Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH:13]([OH:16])[CH:14]=[CH2:15].[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C>N1C=CC=CC=1>[C:17]([O:16][CH:13]([C:12]#[C:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:14]=[CH2:15])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(O)C#CCCCCCCCCCCl
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: C=CC(C#CCCCCCCCCCCl)OC(C)=O
Yield: 55.7 %

Procedure:
To the crude alcohol from Step (D) supra., there is added 2.34 kg. (29.6 moles) of dry pyridine. Under a blanket of nitrogen gas, 6 kg. (59.2 moles) of acetic anhydride is added at room temperature over a 6 hour period. After stirring several additional hours, a sample is pulled and analyzed on a 6' carbowax column for loss of alcohol and appearance of the desired acetate. After completion of the reaction, the crude product is transferred to a distillation apparatus where the excess acetic anhydride and residual pyridine are removed under vacuum. Finally, the product is flash distilled through a thin film evaporator, the first pass removing residual lights and unreacted 11-chloro-1-undecyne from Step (D), supra., and the second pass to flash the product off higher boiling residues at 170° C./3 mm Hg. This yields 15.3 kg. (53.8 moles) of the acetate which is sufficiently pure to carry on to the next step (yield is 55.7% based on 11-chloro-1-undecyne in Step (D) supra.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH:32]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(CC)=NC=2C2C=CC(Cl)=CC=2Cl)CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])[C:11]([CH2:30][CH3:31])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:32][CH2:16]1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.82–1.33, 1.58–1.71, 2.68–2.76, 3.06–3.19, 3.41–3.51, 3.65–3.75, 4.32–4.36, 5.52–5.54, 5.71–5.76, 7.23–7.52; MS (ESI+) for C26H27Cl2N3O m/z 469 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.C[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[C:39]=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[C:42]([CH3:41])=[CH:43][CH:38]=[CH:39][C:40]=2[CH3:44])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1O
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4c(C)cccc4C)c(C)c3C)c2cc1OC
Yield: 93.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2,6-dimethylphenol (28 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 89%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:14][CH2:15][C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1

Procedure:
In the next step, (±)-trans-2-phenylcyclohexanol is reacted with chloroacetyl chloride at reflux in a basic solvent such as a mixture of methylene chloride and pyridine or, more preferably, 4-dimethylaminopyridine and methylene chloride. The resulting (±)-trans-2-phenylcyclohexyl chloroacetate of the formula ##STR29## can be isolated by conventional means such as extraction followed by distillation of the organic layer.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C[O-].[Na+].[I-].[Na+].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>O.CC(N(C)C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]
Reactant: OCCCCCCCl
Reactant: Oc1ccc2ccccc2c1
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: OCCCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A mixture of 50.0 g (0.348 mole) of 2-naphthol, 18.8 g (0.348 mole) of sodium methoxide, 2.0 g of sodium iodide and 800 ml of dimethylacetamide was stirred at room temperature for 1 hour, 47.5 g (0.348 mole) of 6-chlorohexanol was added. The mixture was heated to reflux with stirring for two hours, allowed to cool and poured into 3 liters of water and extracted with diethylether. The ether layer was evaporated to dryness to give a solid residue which was recrystallized from methanol to give 13.3 g of 6-(2-naphthalenyloxy)hexanol, mp=64°-65° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: NCCN1CCSCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 150 ml of methylene chloride under nitrogen atmosphere add 3.1g (14.3 mmole) of 4-thiomorpholinethanamine and 4.42 g (43.6 mmole) of triethylamine. Stir the mixture at ambient temperature for 1 hour, then cool the mixture to -10° C. To the cooled mixture add slowly 3.67 g (15.1 mmole) of 4-[(methylsulfonyl)amino]benzoyl chloride, keeping the temperature below 5° C. When the addition is complete, allow the reaction mixture to stir at ambient temperature. Monitor the progress of the reaction by thin layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 9:1). Upon completion of the reaction, remove the solvent in vacuo. To the resulting solid add 50 ml of water. To the mixture add 50% sodium hydroxide until pH of 14 is reached. Wash the aqueous layer with 3×50 ml of diethyl ether. Add concentrated hydrochloric acid until a white precipitate forms (pH=8.5). Filter the solid and recrystallize from methanol/ethanol to yield the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]#[N:15])[N:4]=1.CC1C2C(=CC=CC=2)NN=1.C(C1C=C(C=CC=1F)[C:35]([O:37][CH3:38])=[O:36])#N>O>[C:14]([C:13]1[CH:16]=[C:17]([CH:18]=[CH:19][C:12]=1[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH2:2][Br:1])=[N:4]1)[C:35]([O:37][CH3:38])=[O:36])#[N:15]
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Reactant: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Agent: Cc1n[nH]c2ccccc12
Solvent: O
Product: COC(=O)c1ccc(-n2nc(CBr)c3ccccc32)c(C#N)c1

Procedure:
In a similar manner to that described for the preparation of 2-(3-(bromomethyl)-1H-indazol-1-yl)benzonitrile except in Step 1 the mixture was diluted with H2O and the product recrystallized from MeOH and in Step 2 1,2-dichoroethane was used in place of CCl4, 3-methyl-1H-indazole (1 g, 7.57 mmol)) and methyl 3-cyano-4-fluorobenzoate (1.36 g, 7.57 mmol) as a white solid.
Reaction SMILES: O[Li:2].O.C[O:5][C:6](=[O:46])[CH2:7][C:8]1[CH:45]=[CH:44][CH:43]=[CH:42][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:13]=1>C1COCC1.O.CO>[C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:42]=[CH:43][CH:44]=[CH:45][C:8]=4[CH2:7][C:6]([O-:46])=[O:5])[C:17]([C:18]([F:20])([F:19])[F:21])=[CH:16][N:15]=3)=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)=[O:36])([CH3:41])([CH3:39])[CH3:40].[Li+:2]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Product: [Li+]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
LiOH.H2O (0.027 g, 0.647 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I47) (0.128 g, 0.214 mmol) in THF (7 mL), water (1.5 mL) and methanol (1 mL). The resulting mixture was allowed to stir at room temperature for 20 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL), the organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (I48) (0.130 g) as a pale yellow viscous oil.
Reaction SMILES: C(OC([C:8]12[CH2:16][NH:15][CH2:14][C:13]31[CH:11]([CH:12]3N)[CH2:10][CH2:9]2)=O)(C)(C)C.C([N:20](CC)CC)C.F[C:26]1[C:35]([CH3:36])=[C:34]2[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]2[C@@H:37]2[CH2:39][C@@H:38]2[F:40])=[CH:28][CH:27]=1>CS(C)=O.C(OCC)(=O)C.Cl>[NH2:20][C:8]12[CH2:16][N:15]([C:26]3[C:35]([CH3:36])=[C:34]4[C:29]([C:30](=[O:44])[C:31]([C:41]([OH:43])=[O:42])=[CH:32][N:33]4[C@@H:37]4[CH2:39][C@@H:38]4[F:40])=[CH:28][CH:27]=3)[CH2:14][C:13]31[CH:11]([CH2:12]3)[CH2:10][CH2:9]2
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)C12CCC3C(N)C31CNC2
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(N2CC3(N)CCC4CC43C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 70 °C
Reaction time: 312 h
Yield: 28.7 %

Procedure:
To a solution of 6-tert-butoxycarbonyl amino-8-azatricyclo[4.3.0.01,3]nonane (290 mg, 1.22 mmol) in dimethyl sulfoxide (2.42 ml) were added triethylamine (0.507 ml, 3.63 mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (337 mg, 1.21 mmol) and the mixture was stirred at 70° C. for 13 days under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate and washed with 10% aqueous solution of citric acid (50 ml), water (60 ml), and saturated aqueous solution of sodium chloride (60 ml). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol; 100:0→99:1→98:2→95:5) to afford a pale yellow solid. The solid was dissolved in concentrated hydrochloric acid (1.0 ml) in an ice bath and the aqueous solution was washed with chloroform (30 ml×5). To the aqueous layer was added saturated aqueous solution of sodium hydroxide to adjust pH to 12.0 and the basic aqueous solution was adjusted with hydrochloric acid to pH 7.4. The solution was extracted with chloroform (80 ml×4) and 10% methanol-chloroform (80 ml×1, 50 ml×1). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from ethanol to afford the title compound 138 mg (29%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])#[CH:21].C(N(CC)CC)C>CCOC(C)=O.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.[Cu]I>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]#[C:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: C#Cc1ccccc1F
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccccc2F)c1)c1ccccc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A mixture of (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (105 mg, 0.31 mmol) and 1-ethynyl-2-fluorobenzene (75 mg, 0.62 mmol) in 2.0 mL EtOAc was degassed with argon at 70° C. Upon cooling to room temperature the reaction mixture was treated with triethylamine (0.16 mL, 1.1 mmol), dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) and copper(I)iodide (2 mg, 0.012 mmol). The reaction was heated at 70° C. for 20 hours then partitioned between EtOAc and H2O. The EtOAc layer was washed with acetic acid solution, saturated NaHCO3, brine, dried with anhydrous Na2SO4 and concentrated. The dark film obtained was purified by chromatography (silica gel, hexane/EtOAc) to give the title compound as a tan foam (110 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:3]=1[C:20](=[O:22])[CH3:21].[C:23]([Mg]Cl)([CH3:26])([CH3:25])[CH3:24].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[C:3]=1[C:20]([OH:22])([C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:21]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC(=O)c1c(F)cccc1Oc1cnc2c(F)cccc2c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(C)(O)c1c(F)cccc1Oc1cnc2c(F)cccc2c1
Temperature: -78 °C

Procedure:
After 0.15 g of 1-[2-fluoro-6-(8-fluoro-quinolin-3-yloxy)-phenyl]-ethanone was dissolved in 1.5 ml of tetrahydrofuran, and then the solution was cooled to −78° C., 0.3 ml of t-butylmagnesium chloride (2.0 M diethyl ether solution) was added dropwise. After the reaction temperature was increased to room temperature, the reaction solution was treated with dilute hydrochloric acid, and then the liquid was separated with ethyl acetate. The organic layer was concentrated and then purified by silica gel column chromatography to obtain 0.04 g of 2-[2-fluoro-6-(8-fluoro-quinolin-3-yloxy)-phenyl]-3,3-dimethylbutan-2-ol (Compound Number 30).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1.I[CH3:24]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[N:16]([CH3:24])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1
Reactant: CI
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.35 g (8.0 mmol) sodium hydride (55%, suspension in mineral oil) were added to 2.2 g (7.6 mmol) 6-(6-chloropyrimidin-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.95 mL (15.0 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. The reaction mixture was combined with ice water and the aqueous phase was extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, filtered and evaporated to dryness by rotary evaporation. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14][OH:15])=[O:6])[CH2:3][CH2:2]1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH3:30][S:27]([O:15][CH2:14][CH2:13][CH2:12][C:11]1[N:10]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:6])(=[O:29])=[O:28]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (3.57 g, 10 mmol) obtained in Example 113 and mesyl chloride (1.37 g, 12 mmol, 1.2 eq.) were dissolved in dichloromethane (50 ml) and triethylamine (1.21 g, 12 mmol, 1.2 eq.) was added dropwise over 10 min while stirring at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. The reaction mixture was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (4.25 g, 97.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH:31]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH:31]1([N:36]2[CH2:37][CH2:38][N:39]([C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:16])[CH2:40][CH2:41]2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C1CCC(N2CCNCC2)C1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C3CCCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (2.2 g) in dry DMF (40 ml) was treated with EDC (3.71 g) followed by HOAT (0.1 g). After 5 min, N-cyclopentylpiperazine (1.5 g) in dry DMF (5 ml) was added and the reaction mixture was stirred at rt for 18 h. Excess DMF was removed by evaporation and the resulting residue was re-dissolved in DCM, adsorbed onto silica gel (10 g) and purified by chromatography [silica gel 0-10% MeOH (containing 10% 0.88 ammonia solution/DCM)]. The pure fractions were combined and the solvent removed by evaporation to give the subtitled compound (2 g). LCMS electrospray(+ve) 366(MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C@H:12]1[CH2:16][O:15]C(C)(C)[O:13]1)[CH2:6][CH2:5]2.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C@H:12]([OH:13])[CH2:16][OH:15])[CH2:6][CH2:5]2
Reactant: CC1(C)OC[C@H](C2CCc3cc(F)ccc3O2)O1
Solvent: O
Solvent: CC(=O)O
Product: OC[C@@H](O)C1CCc2cc(F)ccc2O1
Temperature: 65 °C
Yield: 89 %

Procedure:
6-Fluoro-3,4-dihydro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (40 mg, 0.16 mmol, diastereomeric ratio 75:25) was dissolved in acetic acid (2 ml) and demi water (0.7 ml). The reaction mixture was stirred vigorously and heated to 65° C. After 3 h at 65° C. the reaction mixture was cooled to 25° C. The solution was then concentrated in vacuo at 35° C. to obtain (R)-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethane-1,2-diol as a vetrous oil (89% yield, diastereomeric ratio 73:27).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:40]=[C:41]=[O:42])(=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[C:31]([NH:40][C:41](=[O:42])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCC(=O)N=C=O
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 56 %

Procedure:
The compound 89 (101-1048 (816 mg, 2.00 mmol) was converted to the carbamate with octanoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 91 (650 mg, 56%) as crystals. Mp. 139-141° C. Rf 0.34 (EtOAc).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]([C:22]([F:25])([F:24])[F:23])[O:19]2)=[CH:14][C:13]=1[Cl:31]>CN(C=O)C>[Cl:31][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[CH2:11][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:19][CH:18]([C:22]([F:25])([F:24])[F:23])[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16]2
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(COc3ccccc3)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of phenol (117 mg, 0.69 mmol) in 1 mL DMF was added to a mixture of NaH (30 mg, 0.75 mmol) in 1 mL DMF at 0° C. under argon. After 30 min, a solution of ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (250 mg, 0.62 mmol) in 2 mL DMF described in Example 157 Step 3 was added dropwise. The reaction was warmed to 25° C. After 18 h, the reaction was filtered through a pad of Celite (1″) and washed with EtOAc (20 mL). The filtrate was concentrated to give a pale yellow solid in 230 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+]>O>[Cl-:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N+:6]#[N:9])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(Cl)cc1
Product: [Cl-]

Procedure:
2.6 g of 98% finely powdered 4-chloroaniline (20.0 mmol) were dissolved in 20 ml of water and 20 ml of 10% hydrochloric acid (the solvent mixture beforehand had been evacuated three times on a rotary evaporator and vented with argon). At 0 to 5° C. under argon, a solution of 1.4 g of sodium nitrite (20.0 mmol) in 10 ml of water (degassed with argon beforehand) was added dropwise to the solution over the course of 10 minutes. The clear diazonium salt solution was stirred at 0° C. for a further 15 minutes and stored under argon.