93 Hz, 1 H), 7.20-7.28 (m, 2 H), 7.00 (d, J=7.83 Hz, 2 H), 6.86-6.96 (m, 4 H), 5.00 (s, 4 H), 4.10-4.18 (m, 2 H), 3.82 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:13]=1
Reactant: Cc1cc(CNc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 4-fluoro-3-[[3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2-methyl-phenol (324 mg, 0.95 mmol, 1.0 eq) in DMF (15 mL) was added Cs2CO3 (467 mg, 1.43 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 30 min, then isopropyl bromoacetate (207 mg, 1.15 mmol, 1.2 eq) was added and stirring continued for a further 1 h. Water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 40:1) to give the title compound as a colorless oil (317 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[CH:5](O)[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[I-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl.[Zn]>[CH3:1][O:2][C:3](=[O:17])[C:4]([CH3:15])([CH3:16])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)C(C)(C)C(O)c1cc(OC)ccn1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)Cc1cc(OC)ccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.2 %

Procedure:
3.0 g of 3-hydroxy-3-(4-methoxypyridin-2-yl)-2,2-dimethyl-propionic acid methyl ester (compound C3), 0.153 g of 4-dimethylaminopyridine and 2.58 ml of N,N′-diisopropylethylamine are dissolved in 80 ml of dichloromethane. Trifluoromethanesulfonic acid anhydride is added dropwise under ice-cooling. The cooling bath is removed and the mixture is stirred at room temperature for 2.5 h. After evaporation in vacuo, the remaining residue is dissolved as obtained in 100 ml of 1,2-dimethoxyethane. 9.37 g of sodium iodide and 16.3 g of activated zinc are added and the mixture is stirred at 100° C. for 1.5 h. The solids are filtered off, the filtrate is diluted with 800 ml of dichloromethane and extracted several times with halfsaturated aqueous sodium chloride solution. The organic layer is dried using sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (toluene/ethyl acetate 2:1) to afford 1.6 g of the title compound as an oil. MS: 224.2 (MH+). TLC: Rf=0.26 (toluene/acetone 2:1).