Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:68])[CH:5]=[CH:6][C@H:7]([CH3:67])[C@H:8]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=1)[C@@H:9]([CH3:56])[CH:10]=[CH:11][C@@H:12]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH2:13][C@H:14]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C@H:15]([CH3:39])[CH:16]=[CH:17][CH2:18][O:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C:4](=[O:68])[CH2:5][CH2:6][C@H:7]([CH3:67])[C@@H:8]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=1)[C@@H:9]([CH3:56])[CH:10]=[CH:11][C@@H:12]([O:48][Si:49]([C:52]([CH3:53])([CH3:54])[CH3:55])([CH3:50])[CH3:51])[CH2:13][C@H:14]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[C@H:15]([CH3:39])[CH:16]=[CH:17][CH2:18][O:19][C:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:2]
Reactant: CCOC(=O)C=C[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)C=C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)C=CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC[C@H](C)[C@@H](OCc1ccc(OC)cc1)[C@@H](C)C=C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)C=CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a stirred solution of unsaturated ester 65 (2.02 g, 2.10 μmol) in MeOH (10 ml), THF (1 ml) at 0° C. was added 0.25 g of NiCl·6H2O then portionwise NaBH4 (0.16 g). After 1 h, the reaction mixture was evaporated and filtered with Celite using Et2O as an eluent (5 ml). The organic phase was concentrated and the residue was purified by flash chromatography (EtOAc/Hexane 1:9) to yield 1.96 g (2.04 μmol) of product 66 (97%) as a colorless oil: IR (CHCl3) 2956, 2929, 2856, 1735, 1613, 1514, 1479, 1448, 1374, 1249, 1174, 1072, 836, 773, 706 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.53 (m, 6H), 7.33 (m, 11H), 6.84 (m, 2H), 5.81 (dd, J=15.7, 6.1 Hz, 1H), 5.65 (m, 1H), 5.45 (m, 2H), 4.65 (m, 1H), 4.56 (d, J=10.9 Hz, 1H), 4.45 (d, J=10.9 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.96 (m, 1H), 3.80 (s, 3H), 3.62 (m, 2H), 3.14 (m, 1H), 2.79 (m, 1H), 2.43 (m, 1H), 2.23 (m, 1H), 1.72 (m, 2H), 1.54 (m, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.06 (d, J=6.7 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.97 (s, 18H), 0.93 (d, J=6.4 Hz, 3H), 0.17 (s, 3H), 0.154 (s, 3H), 0.151 (s, 3H), 0.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.6, 158.8, 144.4, 134.6, 133.6, 132.1, 131.2, 129.1, 128.7, 127.7, 126.8, 126.4, 103.4, 86.6, 86.1, 73.8, 72.8, 66.5, 65.2, 60.0, 55.1, 42.8, 42.3, 35.4, 35.1, 32.3, 29.4, 26.0, 25.9, 18.4, 18.1, 14.6, 14.2, 13.9, −2.9, −4.0, 4.1; HRMS (ESI) calcd for C59H86O7Si2K 1001.5549 (M+K)+, found 1001.5586; [α]20D−9.8 (c 0.95, CHCl3).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]=[C:11]2[NH:15][C:14](=[O:16])[CH:13]=[C:12]2[OH:17])=[CH:8][CH:7]=1>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[C:11]2[NH:15][C:14](=[O:16])[C:13](=[N:1][OH:3])[C:12]2=[O:17])=[CH:18][CH:19]=1
Reactant: O=N[O-]
Reactant: O=C1C=C(O)C(=Cc2ccc(Cl)cc2)N1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2ccc(Cl)cc2)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(4-chlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(4-chlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 50%, with a melting point of 190° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH:15]=[CH:14][N:13]=1>O.C(O)(C)C.Cl>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([C:11]([F:27])([F:10])[F:26])[CH:17]=3)=[CH:20][CH:21]=2)[CH:5]=1
Reactant: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A stirred solution containing 2-amino-4,6-dichloropyrimidine (17.74 g, 0.11 mol) and 4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}aniline (Intermediate 2U) in water (400 mL), isopropanol (100 mL) and concentrated hydrochloric acid (5 mL) was heated at 65° C. for 18 h. The reaction was cooled to 0° C. and the yellow-tan solid was collected by suction filtration and washed with water. The filtered product was dissolved in hot N,N-dimethylformamide (90° C.) and triethylamine was slowly added until the solution was slightly basic (pH˜8). The solution was then cooled to rt, added to vigorously stirred ice water (1.2 L), and stirring was continued for 1 h. The tan solids were collected by suction filtration and washed sequentially with water, isopropanol, diethyl ether and finally hexane. The material was dried by air suction to afford a light tan solid, 28.8 g (77%). 1H NMR (DMSO-d6) δ ppm 9.46 (s, 1H), 8.59 (d, 1H, J=5.6 Hz), 7.81 (d, 2H, J=9.0), 7.37 (d, 1H, J=2.4 Hz), 7.17 (d, 2H, J=9.0 Hz), 7.11 (dd, 1H, J=2.6, 5.6 Hz), 6.78 (s, 2H), 6.00 (s, 1H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:28]2[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=2[F:26])=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1F)CCCC3

Procedure:
The title compound was prepared from Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 16, 100 mg, 212 μmol) and 2-(2-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 19, 99 mg, 424 μmol) using the same method as described in Example 44, Step 1 to yield 100 mg, 96%. Material obtained was a mixture of atropisomers, in a 2:1 ratio.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])([CH3:15])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)c1cccc(N)c1
Product: CC(C)(C)c1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and 3-tert-butylaniline with reagents and solvents employed in similar molar ratios. 1H NMR (500 MHz, DMSO-d6): δ 1.28 (s, 9H), 7.00 (d, 1H), 7.18 (m, 1H), 7.24 (m, 1H), 7.46 (dd, 1H), 7.56 (m, 1H), 7.68 (m, 1H), 7.95 (d, 1H), 10.38 (s, 1H), 11.90 (br s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=2)=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[CH3:2].Cl[CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32]>C(O)C.[OH-].[Na+].O>[OH:33][C@@H:30]([CH2:31][OH:32])[CH2:29][O:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:5]=2)=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: OC[C@H](O)CCl
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (47 mg, 0.125 mmol) in ethanol (2 mL) and 3 N aq. NaOH (0.5 mL) is treated with (S)-3-chloro-propane-1,2-diol (90 μL) and the mixture is stirred at 60° C. for 20 h. Another portion of (S)-3-chloro-propane-1,2-diol (60 μL) is added and stirring is continued at 60° C. for 5 days. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 2:1 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-p-tolyl-thiophen-2-yl)-propan-1-one (6 mg) as a colourless resin; LC-MS: tR=1.05 min, [M+1]+=453.25; 1H NMR (CDCl3): δ 7.56 (s, 1H), 7.30-7.21 (m, 4H), 6.88 (s, 2H), 4.11-4.05 (m, 1H), 3.87-3.80 (m, 4H), 3.18-3.11 (m, 2H), 2.98-2.85 (m, 4H), 2.39 (s, 3H), 2.25 (s, 6H), 1.29 (t, J=7.6 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH2:26][CH2:27]Cl>CS(C)=O.O>[CH2:7]([NH:14][CH2:27][CH2:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CNCCOc2ccc3ccccc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and benzyl amine (0.38 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-benzyl-[2-(naphthalen-2-yloxy)-ethyl]amine solid, m.p. 94° C., (yield 0.61 gm, 90.3%).
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].[C:7]([O:11][C:12]([CH2:14][O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH:24]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:39])[NH:37][OH:38])=[CH:32][CH:31]=1)[C:25]([O:27]C)=[O:26])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1.O>[C:7]([O:11][C:12]([CH2:14][O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH:24]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](=[NH:39])[NH:37][OH:38])=[CH:34][CH:35]=1)[C:25]([OH:27])=[O:26])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(Cl)cc(Cl)c1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(Cl)cc1C(Nc1ccc(C(=N)NO)cc1)C(=O)O
Reaction time: 8 h
Yield: 83.5 %

Procedure:
3.7 g of finely powdered lithium carbonate were added to a solution of 1.96 g of methyl (RS)-(2-tert-butoxycarbonylmethoxy-3,5-dichloro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate (see Example 276.2) in 200 ml of THF and 100 ml of water. The suspension was stirred for 8 hours at 55–60° C. The reaction mixture was then concentrated and the aqueous suspension remaining was neutralized with 100 ml 1N HCl. The precipitate was filtered off, washed with water and dried overnight at 50° C. in a high vacuum. There were obtained 1.59 g of (RS)-(2-tert-butoxycarbonylmethoxy-3,5-dichloro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid; MS (ISP) m/z 484.3 (M+H)+, 506.2 (M+Na)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:23])([F:22])[F:24])=[O:25])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A solution of 4-(2-trifluoromethylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester (0.948 g, 2.65 mmol) in 50 mL of a 1:4 mixture of trifluoroacetic acid and dichloromethane was stirred at room temperature for 20 h. After concentration in vacuo, the residue was dissolved in dichloromethane (100 mL) and washed with 1 N NaOH (10 mL), water (15 mL), and brine (15 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the title compound as a light brown oil (0.657 g, 2.54 mmol). 1H NMR (300 MHz, CDCl3) δ 7.69, 7.54, 7.30, 3.78, 3.15, 2.94, 2.76. MS (ES+) m/z 259.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH2:12][N:13]2[CH2:30][CH2:29][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH2:23][O:24][C:25](=[O:28])[C:26]=4[CH3:27])[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:32].[CH3:33][NH2:34].CCO.[BH4-].[Na+]>C1COCC1>[CH3:33][NH:34][CH:11]([C:10]1[CH:9]=[CH:8][C:7]2[C:6](=[O:32])[O:5][CH2:4][C:3]=2[C:2]=1[CH3:1])[CH2:12][N:13]1[CH2:14][CH2:15][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH2:23][O:24][C:25](=[O:28])[C:26]=3[CH3:27])[CH2:18][CH2:17]2)[CH2:29][CH2:30]1
Reactant: CC1=C(N2CCC3(CCN(CC(=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(CN1CCC2(CC1)CCN(C1=C(C)C(=O)OC1)C2=O)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 8-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (25 mg, 0.057 mmol) and methyl amine (4 mg, 0.114 mmol) in anhydrous THF was added Ti(O-iPr)4(35 μL, 0.114 mmol). The reaction was sealed and shaken at ambient temperature for 16 hr. To this reaction, EtOH (200 proof, 0.5 mL) was added followed by adding NaBH4 (11 mg, 0.171 mmol) portion-wise within 30 min. The reaction was shaken for 3 hr and quenched with water (0.5 mL). The reaction was partitioned between EtOAc (4 mL×2) and ammonium (2N, 1.5 mL). The organic phase was combined and evaporated under reduced pressure. The residue was dissolved in DMSO (1.5 mL) and filtered. The crude product was purified by using reversed-phase HPLC (Acetonitrile with 0.1% TFA: water with 0.1% TFA from 10% to 60%) to give the title compound. LC-MS (IE, m/z): 454 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][N:6]([CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=O)[C:4]=2[O:3]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:31][CH:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1>C(OCC)(=O)C>[CH3:16][C:2]1([CH3:1])[CH2:7][N:6]([CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([NH:31][CH:32]3[CH:37]4[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]4)[CH2:33]3)=[O:15])[C:4]=2[O:3]1
Reactant: NC1CN2CCC1CC2
Reactant: CN1CC(C)(C)Oc2c(C(=O)O)cccc21
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CC(C)(C)Oc2c(C(=O)NC3CN4CCC3CC4)cccc21
Temperature: 25 °C

Procedure:
To a solution of 1.0 g of 2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.2 ml of triethylamine, and 0.55 g of pivaloyl chloride was added dropwise thereto at -10° to -5° C. under cooling. After stirring for 15 minutes at the same temperature, 0.57 g of 3-aminoquinuclidine was added at -10° to -5° C. and the mixture was stirred at room temperature for an hour. The resultant mixture was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of isopropyl ether and ethanol to give 2,2,4-trimethyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide as white crystals, melting at 114°-116° C.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:26][O:27][CH3:28])=[N:14][N:15]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:16]=3[CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[N:36]=[N:37][N:38](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:39]=1>CO.ClCCl>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:26][O:27][CH3:28])=[N:14][N:15]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:16]=3[CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1
Reactant: CCCCc1c(Cc2ccc3oc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c(Br)c3c2)c(COC)nn1CC(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCCCc1c(Cc2ccc3oc(-c4ccccc4-c4nnn[nH]4)c(Br)c3c2)c(COC)nn1CC(F)(F)F

Procedure:
From a solution of the Intermediate 14b (210 mg) in methanol (3 ml) and dichloromethane (1 ml) with dl-1-camphor-sulphonic acid (52 mg).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[S:15](Cl)(=[O:17])=[O:16].[OH-].[Na+]>O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[S:15]([OH:17])=[O:16]
Reactant: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Br)c(S(=O)O)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
37.6 g of sodium sulfite are dissolved in 500 ml of water and heated to 70° C. 62 g of 2-bromo-5-methylbenzenesulfonyl chloride are added in portions at this temperature. A 10 N aqueous NaOH solution is simultaneously added dropwise here so that the pH of the solution is kept between pH=9 and pH=10. The mixture is stirred at 70° C. for 1.5 hours, and the solution is filtered off and subsequently adjusted to pH=0 in an ice bath using a saturated aqeuous HCl solution. The mixture is stirred for 30 minutes, then the product is filtered off, subsequently washed with a little water and dried. 49.6 g of white crystals are obtained, mp 120-122° C. MS (ES): 236 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][NH2:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH2:15]([O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH:20]=O)[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH:20]1[N:14]([CH2:13][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([F:1])[CH:3]=2)[C:7](=[O:8])[CH:2]([F:1])[CH2:3]1)[CH3:16]
Reactant: CCOc1cccc(F)c1C=O
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Product: CCOc1cccc(F)c1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)c(F)c1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10I (GP10I) using commercially available (3-fluoro-4-(trifluoromethoxy)phenyl)methanamine and synthesized 2-ethoxy-6-fluorobenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 433.92 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11].S(Cl)([Cl:28])=O>>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([Cl:28])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: O=C(Cl)c1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (2.5 g) was heated under reflux for 5 hours with thionyl chloride (40 ml). The solution was evaporated under reduced pressure and the yellow oil remaining was taken up in toluene (100 ml). The solution was divided into four portions. Each portion was separately evaporated to give 5-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrobenzoyl chloride as an oil. Three portions were used to prepare esters as follows:
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[C:7](=[O:13])[CH2:6]2>O>[C:1]([C:7]1([OH:13])[CH:8]2[CH2:11][CH2:12][N:5]([CH2:10][CH2:9]2)[CH2:6]1)#[N:2]
Reactant: O=C1CN2CCC1CC2
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(O)CN2CCC1CC2
Reaction time: 3 h

Procedure:
A solution of potassium cyanide (10.15 g, 0.156 mol) in water (31.25 ml) was added dropwise to a solution of 1-azabicyclo[2.2.2]octan-3-one hydrochloride (25.0 g, 0.155 mol) in water (31.25 ml) at 0°-5°. Following the addition, the reaction mixture was stirred for 3 h and then filtered. The solid was washed with ice-cold water (2×15 ml) and was then dried over phosphorus pentoxide overnight, m.p. 155°-156°. Recrystallisation of a 1 g sample from dioxane gave pure 3-cyano-3-hydroxy-1-azabicyclo[2.2.2]octane, m.p. 172°-173°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@@H:14]3[CH2:16][C@@H:15]3[CH2:17][CH2:18][O:19][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][N:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(OCC[C@H]2C[C@H]2C2CCN(c3ncc(Cl)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
rac-cis-2-{2-[1-(5-Chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol from step 2 of example 6 (338 mg, 1.2 mmol) was dissolved in DMF (0.7 ml, 0.38 M). Nat (60% in oil, 144 mg, 3.6 mmol) was added and the mixture was stirred for 10 min at RT. 2-Bromo-5-(methylsulfonyl)pyridine (340 mg, 1.44 mmol) was added and the mixture stirred at RT 2½ hours. The mixture was diluted with 75 ml water and extracted with iPrOAc (3×50 ml), adding brine to break the layers. Organic phases were combined, washed with brine, dried over Na2SO4, filtered and stripped. The product was purified by chromatography on SiO2 (40 g) eluting with 40% EtOAc:Hexanes.