Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][C:15]3[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:21][N:22]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]=3[C:12]=2[N:13]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:8][C:9]1[S:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][C:15]3[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:21][N:22]([CH:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[C:14]=3[C:12]=2[N:13]=1
Reactant: CCOC(=O)c1nn(C2CCOCC2)c2c1CS(=O)(=O)c1sc(NC(=O)OC(C)(C)C)nc1-2
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(C2CCOCC2)c2c1CS(=O)(=O)c1sc(N)nc1-2

Procedure:
To a fine suspension of ethyl 7-[(tert-butoxycarbonyl)amino]-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyrazolo[3′,4′:4,5]thiopyrano[3,2-d][1,3]thiazole-3-carboxylate 5,5-dioxide (182 mg; 0.37 mmol; 1.00 eq.) in DCM (540 μl) is added TFA (180 μl; 2.34 mmol; 6.40 eq.). The mixture is stirred at rt overnight after which water is added to the reaction mixture. The precipitate is washed with water then dried under vacuum to afford the title compound as an off-white powder. 1H NMR (DMSO) δ 8.34 (bs, 2H), 5.61-5.43 (m, 1H), 4.91 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 4.12-3.93 (m, 2H), 3.52-3.35 (m, 2H), 3.20-1.87 (m, 4H), 1.33 (t, J=7.1 Hz, 3H). HPLC (max plot) 95.1%; Rt 2.28 min. MS (ESI+): 398.7.
Reaction SMILES: [OH:1][CH:2]1[C:13]2[C:14](=[O:15])[C:9]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])([CH2:10][CH2:11][CH:12]=2)[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]1.N1C=CC=CC=1.[O:30]([CH2:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCOCC>[O:30]([CH2:37][C:38]([O:1][CH:2]1[C:13]2[C:14](=[O:15])[C:9]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])([CH2:10][CH2:11][CH:12]=2)[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC12C#CC=CC#CC(O)C(=CCC1)C2=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC12C#CC=CC#CC(OC(=O)COc3ccccc3)C(=CCC1)C2=O
Reaction time: 15 h
Yield: 32.3 %

Procedure:
To a solution of compound 6 (175 mg, 0,533 mmol) in 10 mL tetrahydrofuran was added pyridine (0.20 mL, 2.47 mmol) and phenoxyacetyl chloride (0.17mL, 1.23 mmol) and stirred for 15 h. The solution was diluted with ether and washed with water and saturated bicarbonate. The organic fraction was dried over MgSO4 and concentrated and the residue chromatographed over silica gel (10:1 hexane/ethyl acetate) to give 8-[(phenoxymethyl)carbonyloxy]-1-(t-butyldimethylsilyloxy)-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-13-one (11a) (184 mg, 75%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:46]=[CH:45][C:38]([O:39][CH2:40][C:41](=[N:43]O)[NH2:42])=[CH:37][CH:36]=1>ClCCl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]2[N:43]=[C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[O:11][N:42]=2)=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: NC(COc1ccc(Cl)cc1)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(COc2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (300 mg, 1.00 mmol) in dichloromethane (15 ml) was treated with 1,1′-carbonyldiimidazole (162 mg, 1.00 mmol) and the solution was stirred at room temperature for 2 hours. 2-(4-chlorophenoxy)-N′-hydroxyethanimidamide (U.S. Pat. No. 97-815671 970313) (197 mg, 0.98 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as a colourless oil (220 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:20][NH:21][C@@H:22]([C@H:25]([OH:29])[CH2:26][S:27][CH3:28])[CH2:23][OH:24])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30].CO>>[NH2:30][C:17]1[C:18]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=[C:12]([CH2:20][NH:21][C@@H:22]([C@H:25]([OH:29])[CH2:26][S:27][CH3:28])[CH2:23][OH:24])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CSC[C@@H](O)[C@@H](CO)NCc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Reactant: N
Solvent: CO
Product: CSC[C@@H](O)[C@@H](CO)NCc1cn(COCc2ccccc2)c2c(N)ncnc12
Temperature: 25 °C
Yield: 60 %

Procedure:
The product from Example 6.7 (0.19 g, 0.435 mmol) was stirred in 7M NH3-MeOH (25 ml) for 24 h in a sealed tube at 135° C. (oil bath). After cooling to rt the solvent was evaporated and the residue chromatographed on silica gel (CH2Cl2-7M NH3-MeOH 96.5:3.5 then 95:5) to give (2R,3S)-2-((4-amino-5-(benzyloxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-4-(methylthio)butane-1,3-diol (0.108 g, 60%) as a yellow gum. 1H NMR (CD3OD) δ 8.17 (s, 1H), 7.46 (s, 1H), 7.28 (m, 5H), 5.63 (s, 2H), 4.57 (s, 2H), 4.07 (d, J=13.7 Hz, 1H), 3.91 (d, J=13.7 Hz, 1H), 3.81-3.73 (m, 2H), 3.64 (dd, J=11.4, 5.0 Hz, 1H), 2.81-2.69 (m, 2H), 2.54 (dd, J=13.5, 7.4 Hz, 1H), 2.04 (s, 3H). 13C NMR (CD3OD, referenced to the centre line of CD3OD at 49.0 ppm) δ 152.8, 151.5, 149.4, 137.8, 133.6, 129.5, 129.3, 129.2, 116.2, 115.1, 78.6, 71.4, 71.3, 62.1, 62.0, 42.0, 39.3, 16.0. +ESMS Found 418.1907 (M+H)+ C20H28N5O3S requires 418.1913.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[SH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: Sc1ccccn1
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Product: O=C(O)CNC(=O)c1nc(Sc2ccccn2)c2ccccc2c1O

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 2-mercaptopyridine under conditions analogous to Example D-110. The final product was purified by column chromatography on silica gel using a gradient of 3-15% methanol in dichloromethane with 0.5% acetic acid to elute the product; MS (−) m/z 354.10 (M−1)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][CH2:20][CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:19][CH2:20][CH2:21][CH2:22][S:23]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:25])=[O:24]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)CCCCl
Product: O=S(=O)(CCCCl)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 3-chloropropane-1-sulfonyl chloride to obtain the desired product. 1H NMR (500 MHz, CDCl3): 7.39-7.38 (d, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.10-7.0 (q, 1H), 6.63 (s, 1H, br), 6.15-6.11 (q, 1H), 5.60 (s, 1H, br), 3.60-3.56 (t, 2H), 3.22-3.20 (m, 2H), 2.22-2.16 (m, 2H).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][C:23]2=O)=[CH:19][CH:18]=1.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](=[CH:19][CH:18]=1)[CH2:21][CH:22]=[C:23]2[C:8]1[CH:7]=[CH:6][CH:5]=[C:2]([O:3][CH3:4])[C:1]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: O=C1CCc2ccc(Cl)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C2=CCc3ccc(Cl)cc32)c1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, 45.9 ml of veratrole (49.78 g, 360.1 mol) are dissolved in 240 ml of THF and, at −78° C., 236.2 ml of a 1.6 M solution of n-butyllithium in THF (377.7 mol) are added drop wise. The reaction mixture is warmed to 0° C. and stirred at this temperature for 3 h. The mixture is cooled to −60° C., and 30.0 g of the compound from Example 16A (180.1 mol) dissolved in 150 ml of THF are added drop wise. The reaction mixture is warmed to room temperature over the course of 3 h and then acidified with 1 N hydrochloric acid and extracted with dichloromethane. The combined organic phases are dried over magnesium sulphate, and the solvent is removed in a rotary evaporator. The residue is is purified by filtration through silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). The crude product [6-chloro-1-(2,3-dimethoxyphenyl)indan-1-ol] is dissolved in 1 l of dichloromethane and, after addition of 75 mg of 4-toluenesulphonic acid monohydrate (0.39 mol), stirred at RT for. 16 h. The reaction solution is washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1). 10.5 g (20% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[C:19]3[CH2:25][CH:24]4[N:26]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[NH:4].[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>O1CCOCC1>[F:30][C:28]([F:31])([F:29])[C:27]([N:26]1[CH:21]2[CH2:22][CH2:23][CH:24]1[CH2:25][C:19](=[C:9]1[C:8]3[CH:7]=[CH:6][C:5]([C:3]4[NH:4][C:33](=[O:34])[O:1][N:2]=4)=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:20]2)=[O:32]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(NO)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3cc(-c4noc(=O)[nH]4)ccc31)C2)C(F)(F)F
Temperature: 110 °C
Reaction time: 0.67 h

Procedure:
To a solution of compound 6a (0.1 g, 0.23 mmol) in 1,4-dioxane (4 mL) was added 1,1′-carbonyldiimidazole (CDl, 0.055 g, 0.34 mmol). The mixture was stirred at 110° C. for 40 min under a nitrogen atmosphere. After being cooled, the reaction was concentrated. The crude compound 6b was used in the next reaction without further purification. MS m/z (MH+) 469.8.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([CH:11]([S:13][CH3:14])[CH3:12])[CH:8]=[N:7][C:6]=1[C:15]([F:18])([F:17])[F:16])C.[OH-].[Li+].Cl>O1CCCC1>[CH3:14][S:13][CH:11]([C:9]1[CH:8]=[N:7][C:6]([C:15]([F:18])([F:17])[F:16])=[C:5]([CH:10]=1)[C:4]([OH:19])=[O:3])[CH3:12]
Reactant: CCOC(=O)c1cc(C(C)SC)cnc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSC(C)c1cnc(C(F)(F)F)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a dry 50 mL glass vial equipped with magnetic stirrer, and nitrogen inlet, was charged 0.5 g (0.00170 moles) of 5-(1-methylthioethyl)-2-trifluoromethylnicotinic acid ethyl ester, and 10 mL of tetrahydrofuran (THF). The solution was cooled to about 0° C. and 5.1 mL of 1N aqueous lithium hydroxide solution (0.00511 moles) was added slowly via syringe. The reaction was stirred at 0° C. for 1 hour, then overnight at ambient temperature. An aliquot was analyzed by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), which indicated that the reaction was essentially complete. The mixture was acidified to pH=2 with 1 M aqueous hydrochloric acid, and extracted with 3 aliquots of 50 mL of ethyl acetate. The extract was dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under vacuum on a rotary evaporator to afford 0.410 g of the title compound as a tan solid. 1H NMR (CDCl3): δ 1.66 (d, 3H), 1.96 (s, 3H), 3.98 (q, 1H), 8.01 (bs, 1H), 8.30 (s, 1H), and 8.80 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[O:32])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)[C@@H:7]([C:33](=[O:43])[NH:34][O:35]CC2C=CC=CC=2)[CH2:6]1.C1CN([P+](ON2N=[N:69][C:64]3C=[CH:66][CH:67]=[CH:68][C:63]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.C(ON)C1C=CC=CC=1.CN1CCOCC1>CN(C=O)C>[OH:35][NH:34][C:33]([C@H:7]1[CH2:6][CH:5]([CH2:4][C:3](=[O:2])[N:69]2[CH2:66][CH2:67][CH2:68][CH2:63][CH2:64]2)[CH2:10][CH2:9][C@@H:8]1[C:11]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([CH3:31])[CH:22]=2)=[CH:17][CH:18]=1)=[O:32])=[O:43]
Reactant: COC(=O)CC1CC[C@H](C(=O)Nc2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NOCc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(COc2ccc(NC(=O)[C@H]3CCC(CC(=O)N4CCCCC4)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 93 %

Procedure:
Part 8: {3-(S)-Benzyloxycarbamoyl-4-(S)-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexyl}-acetic acid methyl ester. To an oven-dried 5 mL conical vial equipped with a magnetic stir bar and under a nitrogen gas atmosphere was placed sequentially: 5-methoxycarbonylmethyl-2-(S)-[4-(2-methylquinolin-4-ylmethoxy)-phenylcarbamoyl]-cyclohexane-(S)-carboxylic acid (212 mg, 0.43 mmol), anhydrous DMF (3 mL), PyBOP reagent (320 mg, 0.61 mmol), O-benzylhydroxylamine hydrochloride (100 mg, 0.627 mmol), and 4-methyl morpholine (0.160 mL, 1.47 mmol). After stirring the reaction mixture overnight, the reaction was quenched with 5% citric acid (1 mL) and the reaction mixture was diluted with ethyl acetate (15 mL) and water (4 mL). The aqueous layer was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with saturated sodium bicarbonate (3×5 mL), brine (5 mL), dried (NaSO4), and concentrated in-vacuo. Purification by Combiflash (0 to 15% methanol in methylene chloride over 30 min) to afford 238 mg (93%) of the pure amide. LCMS (ESI): 596 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[ClH:1].[ClH:1].[Cl:22][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]
Reactant: C1CNCCN1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CC#N
Product: Cl
Product: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(N3CCNCC3)ccc12
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A stirred solution of 2,6-dichloro-N-(cyclohexylmethyl)quinoline-5-carboxamide (Example 43 (a)) (200 mg) and piperazine (160 mg) in acetonitrile (2 mL) was heated at 80° C. in a CEM Discover microwave for 1 hour after which it was cooled to room temperature and concentrated. The residue was purified (Waters' SCX resin, ammonia in methanol (7 M) as eluant) and the resultant product was converted to the dihydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane). Recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (110 mg).
Reaction SMILES: [C:1]1([Bi:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([OH:25])(=[O:24])[C:21]([CH3:23])=[CH2:22].C(OO)(C)(C)C>C(OCC)C>[C:20]([O-:25])(=[O:24])[C:21]([CH3:23])=[CH2:22].[C:14]1([Bi+2:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:20]([O-:25])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)O
Reactant: c1ccc([Bi](c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OO
Solvent: CCOCC
Product: C=C(C)C(=O)[O-]
Product: c1ccc([Bi+2](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The general method as outlined by V. A. Dodonov, A. V. Gustichin and T. G. Brilkina (Zh. Obsch. Khim 55, 1(73) 1985) was followed for the preparation of this compound. The details of a typical preparation are: Triphenyl bismuthine (4.4 g, 0.01 mol.), methacrylic acid (1.97 g) (0.02 mol), tert-butyl hydroperoxide (1.39 g) were mixed with 20 ml of diethyl ether in a round bottom flask. The contents were stirred overnight (20 hr) at ambient temperature. The volatile matter was then removed in vacuo (0.1 mm Hg) for 5 hr to obtain a solid which was analyzed for its metal content.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16]>ClC1C=CC=CC=1>[CH3:18][CH:14]1[CH2:19][C:8]2[C:9](=[CH:10][C:5]([CH3:12])=[CH:6][C:7]=2[CH3:11])[C:15]1=[O:16]
Reactant: Cc1cccc(C)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1cc(C)c2c(c1)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A 500 μL, 3-neck rounded bottom flask equipped with a magnetic stirring bar and a reflux condenser, was charged under nitrogen with 71.16 g of AlCl3 (0.53 mol) dissolved in 240 mL of chlorobenzene. At room temperature 28.38 mL of m-xylene (0.23 mol) were added dropwise obtaining a light yellow suspension. The flask was then cooled to 0° C. and 28.68 mL of 2-bromoisobutyryl bromide (0.23 mol) were slowly added. At the end of the addition a dark-red slurry was obtained. The reaction mixture was then allowed to warm up to room temperature (r.t.) and stirred for 2 hours. Then it was transferred into a flask containing a solution of 3/1 ice/37% HCl. The organic phase was extracted with Et2O (3×200 mL), the combined organic phases were dried over Na2SO4, filtered and the solvents were removed in vacuo to leave 37.48 g of an orange oil (yield 93.5%). The latter was used as such in the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[P:19]([O-:36])([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:2]([N:9]([CH:11]([P:19](=[O:36])([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ONCc1ccccc1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=P(OCc1ccccc1)(OCc1ccccc1)C(c1ccccc1)N(O)Cc1ccccc1
Temperature: 60 °C

Procedure:
Using the procedure of Example 1, the title compound is prepared from 15.0 g (94 mmol) of N-benzylhydroxylamine hydrochloride, 10.6 g (100 mmol) of benzaldehyde, 26.7 g (100 mmol) of dibenzyl phosphite, 3.78 g (45 mmol) of sodium bicarbonate and 300 ml of THF by heating at 60° C. for four hours. The residue is purified by column chromatography (silica gel, 2.5:1 hexane:ethyl acetate eluent) followed by recrystallization from a mixture of methylene chloride and hexane to give 5.6 g (13% yield) of a white solid melting at 116°-118° C.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[CH3:11][C:12]1[CH:13]=[C:14]([O:18][CH3:19])C=[CH:16][CH:17]=1.Cl[CH2:21]Cl>Cl[Ti](Cl)(Cl)Cl>[CH3:3][C:2]1([CH3:10])[C:16]2[C:7](=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:11])[CH:17]=2)[C:6]([CH3:21])([CH3:8])[CH2:5][CH2:4]1
Reactant: COc1cccc(C)c1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1cc(C)cc2c1C(C)(C)CCC2(C)C
Temperature: 35 °C

Procedure:
The starting material 1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene was prepared as follows. First, a 500 flask was charged with 230 ml dichloromethane, 19 g TiCl4, and 18.3 g 2,5-dichloro-2,5-dimethylhexane, at 22° C. Next, 3-methyl anisole (12.2 g in 20 ml dichloromethane) was added dropwise over a period of an hour. After the addition was completed, the solution was heated to 35° C. and the temperature maintained for an additional 2.5 hours. The solution was then cooled to 5° C. and quenched with water. After transfer to a separatory funnel, the solution was washed with water, then twice with brine, dried over anhydrous sodium sulfate, and rotary evaporated to give a crude product (23.78 g) containing 79.4% (by area % GC) of 1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClC1C=CC=CC=1>[CH:5]1([N:11]=[C:1]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NC1CCCCC1
Yield: 175.6 %

Procedure:
500 g of chlorobenzene were placed in the glass vessel and 40 g of gaseous phosgene was introduced at room temperature. The reaction mixture was subsequently heated to 77° C., with vigorous phosgene reflux being established. While stirring vigorously at 77–80° C., a total of 99.2 g of cyclohexylamine (1 mol) dissolved in 200 g of chlorobenzene and at the same time a further 92 g of phosgene were introduced over a period of 3 hours. After addition was complete, the system was maintained at 77–80° C. for a further one hour without introduction of phosgene to allow further reaction to occur and the residual unreacted phosgene was subsequently stripped out at 50° C. by means of nitrogen. The reaction mixture obtained was a suspension from which the solid obtained was separated by filtration. 15 g of solid which, according to IR-spectroscopic analysis, was mainly amine hydrochloride were able to be isolated in this way. The filtered crude product was worked up by distillation. Removal of the solvent and fractional distillation gave 88.8 g of cyclohexyl isocyanate (0.710 mol). This corresponds to 71.0% of the theoretical yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:14][C:15](=[O:17])[CH3:16])[CH2:8]2)(=[O:3])[CH3:2].[Br:18]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:18])[CH2:10][CH:9]([NH:14][C:15](=[O:17])[CH3:16])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc2c(c1)CC(NC(C)=O)C2
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1Br)CC(NC(C)=O)C2
Yield: 77 %

Procedure:
A solution of N-(5-acetylamino-indan-2-yl)-acetamide (9.8 g, 42 mmol) and bromine (8.5 g, 53 mmol) in acetic acid (200 mL) was stirred at room temperature for 3 h. After evaporation of the solvent, the syrupy residue was dissolved in ether and washed with water. The organic layer was washed with aqueous sodium bisulfite and dried over magnesium sulfate. The solvent was concentrated and the resulting solid collected by filtration (10 g, 77% yield).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=C(N2C=C(C([Cl:14])=O)N=C2)C=1.[F:21][C:22]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH:38]=[C:37]([C:39](O)=[O:40])[N:36]=[CH:35]3)[CH:29]=2)=[C:26]([O:42][CH3:43])[CH:25]=[CH:24][CH:23]=1>>[F:21][C:22]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH:38]=[C:37]([C:39]([Cl:14])=[O:40])[N:36]=[CH:35]3)[CH:29]=2)=[C:26]([O:42][CH3:43])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)O)c2)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)Cl)c2)c1

Procedure:
This compound is prepared analogously to 11a from 10g.