Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[F:1][C:2]([F:30])([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
23 g (53.4 mmol) of methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}-phenyl)prop-2-enoate is dissolved in 400 ml of dioxane. 30 ml of NaOH (30%) diluted in 250 ml of water is added to the solution. The mixture is heated to 55° C. for 2 hours. The mixture is cooled to room temperature and is carefully acidified to pH=2 with a HCl solution (25%) and is stirred for 15 min. The product is filtrated off and dried at room temperature under vacuum for 10 h to give 18 g of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-methyl}phenyl)-prop-2-enoic acid as a colourless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
A stirred suspension of 4-(4-(4-pyridyl)piperazin-1-yl)-phenol (1.34 g) in dry DMF (20 ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.21 g) and the mixture stirred for 1 hour. To the resulting solution was added ethyl 4-bromobutyrate and the mixture was stirred for 16 hours. Solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, filtered through phase separating paper (Whatman 1PS) and evaporated. The residue was purified by flash chromatography on silica, eluting with 1-5/92.5/6 v/v/v methanol/ethyl acetate/aqueous ammonia (SG 0.89) and recrystallised from ethyl acetate/hexane to give the title compound (0.7 g) as a solid: m.p. 84°-85° C.; NMR (CDCl3) δ 8.3(2H,d); 6.86(4H,c); 6.72(2H,d); 4.12(2H,q); 4.0(2H,t); 3.47(4H,m); 3.20(4H,m); 2.5(2H,t); 2.1(2H,m); 1.26(3H,t); m/e 370(M+H)+ ; calculated for C21H27N3O3C, 68.3; H, 7.4; N, 11.4. Found: C, 68.1; H, 7.4; N, 11.1%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([F:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]([F:21])([F:20])[C@@H:17]([OH:19])[CH3:18].[H-].[Na+]>>[F:12][C:8]1([C:7]2[C:2]([O:19][C@@H:17]([CH3:18])[C:16]([F:21])([F:20])[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5][CH:6]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: N#Cc1cc(Cl)c(C2(F)CCC2)cn1
Reactant: C[C@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: C[C@H](Oc1cc(C#N)ncc1C1(F)CCC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-(1-fluorocyclobutyl)-pyridine-2-carbonitrile (example 305c) and (S)-1,1,1-Trifluoro-propan-2-ol (CAN 3539-97-7) as starting materials and sodium hydride as reagent. The title was isolated (1.23 g, 90%) as a yellow oil; MS (ESI, m/z): 289.2 (M+H+).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:33]1([N:39]=[C:40]=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(#N)C>[CH:33]1([NH:39][C:40]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2Cc3c(CNC(=O)NC4CCCCC4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.4 g, 2.9 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (100 mL). The mixture was heated for 30 minutes, then cooled to room temperature. Cyclohexyl isocyanate (0.4 g, 2.9 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solid was stirred with water (25 mL) to give 0.9 g of crude product. The crude product was recrystallized from methanol to give 1-cyclohexyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.12 g, 16%) as a white solid: mp 309-311° C.; 1H NMR (DMSO-d6) δ 0.97-1.75 (m, 10H), 1.99-2.04 (m, 1H), 2.32-2.64 (m, 3H), 2.86-2.98 (m, 1H), 4.27-4.51 (m, 4H), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 5.86 (d, J=7.9 Hz, 1H), 6.26 (t, J=5.5 Hz, 1H, NH), 7.47-7.62 (m, 3H, Ar), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.64, 24.44, 25.29, 31.16, 33.32, 46.09, 47.50, 47.85, 51.47, 121.36, 128.18, 130.26, 131.61, 136.28, 139.77, 157.20, 168.09, 170.97, 172.82; Anal. calcd. for C21H26N4O4: C, 63.30; H, 6.58; N, 14.06. Found: C, 63.18; N, 6.58; N, 13.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH2:18][N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)=[C:14]([C:26]2[N:27]([CH3:32])[N:28]=[CH:29][C:30]=2[Cl:31])[CH:13]=1>ClCCl.CN(C=O)C>[Cl:31][C:30]1[CH:29]=[N:28][N:27]([CH3:32])[C:26]=1[C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH:25]=[CH:24][C:15]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CC(O)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
4-Chlorophenylisocyanate (19.0 mg, 0.124 mmol) was added to a solution of 1-{2-[4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-azetidin-3-ol (40.0 mg, 0.124 mmol) in dichloromethane (2.0 mL) and DMF (0.1 mL), and the mixture stirred at room temperature overnight. The solution was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (28 mg, 47%). LCMS m/z (%)=476 (M+H35Cl, 100), 478 (M+H37Cl, 67). 1H NMR (400 MHz, DMSO-d6) δ: 8.81 (bs, 1H), 8.71 (bs, 1H), 7.60 (s, 1H), 7.53-7.50 (m, 1H), 7.47 (d, J=2.08 Hz, 1H), 7.46 (d, J=2.10 Hz, 1H), 7.36 (d, J=2.71 Hz, 1H), 7.32 (d, J=2.11 Hz, 1H), 7.30 (d, J=2.04 Hz, 1H), 7.11 (d, J=9.06 Hz, 1H), 5.19 (d, J=8.00 Hz, 1H), 4.10-4.00 (m, 1H), 3.99-3.85 (m, 2H), 3.65 (s, 3H), 3.40-3.30 (m, 2H), 2.70-2.55 (m, 4H).
Reaction SMILES: [CH:1]1([C:6]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[C:17]([O:11][C:6]1([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1(C2CCCC2)CCCC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C(=O)OC1(C2CCCC2)CCCC1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a 1-L 3-necked round bottom flask equipped with a 250-mL pressure equalizing addition funnel, a nitrogen inlet with thermocouple and an overhead stirrer was added 56 g (0.364 mol) of 1-cyclopentyl-1-cyclopentanol and 400 mL of anhydrous tetrahydrofuran. The addition funnel was charged with 250 mL (0.4 mol) of n-butyllithium (1.6M in hexane) which was then added to the cooled alcohol over 2 hours. The addition funnel was then charged with a solution of 41 g (0.39 mol) of freshly distilled methacryloyl chloride in 100 mL of dry tetrahydrofuran which was then added slowly with cooling over 1.5 hours. The reaction mixture was allowed to warm to room temperature with stirring overnight after which 100 mL of saturated sodium bicarbonate was carefully added with stirring. The mixture was stirred for 1 hour at which time it was diluted with 1 L of diethyl ether and the organics washed with water, brine and dried for 1 hour over anhydrous magnesium sulfate. Filtration and removal of the solvent at reduced pressure resulted in a light-colored oil which was eluted with hexane through a column of 600 g of silica gel. The UV active fractions were collected and the solvent removed at reduced pressure to yield 74 g (91%) of the title compound as a clear, colorless oil.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[N:9]1[S:10][CH:11]=[C:12]2[C:17](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:13]=12.O>CS(C)=O>[N:9]1[S:10][CH:11]=[C:12]2[C:17]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:13]=12
Reactant: CCOC(=O)/C=C/c1cccc2nscc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccc2nscc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (60%, 1.08 g, 24.7 mmol) in dimethyl sulfoxide (100 mL) was added a solution of trimethylsulfoxonium iodide (5.43 g, 24.7 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl(2E)-3-(2,1-benzisothiazol-4-yl)acrylate (4.80 g, 20.6 mmol) in dimethyl sulfoxide (200 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (2.70 g, yield 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[C:22](OC(=O)C)(=O)[CH3:23].C(=O)([O-])[O-].[K+].[K+].[CH3:35][S:36]([OH:39])(=[O:38])=[O:37]>O.CC(C)=O>[CH3:35][S:36]([OH:39])(=[O:38])=[O:37].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1O2
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1
Reaction time: 1 h

Procedure:
A solution of 4-(2-chloro-9-xanthenylidene)piperidine (2.0 g., 6.75 mmol) in 5 ml. of acetic anhydride is heated on a steam bath for 2.5 hours. Acetone (30 ml.) and 50 ml. and 20% aqueous potassium carbonate is added to the cooled solution and the mixture stirred for one hour. Additional water is added and the mixture is extracted with ether. The extract is washed with 1N hydrochloric acid, water and dried. The solvent is evaporated to give the crude amide, 2.2 g. (recrystallized amide m.p. 165°-166° C.). The amide is dissolved in 500 ml. of ether and added to a stirred suspension of 2.0 g. of lithium aluminum hydride in 200 ml. of ether. After two hours at 23° C. excess hydride is decomposed with water (4 ml.) and 10% sodium hydrixode (3.2 ml.). The mixture is filtered and the filtrate is evaporated. The residue is dissolved in a mixture of methanol and ether and treated with one equivalent of methanesulfonic acid. The precipitated salt is filtered and recrystallized from methanol/ether to give 4-(2-chloro-9-xanthenylidene)-1-ethylpiperidine methanesulfonate, m.p. 249°-252° C.
Reaction SMILES: C(O)(=O)C.C(O[C:8]1(O[Si](C)(C)C)[CH2:10][CH2:9]1)C.[NH2:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])([CH3:32])[C:23]2=[O:40])=[C:19]([O:43][CH3:44])[CH:18]=1.C([BH3-])#N.[Na+]>CO>[Cl:31][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([CH2:21][C:20]1[CH:41]=[CH:42][C:17]([NH:16][CH:8]3[CH2:10][CH2:9]3)=[CH:18][C:19]=1[O:43][CH3:44])[C:23](=[O:40])[C:24]2([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[CH3:32]
Reactant: COc1cc(N)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(NC2CC2)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.54 ml of acetic acid, 0.4 g of 3 Å molecular sieve and 0.207 ml of (1-ethoxycyclopropyl)oxytrimethylsilane are added to 0.4 g of the compound of Example 48 in solution in 10 ml of methanol. After stirring for 30 minutes at room temperature, 0.265 g of sodium cyanoborohydride is added and then the mixture is heated at reflux for 10 hours. After cooling, hydrolysis is carried out with 20 ml of 2N sodium hydroxide solution, filtration is carried out through celite and the celite is rinsed with ethyl acetate. The organic phase is washed with a 10% aqueous sodium chloride solution and dried over sodium sulphate and the solvents are evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([O:3]C(C1C=CC=CC=1)C=O)C.[CH:13]([O:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:18]=[O:19])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:1][OH:3])[CH2:18][OH:19])([CH3:15])[CH3:14]
Reactant: CCOC(C=O)c1ccccc1
Reactant: CC(C)OC(C=O)c1ccccc1
Product: CC(C)OC(CO)(CO)c1ccccc1

Procedure:
The procedure in Example 6 was repeated except that 2-ethoxy-2-phenylethanal was replaced with 2-isopropoxy-2-phenylethanal, to obtain 2-isopropoxy-2-phenyl-1,3-propanediol.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH2:18][CH3:19])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:20]([C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:37][C:35]1[CH:36]=[C:28]2[C:29](=[CH:33][CH:34]=1)[C:30](=[O:31])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH2:18][CH3:19])=[C:20]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 2, the title compound was synthesized from 4-[(2-hydroxypentylamino)methyl]benzenesulfonamide hydrochloride and 2-benzoyl-4-chlorobenzoic acid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:25]2)=[O:23])[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31][C:30]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:24]([C:22](=[O:23])[NH:21][C@H:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([OH:8])[CH:10]=3)[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:25]2)=[O:46])[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-({(1S)-1-[5-(benzyloxy)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (650 mg, 1.02 mmol) was dissolved in ethyl acetate (45 mL) and methanol (7.4 mL) and palladium on charcoal (65 mg, 10%) was added. The mixture was shaken under a hydrogen atmosphere for 16 hours filtrated through celite which were washed with methanol. The filtrate was concentrated and purified by chromatography on silica gel (methanol in ethyl acetate 0% to 25%) to yield 422 mg of tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:7])=[N:4][NH:5][CH:6]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1OB(O)O.N1C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([CH3:7])=[N:4][N:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[F:8])[CH:6]=1
Reactant: Cc1n[nH]cc1Br
Reactant: OB(O)Oc1ccccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nn(-c2ccccc2F)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.5 %

Procedure:
580 mg of 4-bromo-3-methylpyrazole, 1.0 g of 2-fluorophenylboric acid, 3.3 g of copper acetate, 1.0 g of molecular sieves 4A, and 1.6 ml of pyridine were suspended in 8.0 ml of dimethylformamide, and the mixture was stirred at room temperature for 3 days. The obtained suspended solution was filtrated by celite, and the filtrate was diluted with ethyl acetate. Organic layer was washed with 0.5 N sodium hydride, dried with sodium sulfate, and the solvents were distilled outunder reduced pressure. The residues were purified by silicagel column chromatography (hexane:ethyl acetate=50:50) to obtain 78 mg of the above compound as a crude product.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1.O>O1CCCC1>[N+:15]([C:14]1[C:9]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[N:10][CH:11]=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)([O-:17])=[O:16]
Reactant: CS(N)(=O)=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 65.8 %

Procedure:
4.4 g of methanesulfonamide was dissolved in 70 ml of dry tetrahydrofuran, and 1.9 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 7.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and the mixture was reacted for 6 hours under reflux. After completion of the reaction, the reaction product was poured into 300 ml of water and washed with ethyl ether. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 5.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)methanesulfonamide having a melting point of from 138° to 139° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:8]1)[C:20]([NH2:22])=[NH:21]
Reactant: COc1ccc(C2CC(=O)c3c(C)coc3C2)cc1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C2CC(=NNC(=N)N)c3c(C)coc3C2)cc1
Yield: 58.8 %

Procedure:
A mixture of 3-methyl-6-(4-methoxyphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.10 g), aminoguanidine hydrochloride (0.045 g), concentrated hydrochloric acid (0.02 ml), water (0.02 ml) and ethanol (30 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-6-(4-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 36) (0.08 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=2[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:27]I>CN(C)C=O.C(OCC)(=O)C>[CH3:27][N:6]1[C:5]2[CH:23]=[CH:24][CH:25]=[CH:26][C:4]=2[NH:3][C:2]([CH3:1])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: CI
Reactant: CCOC(=O)C1=C(C)Nc2ccccc2NC1c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2ccccc2N(C)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A reaction mixture containing 2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, ethyl ester (1,5 g., 4.25 mmole) in dry dimethylformamide (5 ml.) is treated with methyl iodide (581 mg., 5.5 mmole) and then allowed to stir at room temperature for 24 hours. The reaction mixture is diluted with ethyl acetate and is washed with sodium bicarbonate, water, and brine. After drying over magnesium sulfate, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (30% ethyl acetate in hexanes). The yellow foam obtained (701 mg.) is crystallized from ether-hexanes to provide yellow crystalline 2,5-dihydro-1,4-dimethyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, ethyl ester; m.p. 113°-115.5°. TLC (silica gel; ethyl acetate:hexanes, 1:1) Rf =0.5.
Reaction SMILES: CS([O:5][C@@:6]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[NH2:22])([C:11]#[C:12][CH:13]1[CH2:15][CH2:14]1)[C:7]([F:10])([F:9])[F:8])(=O)=O.[OH-].[Na+].[C:31]([O-])([O-])=[O:32].[Na+].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C>[CH:13]1([C:12]#[C:11][C@:6]2([C:7]([F:10])([F:9])[F:8])[C:16]3[CH:17]=[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=[CH:20][C:21]=3[NH:22][C:31](=[O:32])[O:5]2)[CH2:15][CH2:14]1
Reactant: CS(=O)(=O)O[C@](C#CC1CC1)(c1cc(-c2ccccc2)ccc1N)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(-c3ccccc3)cc2[C@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
(R)-2-(4-Aminobiphenyl-3-yl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol methanesulfonate (CN46630-MSA) of example 2 (14.7 g, 34.4 mmol) in ethyl acetate/heptanes (1:1 v/v, 27.9 g) was charged in a jacketed 150 mL-reactor with agitator and off-gas scrubber with caustic soda. After addition of aqueous Na2CO3 (12%-w/w, 32.3 g, 36.4 mmol, formation of gas during addition!) the mixture was stirred for 15 min at 15° C. The aqueous phase was separated and discarded. Aqueous Na2CO3 (12%-w/w, 41 g, 46 mol) and ethyl acetate (20 g) were charged to the organic phase. Triphosgene (4.41 g, 14.9 mmol) was added in portions over a period of 25 min at 10° C. The reaction mixture was stirred for 2 h at 8° C. The mixture was diluted with ethyl acetate (45 g) and the phases were separated. The aqueous phase was discarded. The organic phase was washed with water (12 mL), dried over MgSO4, filtered and concentrated and dried at 50° C. under reduced pressure to obtain (R)-4-(cyclopropylethynyl)-6-phenyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (CN46685, 12.1 g, 33.9 mmol, 98%) as a yellowish solid (99.5% purity, according to Method C).