Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)[N:3]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([OH:52])[C:48]([F:51])([F:50])[F:49])=[C:43]([N:53]2[CH:57]=[CH:56][C:55]([CH:58]([CH3:60])[CH3:59])=[N:54]2)[CH:42]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:52][C@H:47]([C:44]2[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][C:43]=2[N:53]2[CH:57]=[CH:56][C:55]([CH:58]([CH3:60])[CH3:59])=[N:54]2)[C:48]([F:51])([F:50])[F:49])[N:3]=1
Reactant: CC(C)c1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: CC(C)c1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro-2-(3-isopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 41).
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][C@H:4]([O:8]/[CH:9]=[C:10]2\[C@H:11]3[CH2:18][CH:17]=[CH:16][C@H:12]3[NH:13][C:14]\2=[O:15])[CH:3]=1.[O:19]1CCOCC1>>[OH:19][C@H:18]1[C@H:11]2[C@H:12]([NH:13][C:14](=[O:15])/[C:10]/2=[CH:9]/[O:8][C@@H:4]2[CH:3]=[C:2]([CH3:1])[C:6](=[O:7])[O:5]2)[CH:16]=[CH:17]1
Reactant: CC1=C[C@@H](O/C=C2/C(=O)N[C@@H]3C=CC[C@H]23)OC1=O
Reactant: C1COCCO1
Product: CC1=C[C@@H](O/C=C2/C(=O)N[C@@H]3C=C[C@@H](O)[C@H]23)OC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a solution of (3E,3aR,6aR)-3-[[(2S)-4-methyl-5-oxo-2H-furan-2-yl]oxymethylene]-1,3a,4,6a-tetrahydrocyclopenta[b]pyrrol-2-one Ia-1″ (125 mg, 0.50 mmol) in 1,4-dioxane (2.5 mL) was added SeO2 (67.1 mg, 0.60 mmol) The suspension was stirred at 100° C. for 4 h then the dark suspension was then allowed to cool to room temperature followed by filtration and concentration under reduced pressure. Purification using flash chromatography (CH2Cl2/MeOH, gradient) afforded the desired compound as a dark oil (58 mg, 44%); 1H NMR (400 MHz, MeOH-d4) 7.35 (1H, d), 7.16 (1H, m), 6.38 (1H, m), 5.95 (1H, dd), 5.91 (1H, m), 4.76 (1H, m), 4.72 (1H, m), 3.39 (1H, m), 1.97 (3H, m): LCMS (Method D): 0.24 min; ES+264 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[CH3:11][NH:12][CH3:13].[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[CH3:11][N:12]([CH3:13])[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1ccccn1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(c1ccccn1)N(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of g 1.21 (0.01 moles) of 2-acetylpyridine, 1.63 (0.02 moles) of dimethylamine hydrochloride, g 0.63 (0.01 moles) of NaCNBH3 and g 0.4 (0.01 moles) of NaOH in ml.80 of dry methanol was stirred at room temperature for 4 days. The insoluble matter was filtered off and the filtrate was made strongly alkaline with 15% aqueous NaOH. After evaporation of the mathanol, some NaOH pellets were added into the aqueous residue, and the solution was extracted with ether. The combined ethereal solutions were dried on solid NaOH and evaporated i.v. The oily residue (gr 2.8) was chromatographed on 12 g. of silicagel, eluting with CH2Cl2 containing 2% to 10% methanol. 1.7 g. of oily product were obtained, sufficiently pure for the subsequent step.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]3[CH:14]([CH2:15][CH2:16][CH:17]([O:30]C(=O)C)[CH2:18]3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+]>CO.ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]3[CH:14]([CH2:15][CH2:16][CH:17]([OH:30])[CH2:18]3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C2=NC3CCC(OC(C)=O)CC3c3cc(OC)c(OC)cc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Product: CCCCOc1ccc(C2=NC3CCC(O)CC3c3cc(OC)c(OC)cc32)cc1
Reaction time: 19 h
Yield: 83 %

Procedure:
717 mg of (±)-acetic acid (2RS,4aRS,10bRS)-6-(4-butoxy-phenyl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-2-yl ester (compound 14) are dissolved in 8 ml of methanol and 1 ml of di-chloromethane, 259 mg of cesium carbonate are added and the mixture stirred for 19 h. The solvent is removed and the crude product is purified by flash chromatography (silica, ethyl acetate/triethylamine=9:1) to give 540 mg of the title compound as a colorless foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1)[CH3:2].Cl[C:33]([O:35][CH3:36])=[O:34]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][N:23]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:33]([O:35][CH3:36])=[O:34])[CH:7]=1)[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CNCc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN(Cc2ccccc2)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(benzylamino-methyl)-4-bromo-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and methyl chloroformate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH2:39][CH3:40]>>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][CH3:34])[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:40]
Reactant: CCNCCOC
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN(CCOC)c1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-(2methoxyethyl)ethylamine. ES-MS m/e (%): 472 (M+H+, 100).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[S:14][CH:13]=[C:12]([Br:15])[C:7]=2[N:8]=[C:9](Cl)[N:10]=1)[CH:2]=[CH2:3].[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:9]1[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([Br:15])[C:7]=2[N:8]=1)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: C=CCNc1nc(Cl)nc2c(Br)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C)c2scc(Br)c2n1
Yield: 93.5 %

Procedure:
305 mg (1.0 mmol) of 4-allylamino-7-bromo-2-chlorothieno[3,2-d]pyrimidine and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 304 mg (yield: 93.3%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([B:29]([OH:34])[OH:30])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccc3ccccc3c2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccc3ccccc3c2)cc1
Temperature: -60 °C
Yield: 76.5 %

Procedure:
Under an argon gas atmosphere, a mixture of 50.0 g (177 mmol) of 2(4-bromophenyl) naphthalene and 500 mL of dehydrated THF was cooled down to −60 degrees C., and added with 136 mL (212 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for one hour at −60 degrees C. 99.6 g (529 mmol) of triisopropyl borate was dropped into the reaction solution at −60 degrees C. Subsequently, the reaction mixture was warmed up to room temperature, and stirred for 18 hours. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By crystallizing the obtained solid by toluene, 33.6 g of 4-(2-naphthyl) phenylboronic acid was obtained at an yield of 84%.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:27]([O:30][C:31]1[C:36]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:35][C:34]([CH3:41])=[CH:33][C:32]=1[SiH:42]([CH2:44][CH2:45]Cl)[CH3:43])[CH:28]=[CH2:29].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1(C)C=CC=CC=1.CCCCCC>[CH2:27]([O:30][C:31]1[C:36]([C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:35][C:34]([CH3:41])=[CH:33][C:32]=1[SiH:42]([CH2:44][CH2:45][CH:8]1[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=2)[CH3:43])[CH:28]=[CH2:29]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: C=CCOc1c([SiH](C)CCCl)cc(C)cc1C(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOc1c([SiH](C)CCC2c3cc(C(C)(C)C)ccc3-c3ccc(C(C)(C)C)cc32)cc(C)cc1C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
There was dissolved 2.00 g (7.18 mmol) of 2,7-di-tert-butylfluorene in 45 mL of THF, and the obtained solution was cooled down to −78° C. To the solution, 4.49 mL of a 1.60 M-concentration hexane solution of n-butyllithium was added slowly, 4.49 mL of said hexane solution containing 7.18 mmol of n-butyllithium. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 3 hours at a room temperature. The mixture was cooled down to −78° C., and a solution of 2.23 g (7.18 mmol) of (2-allyloxy-3-tert-butyl-5-methyl phenyl)chloroethylmethylsilane in 9 mL of toluene was added to the mixture. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 3 hours, thereby obtaining a reaction solution. A mixture of 20 mL of a 10% aqueous solution of sodium hydrogen carbonate and 20 mL of a 10% aqueous solution of sodium carbonate was added to the reaction solution at 0° C. To the obtained mixture, 23 mL of toluene was added, and the mixture was separated to the toluene solution and the aqueous solution. The toluene solution was dried over sodium sulfate, and the mixture was filtered. The obtained filtrate was concentrated under a reduced pressure, thereby obtaining quantitatively (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,7-di-tert-butyl fluoren-9-yl)ethylmethylsilane.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)C)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:16]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:25][CH:26]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Product: COC(=O)C(c1ccc(OCCOc2ccc(F)cc2)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
As described in Example 35, 4.66 g of p-phenoxyphenol is reacted with methyl bromo{p-[2-(p-fluorophenoxy)propoxy]phenyl}acetate (0.02 mole) in refluxing methanol-benzene for 24 hrs to give the product as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[CH2:7][CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CC[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc21
Solvent: CCOCC
Product: CN(C)C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3.4 g (11 mmole) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide and 26 ml of dimethylformamide dimethyl acetal was stirred at room temperature for 12 hr. The mixture was diluted with ether and the precipitate collected to give a yellow solid, mp 175°-178° C. Recrystallization from a mixture of ether and ethyl acetate gave yellow needles, mp 193°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([OH:23])=[O:22]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:21]([OH:23])=[O:22])=[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-2-benzoylphenol (1.95 g) in DMF (30 ml) was added sodium hydride (60% oil) (400 mg). The mixture was stirred for 30 minutes at room temperature, to which was then added methyl ester of bromoacetic acid (1.0 ml). The mixture was stirred for 2 hours under cooling with ice-water. The reaction mixture was concentrated, to which was added ethyl acetate. The mixture was washed with water, which was then dried. The solvent was distilled off, and the residue was purified by means of a silica gel (40 g) column chromatography (hexane-ethyl acetate=3:1) to afford methyl ester of 4-chloro-2-benzoylphenoxyacetic acid as colorless crystals (2.21 g).
Reaction SMILES: [N:1]1([CH:6]=[C:7]([C:12](=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([Cl:20])=[CH:15][C:14]=2[Cl:21])[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3]C1.C1(N)CC1>C1(C)C=CC=CC=1>[CH:5]1([NH:1][CH:6]=[C:7]([C:12](=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([Cl:20])=[CH:15][C:14]=2[Cl:21])[C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C(=CN1CCCC1)C(=O)c1cc(F)c(Cl)cc1Cl
Agent: NC1CC1
Solvent: Cc1ccccc1
Product: COC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 74.4 %

Procedure:
3.5 g of methyl 3-(1-pyrrolidinyl)-2-(2,4-dichloro-5-fluorobenzoyl)acrylate are heated to boiling under reflux with 0.8 g of cyclopropylamine and 50 ml of toluene for one hour. The toluene is removed by distillation in vacuo, and the residue is recrystallized from acetonitrile. 2.5 g of methyl 3-cyclopropylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 150°-151° C. are obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:23]=[CH:22][C:11]2[C:12](=O)[NH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:10]=2[CH:9]=1.O>O1CCCC1.O1CCOCC1>[Cl:7][C:8]1[CH:23]=[CH:22][C:11]2[CH2:12][NH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:10]=2[CH:9]=1
Reactant: O=C1Nc2ccccc2Oc2cc(Cl)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc2c(c1)Oc1ccccc1NC2
Yield: 84 %

Procedure:
LiAlH4 (1M) in tetrahydrofuran (100 ml) was added dropwise to a mixture of 3-chlorodibenz[b,f][1,4]oxazepin-11(10H)-one (12.3 g) (prepared as described in Indian J. Chem. 1974, 12(3), 227-35) in 1,4-dioxane (400ml) under a N2 atmosphere. The mixture was stirred, refluxed for 1 hour 30 minutes, cooled and water was added dropwise. The mixture was acidified and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered off and evaporated. The residue was purified by open column chromatography over silica gel (eluent: CH2Cl2). The pure fractions were collected and evaporated, yielding 9.74 g (84%) of 3-chloro-10,11-dihydrodibenz[b,f]-[1,4]oxazepine (interm.8).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@H]1[C@H](NC)CCCC1.IC1C=CC(C)=CC=1>C1(C)C=CC=CC=1.[Cu](I)I>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=3)[CH:3]=[N:2]2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Reactant: Cc1ccc(Br)cc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cc1ccc(I)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cnn(-c3ccc(C)cc3)c2c1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a solution of methyl 1H-indazole-6-carboxylate (2.0 g, 11.4 mmol) in toluene (11.4 mL) was added 4-bromotoluene (2.33 g, 13.6 mmol), tribasic potassium phophate (4.8 g, 22.7 mmol), copper iodide (0.12 g, 0.60 mmol) and trans-(1R,2R)—N,N′-bismethyl-1,2-cyclohexanediamine (0.18 mL, 1.14 mmol). The reaction mixture was stirred in a sealed tube at 120° C. After 10 min, 4-iodotoluene (3.01 g) was added and the mixture was stirred at 120° C. for another 2 h. The mixture was cooled to ambient temperature and quenched with saturated sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1×15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.76 g): LC-MS [M+1]=267.1.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][N:24]([CH3:26])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:45]1([CH2:51][C:52]([N:54]=[C:55]=[S:56])=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)C.C(OCC)(=O)C>[F:29][C:4]1[CH:3]=[C:2]([NH:1][C:55]([NH:54][C:52](=[O:53])[CH2:51][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[S:56])[CH:28]=[CH:27][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:23][N:24]([CH3:26])[CH2:25]3)[CH2:20][CH2:21]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)C1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (76 mg) in ethanol (2.0 ml) was added (1S)-(+)-10-camphorsulfonic acid (83.9 mg), followed by stirring at room temperature for 15 min. A solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.28 ml) was added to the reaction mixture, followed by stirring at room temperature for 2 hrs. Ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing a target compound were concentrated to give crystals, which were suspended in diethyl ether (5 ml). Then the crystals were filtered off, washed with hexane, and dried under aeration to provide the titled compound (32.1 mg, 29%) as colorless crystals.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[Br:6][C:7]1[N:12]=[C:11](CO)[CH:10]=[CH:9][CH:8]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl>[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH2:1][Br:5])[N:12]=1
Reactant: OCc1cccc(Br)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Carbon tetrabromide (12.90 g, 38.88 mmol) was added in four portions to a solution of (6-bromo-pyridin-2-yl)methanol (5.00 g, 29.91 mmol) and PPh3 (8.24 g, 31.40 mmol) in dichloromethane (50 ml) at 0° C. The resulting solution was stirred 2 hours at 0° C. Solvent was removed under reduced pressure. The title compound was obtained by column chromatography. Spectroscopic data: 1H NMR (300 MHz, Acetone-d6) δ 4.66 (s, 2H) 7.57-7.60 (m, 2H) 7.76 (t, J=7.42 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.O=[CH:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:16][CH2:17]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: O=C1NC[C@@H](c2ccc(F)cc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN1CCC2(CC1)C(=O)NC[C@H]2c1ccc(F)cc1
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture containing 0.25 g (1.0 mmol) of (S)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one, 0.2 g (1.41 mmol) of tert-butyl 2-oxoethylcarbamate, 2 mL of THF, 1 mL of DCM, and 1 g (2.5 mmol) of MP-sodium triacetoxyborohydride resin was rotated overnight. The reaction mixture was filtered and the solvents were removed under reduced pressure. The residue was subjected to silica gel chromatography to give 131 mg (33%) of (S)-tert-butyl 2-(4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)ethylcarbamate as a colorless oil: 1HNMR (400 MHz, CD3OD) δ ppm 7.35-7.32 (m, 2H), 7.12-7.07 (m, 2H), 3.68 (dd, 1H, J=10.4 and 7.6 Hz), 3.57 (dd, 1H, J=10.4 and 6.4 Hz), 3.32-3.28 (m, 3H), 3.11-3.08 (m, 2H), 2.87-2.84 (m, 3H), 2.02-1.80 (m, 4H), 1.41 (s, 9H), and 1.34-1.27 (m, 2H); LCMS m/z: 392.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O:5]1[CH:7]([CH2:8][O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:6]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:6][CH:7]([OH:5])[CH2:8][O:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1
Reactant: c1csc(OCC2CO2)n1
Reactant: NCCO
Solvent: CCO
Product: OCCNCC(O)COc1nccs1

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I of the invention. In this example 0.6 g. of ethanolamine is added to a solution of 0.3 g. of 1,2-epoxy-3-(thiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20°C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of 1,2-epoxy-3-(thiazol-2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue of 1-(β-hydroxyethylamino)-3-(thiazol-2-oxy)-2-propanol which is then further purified by thin-layer chromatography.