Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.CN.[CH2:22]([N:24](CC)CC)C.[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:24][CH3:22])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CN
Solvent: CCO
Product: CNC(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
A mixture of 1,3-bis-(4-chlorophenyl)-propan-2-one (3.20 g, 11.46 mmol), (Yang, H. and Hay, A. S., Synthesis, 1992, 467-472), in anhydrous ethanol (25 ml) was treated successively with titanium (IV) isopropoxide (6.8 ml, 22.9 mmol), methylamine hydrochloride (1.55 g, 22.9 mmol) and triethylamine (3.2 ml, 22.9 mmol). The resulting mixture was stirred at 22° C. for 18 h and then treated with sodium borohydride (0.65 g, 17.2 mmol). After 6 h at 22° C., the reaction mixture was quenched by the addition of 2 N aqueous ammonia (60 ml) and the resulting precipitate was filtered and rinced with ether. The combined ether extracts were washed with brine, dried (anhydrous sodium carbonate) and concentrated. Distillation of the residue in vacuo gave 2.60 g (77% yield) of the title amine as a clear oil: bp 135-140° C./0.2 torr, (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (C6D6) δ (ppm): 2.19 (3H, s, NCH3), 2.42 (4H, d, J=6.5 Hz, CH2), 2.69 (1H, m, CH), 6.84 (4H, d, J=8.5 Hz, aromatics), 7.22 (4H, d, J=8.5 Hz, aromatics). The hydrochloride salt was obtained as a white solid. Anal. calcd for C16H17C2N—HCl: C, 58.11; H, 5.49; N, 4.24. Found: C, 57.85; H, 5.35; N, 4.13.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=1>O1CCCC1.CO.[Pd]>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:17]=[CH:18][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:20][CH:21]=1
Reactant: CNS(=O)(=O)c1ccc(C2=Nc3ccc(C(=O)OC)cc3CC2(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.4 %

Procedure:
To a round bottom flask, Pd/C (100 mg, 40%) was added to a solution of methyl 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate (230 mg, 0.81 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL). The resultant mixture was allowed to stir at room temperature for 10 hours under H2 pressure. Filtered and concentrated to provide methyl 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid (190 mg). MS (ES+APCI) M+1=389.1.
Reaction SMILES: [CH2:1]1[CH2:6][CH:5]([NH2:7])[CH:4]([NH2:8])[CH2:3][CH2:2]1.[Cl-].[Cl-].[Pt+2:11]>O>[Pt+2:11].[NH2:7][C@@H:5]1[CH2:6][CH2:1][CH2:2][CH2:3][C@H:4]1[NH2:8]
Reactant: NC1CCCCC1N
Agent: [Pt+2]
Agent: [Cl-]
Solvent: O
Product: N[C@@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of dichloro(1,2-diaminocyclohexane)platinum(II) (380 mg) and 310 mg Ag2CrO4 was suspended in water and stirred for 48 hours in the dark at room temperature. After 48 hours, the solution was filtered and evaporated to dryness to give the title product as a light greenish-yellow solid. The product is soluble in water but only slightly soluble in alcohol. The product was washed with alcohol and dried in vacuo to give a final yield of 85 mg. TLC indicates one band at Rf =0.74 in the n-butanol:acetic acid:water (12:3:5) system. The IR was consistent for the indicated structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35]([CH:38]([OH:44])[CH:39]([CH3:43])[C:40]([OH:42])=[O:41])=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:33]=[CH:34][C:35]([C@@H:38]([OH:44])[C@H:39]([CH3:43])[C:40]([OH:42])=[O:41])=[CH:36][CH:37]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C(=O)O)C(O)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: C[C@H](C(=O)O)[C@H](O)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 3-(4-formyl-phenyl)-3-hydroxy-2-methyl-propionic acid according to the procedure of Example 66. MS (ES) m/z 583.0.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:16][CH2:15][CH:14]([NH:17][CH3:18])[CH2:13][CH2:12]2.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH2:28][CH2:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:32]>CN(C)C=O>[ClH:27].[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:31](=[O:32])[CH2:30][CH2:29][CH2:28][N:17]([CH:14]2[CH2:15][CH2:16][C:3]3([CH2:4][CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:2]3)[CH2:12][CH2:13]2)[CH3:18])=[CH:34][CH:35]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CNC1CCC2(CCc3ccccc3C2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(CCCC(=O)c1ccc(F)cc1)C1CCC2(CCc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of the free base prepared from 0.81 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamine hydrochloride [I(c)] (obtained as in Example 14C), 0.63 g. of potassium iodide, 0.96 g. of potassium carbonate and 0.87 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in 15 ml. of dimethylformamide is heated together in an oil bath at about 90° C. for about 20 hours. The solvent is removed under vacuum and the residue dissolved in water and benzene. The organic layer is washed with water and brine and evaporated to dryness. A mixture of the residue, 6 ml. of 2.5 N hydrochloric acid and 12 ml. of methanol is stirred at room temperature for about 1.5 hours and most of the methanol removed under vacuum. The residual suspended solid is collected on a filter, washed with ether and recrystallized from methanol: ethyl acetate to give 4'-fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamino]butyrophenone hydrochloride [I(c)].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=2)=[C:16]([F:23])[CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cnc(C)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 29.9 %

Procedure:
A mixture of methyl 4-chloro-6-methylnicotinate (0.1 g, 0.539 mmol), (4-chloro-2-fluorophenyl) boronic acid (0.094 g, 0.539 mmol), Pd(PPh3)4 (0.031 g, 0.027 mmol) and Cs2CO3 (0.527 g, 1.616 mmol) in 1,4-dioxane (10 mL) was heated at 80° C. for 16 h. After cooling, the mixture was diluted with water (30 mL) and ethyl acetate (50 mL). The organic phase was collected, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc in pet. ether) to afford methyl 4-(4-chloro-2-fluorophenyl)-6-methylnicotinate (0.045 g, 0.161 mmol, 30% yield) as a yellow liquid. LCMS (ESI) m/e 280.0 [(M+H)+, calcd for C14H12ClFNO2 280.04]; LC/MS retention time (Method H): tR=2.51 min. 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.13-7.29 (m, 3H), 6.44 (s, 1H), 3.94 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH2:10][N+:11]([O-])=O)[CH2:3][C:4]1([CH3:9])[O:8][CH2:7][CH2:6][O:5]1.[H][H]>[Pt].C(O)C>[CH3:1][C:2]([CH3:14])([CH2:3][C:4]1([CH3:9])[O:5][CH2:6][CH2:7][O:8]1)[CH2:10][NH2:11]
Reactant: [H][H]
Reactant: CC(C)(C[N+](=O)[O-])CC1(C)OCCO1
Agent: [Pt]
Solvent: CCO
Product: CC(C)(CN)CC1(C)OCCO1
Reaction time: 24 h
Yield: 101.1 %

Procedure:
A Parr hydrogenation vessel was charged with 2-(2,2-dimethyl-3-nitropropyl)-2-methyl-[1,3]dioxolane (23.1 g, 113 mmol), 5% platinum on carbon catalyst (3.0 g) and ethanol (250 mL); placed on a Parr shaker; and the system pressurized to 50 psi (3.4×105 Pa) hydrogen. After shaking for 24 hours, the reaction mixture was filtered through CELITE filter agent and concentrated under reduced pressure to provide 2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propylamine (19.8 g) as an oil that was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH:22]1[CH2:24][CH2:23]1)[C:20]#[N:21].CO>CCCCCCC>[C:20]([CH:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH:22]1[CH2:24][CH2:23]1)#[N:21]
Reactant: N#CC(N)C1CC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CCCCCCC
Solvent: CO
Product: N#CC(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and α-amino-cyclopropaneacetonitrile (CAN 149357-92-6) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (+)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 312.1706 (M+H)+, αD20 (MeOH)=+9.0°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[C@@H:9]1[OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH:19](Br)[CH3:20]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]2[O:14][CH2:19][CH2:20][O:15][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1O
Reactant: CC(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2OCCOC21
Temperature: 55 °C

Procedure:
cis-2,3-Dihydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.246 g, 1.13 mmol) was dissolved in dibromoethane (1.7 mL) and tetrabutyl ammonium bromide (71 mg, 2.2 mmol) was added. Sodium hydroxide (50% aqueous solution, 17.8 g) was added slowly over 10 minutes at 50° C. A further amount of dibromoethane (7.4 mL, 105.5 mmol in total) was added and the mixture was heated at 55° C. overnight. Dibromoethane (3 mL) was added and the mixture was heated at 55° C. for a further 4 hours and then diluted with water and extracted with DCM (×2). The organics were washed with brine then dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on a 5 g silica II cartridge, eluting with 10-33% diethyl ether in pentane to afford hexahydro-[1,4]dioxino[2,3-b]pyridine-5-carboxylic acid tert-butyl ester as an off-white oil (0.106 g).
Reaction SMILES: [N+:1]1([O-])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC(OCC(C)C)=O.C([Mg]Br)=C.O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [O-][n+]1cccc2ccccc21
Agent: C=C[Mg]Br
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
0.8 g (5.51 mmol) of quinoline N-oxide is dissolved in 15 ml of anhydrous THF at 20° C., in a dry round-bottomed flask equipped with a magnetic stirrer and a nitrogen inlet. This solution is treated with 0.78 ml (6.07 mmol) of isobutyl chloroformate; the suspension obtained is cooled to −78° C. 11 ml (11 mmol) of a 1M solution of vinylmagnesium bromide in THF are then added dropwise. After stirring for 90 minutes at −78° C., the solution is slowly returned to ambient temperature (30 minutes), and then hydrolyzed with 15 ml of water.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](O)=[O:13])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:23])=[O:13])=[CH:6][CH:5]=1
Reactant: N
Reactant: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.90 g (21.1 mmol) 3-(4-Trifluoromethoxy-phenyl)-acrylic acid in 30.0 ml tetrahydrofuran and 0.3 ml N,N-dimethyl formamide a solution of 2.70 ml (32.0 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 75 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 4.48 g (92%) 3-(4-Trifluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[CH2:4][CH:3]([C:11]2[N:19]3[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]3)=[C:13]([C:21]3[CH:22]=[CH:23][C:24]4[C:28]([CH:29]=3)=[N:27][N:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:25]=4)[CH:12]=2)[O:2]1.I[CH3:37]>>[CH3:37][N:8]1[CH2:9][CH2:10][N:5]2[CH:6]([CH2:1][O:2][CH:3]([C:11]3[N:19]4[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]4)=[C:13]([C:21]4[CH:22]=[CH:23][C:24]5[C:28]([CH:29]=4)=[N:27][N:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:25]=5)[CH:12]=3)[CH2:4]2)[CH2:7]1
Reactant: CI
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Product: CN1CCN2CC(c3cc(-c4ccc5cn(-c6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Yield: 52 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 103 and using 7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-5-(2-phenyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and iodomethane as the starting materials, 27 mg (52%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) 9.16 (s, 1 H), 8.10 (d, 2 H), 7.94 (s, 1 H), 7.85 (d, 1 H), 7.68 (s, 1 H), 7.59 (t, 2 H), 7.44 (t, 1 H), 7.21 (dd, 1H), 6.78 (s, 1H), 5.12 (dd, 1H), 3.78 (dd, 1H), 3.39-3.30 (m, 1H), 3.00 (dd, 1H), 2.71-2.67 (m, 2H), 2.61-2.54 (m, 1H), 2.48-2.38 (m, 1H), 2.27-2.19 (m, 2H), 2.15 (s, 3H), 2.10-2.02 (m, 1H), 1.63 (t, 1H); LC-MS [M+H]+=481, RT=1.08 min.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:31][C:32]1[C:37]([F:38])=[C:36]([F:39])[CH:35]=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([CH:46]3[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[C:33]=1C=O.C1CCCCC1.[CH2:63]([O:65][CH2:66][CH3:67])C>C(OCC)C>[F:31][C:32]1[C:33]([CH:67]=[CH:66][O:65][CH3:63])=[C:34]([C:40]2[CH:45]=[CH:44][C:43]([CH:46]3[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[CH:35]=[C:36]([F:39])[C:37]=1[F:38]
Reactant: CCOCC
Reactant: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3C=O)cc2)CC1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCCCC1
Product: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3C=COC)cc2)CC1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
27 ml (48 mmol) of a 1.8 M solution of phenyllithium in cyclohexane/diethyl ether (7:3) are added dropwise at −65° C. to a solution/suspension of 45 mmol of methoxymethyltriphenylphosphonium chloride in 280 ml of dry diethyl ether. The mixture is stirred at the same temperature for 30 minutes, then kept at −10° C. for 30 minutes and subsequently re-cooled to −50° C. 16 mmol of 3,4,5-trifluoro-4′-(4-propylcyclohexyl)biphenyl -2-carbaldehyde are added at this temperature. The reaction mixture is allowed to thaw slowly, and stirring is continued at room temperature. Ice-water is added to the reaction mixture, and the organic phase is separated off and washed with cold water. After drying using sodium sulfate, the mixture is evaporated under reduced pressure, and the residue is stirred with n-heptane and filtered. The filtrate is chromatographed on silica gel (n-heptane/ethyl acetate 98:2), giving 3,4,5-trifluoro-2-(2-methoxyvinyl)-4′-(4-propylcyclohexyl)biphenyl (mixture of Z and E isomers).
Reaction SMILES: C(O)C#C.[CH2:5]([OH:17])[C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CCOCC.COCCO[AlH2-]OCCOC.[Na+]>[CH2:5]([OH:17])/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCC#CCO
Agent: C#CCO
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCC/C=C/CO

Procedure:
trans-2-Dodecen-1-ol was prepared by reduction of the propargyl alcohol by the method described by Jones and Denmark (Org. Syn., 1985, 64, 182-8) using 6.0 g (33 mmole) of 2-dodecyn-1-ol in 25 ml of ether and 16.2 ml of Red-Al in 30 ml of ether. Kugelrohr distillation afforded 5.73 g of a clear oil. 1H NMR δ5.66 (m, 2), 4.07 (d, 2, J=4 Hz), 2.03 (dd, 2, J=6, 13 Hz), 1.62 (br, 1), 1.4-1.2 (m, 14), 0.88 (t, 3, J=7 Hz).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36][CH3:37])=[O:35])(=O)C.C[O-].[Na+]>CO>[C@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36][CH3:37])=[O:35])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:5]1[OH:4]
Reactant: COC(=O)c1cccc(-c2ccccc2O[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-c2ccccc2O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
In a dry 50 ml flask under nitrogen, methyl 3-(2-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyloxy)phenyl)benzoate (2.18 g, 3.9 mmol) was dissolved in methanol (20 ml) and treated in one portion with sodium methoxide (250 mg) and the mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 7:3 methylene chloride/methanol) which gave methyl 3-(2-(α-D-mannopyranosyloxy)phenyl)benzoate in 84% yield.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[K+].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH-:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:38][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:3]=2)(=[O:36])=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Agent: [K+]
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was prepared as disclosed in EP 0 526 708 A1 from 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine and p-tert.-butyl benzene sulfonamide potassium salt. LC-MS: tR=5.50 min, [M+1]+=526.29, [M−1]−=524.43.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:14][N:6]([CH2:5][CH2:4][CH2:3][CH:2]=[O:1])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: CN(CCCCO)C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CN(CCCC=O)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 50 parts of (1,1-dimethylethyl) (4-hydroxybutyl)methylcarbamate in 91 parts of dichloromethane was added dropwise to a mixture of 150 parts of pyridinium dichromate, 112 parts of molecular sieves and 1300 parts of dichloromethane at a temperature about 10° C. Upon completion, stirring was continued for 3 hours at room temperature. The reaction mixture was filtered, washed with 1,1'-oxybisethane and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using dichloromethane as eluent. The pure fractions were collected and the eluent was evaporated with methylbenzene, yielding 35 parts (70%) of (1,1-dimethylethyl) methyl(4-oxobutyl)carbamate as a residue (int. 38).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[Br:27])=[CH:17][C:16]([S:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.CCO.[OH-].[Na+]>O>[Br:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=[C:16]([S:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)[CH:17]=1
Reactant: COc1cccc(Sc2cnc(NC(=S)NC(=O)c3ccccc3)c(Oc3ccc(F)cc3Br)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(Sc2cnc(NC(N)=S)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A 250 mL round-bottomed flask was charged with 1-benzoyl-3-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea (10.3 g, 17.6 mmol) and EtOH (125 mL). 3M Sodium hydroxide (11.7 mL, 35.2 mmol) was added and heated to 50° C. overnight. The reaction was cooled to room temperature and poured into 750 mL water and stirred vigorously for 1 hour. The solids were filtered to afford the title compound (6.5 g, 76.8% yield).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.COC([NH:22][C@H:23]1[C@H:26]([CH3:27])[N:25]([S:28]([O-:31])(=[O:30])=[O:29])[C:24]1=[O:32])=O.C(N(CC)CC)C.Cl[SiH](Cl)Cl.O>ClCCl.C(O)=O>[NH2:22][C@H:23]1[C@H:26]([CH3:27])[N:25]([S:28]([OH:31])(=[O:29])=[O:30])[C:24]1=[O:32]
Reactant: COC(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl[SiH](Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=CO
Product: C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A solution of 479 mg (0.001 mole) of (3S-trans)-3-methoxycarbonylamino-4-methyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt in 10 ml of dichloromethane is treated with 139 μl of triethylamine and 112 μl of trichlorosilane. The resulting solution is refluxed for 3 hours and cooled to 0° C. Triethylamine (139 μl) and 0.5 ml of water are added, and the solution is stirred overnight. The resulting slurry is diluted with 20 ml of formic acid, stirred for 1 hour, and the solid filtered to give 117 mg of (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid, inner salt.