Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([C@@H:9]2[C:14]3[CH:15]=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:24])([CH3:23])[C@H:10]2[OH:25])[CH2:7][CH2:6][S:5]1)#[N:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:25][C@H:10]1[C@H:9]([N:8]2[CH2:7][CH2:6][S:5][C:4]2=[N:3][C:1]#[N:2])[C:14]2[CH:15]=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]1([CH3:23])[CH3:24])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](N2CCSC2=NC#N)c2cc(S(C)(=O)=O)ccc2OC1(C)C
Reaction time: 8 h

Procedure:
A mixture of trans-4-(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (5.5 g) and acetic anhydride (25 ml) in pyridine (50 ml) was allowed to stand at room temperature overnight. The mixture was concentrated to give a residue of trans-3-acetoxy-4-[2-(cyanoimino)thiazolidin-3-yl]-3,4-dihydro-6-mesyl-2,2-dimethyl-2H-1-benzopyran, which was washed with diisopropyl ether and dried in vacuo. To a suspension of this residue in toluene (21 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (10.5 ml), and the mixture was stirred at 100° C. for 1 hour. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography using ethyl acetate as an eluent to afford 4-(2-cyanoiminothiazolidin-3-yl)-6-mesyl-2,2-dimethyl-2H-1-benzopyran as a white solid. Recrystallization from 50% aqueous acetonitrile gave the pure product (1.44 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([C:33]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[O:25][CH2:26][CH:27]5[CH2:28][CH2:29]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:34])[CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Product: O=C(NC1CCN(C(=O)C2CC2)CC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A162) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: Fc1ccccc1CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Fc1ccccc1CC[C@H]1CNCCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
Combine (S)-1,4-dibenzyl-2-(2-(2-fluoro-phenyl)-ethyl)-piperazine (1.06 g, 2.73 mmol), ammonium formate (861.0 mg, 13.66 mmol), 5% Pd/C (132.0 mg), and ethanol (50 mL). Stir and heat the mixture at reflux. After 4 hours 30 minutes, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give (443.8 mg, 78%) of the title compound as a white solid: mp 94–99° C.; mass spectrum (ion spray): m/z=209.3 (M+1); Analysis for C12H17FN2: calcd: C, 69.20; H, 8.23; N, 13.45; found: C, 69.20; H, 8.26; N, 13.57.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:42])[C:30]=1[O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:5][CH:6](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[C:43]([C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1)([CH3:46])([CH3:45])[CH3:44].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:43]([C:47]1[CH:48]=[CH:49][C:50]([CH2:51][O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2/[CH:20]=[CH:19]/[CH:6]([CH2:5][C:4]2[CH:28]=[C:29]([F:42])[C:30]([O:31][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])=[C:2]([F:1])[CH:3]=2)[CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=2)=[CH:53][CH:54]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1

Procedure:
A solution of 1.3 g (2.19 mmol) of methyl E4-[3-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate in 20 ml of dry acetonitrile is mixed with 600 mg (2.62 mmol) of 4-tert-butylbenzyl bromide and 450 mg (3.28 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated. The resulting crude product is purified by preparative HPLC. 780 mg (48% of theory) of a colorless oil are obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].N1CCCCC1>C(O)(=O)C>[CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH2:9][CH2:10][CH2:11][CH:19]2[S:15][C:16](=[O:21])[NH:17][C:18]2=[O:20])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C=CC=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C)Oc1ccc(CCCC2SC(=O)NC2=O)cc1
Yield: 39 %

Procedure:
A mixture of 4-isopropoxycinnamaldehyde (6.00 g), 2,4-thiazolidinedione (5.54 g), piperidine (2.69 g) and acetic acid (30 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure to give precipitated crystals of 5-(4-isopropoxycinnamylidene)-2,4-thiazolidinedione, and the crystals (4.40 g) were collected by filtration and washed with ethyl acetate. The crystals were dissolved in tetrahydrofuran (100 ml), 5% palladium-carbon (2.20 g) was added, and the mixture was subjected to catalytic hydrogenation at room temperature at a hydroaen pressure of 3.8 kgf/cm2. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-chloroform (1:9, v/v) gave 5-[3-(4-isopropoxyphenyl)propyl]-2,4-thiazolidinedione (3.61 g, 39%) as an oil.
Reaction SMILES: Br[C@:2]1([CH3:12])[O:6][C@@H:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][C:3]1=[O:11].C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[C:7]([C@@H:5]1[O:4][C:3](=[O:11])[C:2](=[CH2:12])[O:6]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](C)(Br)O1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C1O[C@H](C(C)(C)C)OC1=O
Yield: 88.7 %

Procedure:
In 500 ml of carbon tetrachloride, 50.5 g of the (2S,5S)-5-bromo-2-tert-butyl-5-methyl-1,3-dioxolan-4-one obtained in Step 2 was dissolved. To the resulting solution, 50.0 g of triethylamine was added, and the solution was refluxed for 4 hours. After the reaction solution was left to have cooled, insolubles were separated by filtration, the carbon tetrachloride was evaporated under reduced pressure, and the resulting residue was recrystallized from hexane to obtain 29.5 g of (2S)-2-tert-butyl-5-methylene-1,3-dioxolan-4-one.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23]Cl)[N:9]=1.[N-:34]=[N+]=[N-].[Na+]>CN(C=O)C.O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][NH2:34])[N:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1n(CCCCl)nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NCCCn1nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(Cc2ccccc2)c1=O
Temperature: 80 °C

Procedure:
3-(3,5-Bis(trifluoromethyl)phenethyl)-4-benzyl-1-(3-chloropropyl)-5-oxo-1,2,4-triazole (Description 2, 2.5 g, 0.005 mol) was dissolved in DMF (30 ml) and sodium azide (0.495 g, 0.0076 mol) added and the reaction heated to 80° C. for 16 hours. The reaction was cooled, diluted with water (50 ml) and extracted into ethyl acetate (75 ml). The organic layer was washed with water (3×25 ml), brine and dried (MgSO4). The solvent was removed and the resulting azide (colourless off) was dissolved in ethanol (30 ml) and hydrogenated over palladium hydroxide (0.300 g) at 50 psi for 4 hours. The catalyst was filtered and the solvent removed in vacuo to furnish the title compound as a colourless oil. (2.4 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:35]4[CH2:36][CH2:37][CH:32]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:33][CH2:34]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)CCN3)cc1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 22 %

Procedure:
4-(1-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)benzoic acid (20 mg) was reacted with 4-(1 pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a yellow solid (22% yield). M.p. 120° C., LCMS: m/z=482.26 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.53-1.65 (m, 7H), 1.90-2.04 (m, 3H), 2.25-2.35 (m, 1H), 2.53-2.63 (m, 4H), 2.91-3.06 (m, 2H), 3.38-3.44 (m, 2H), 3.59-3.62 (m, 2H), 4.48 (s, 2H), 5.01 (bs, 1H), 6.84 (s, 1H), 7.28-7.40 (m, 9H), 7.70 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CO[CH2:11][CH2:12][C:13](OC)(OC)[CH3:14]>[Cl-].[Zn+2].[Cl-].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:13]([CH3:14])=[CH:12][CH:11]=[N:5]2)=[CH:7][CH:8]=1
Reactant: COCCC(C)(OC)OC
Reactant: Nc1cccc(Cl)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1ccnc2cc(Cl)ccc12
Reaction time: 8 h

Procedure:
To a mixture containing 3-chloroaniline (1.59 g), ferric chloride hexahydrate (5.4 g), zinc chloride (0.2 g), ethanol (20 ml of 95% aqueous solution) preheated to 60° C. was added 1,3,3-trimethoxybutane (1.48 g). The resulting mixture was refluxed for two hours and allowed to stand overnight. The volatile materials were then removed in vacuo and the residue rendered basic with 10% aqueous sodium hydroxide. The resulting mixture was partitioned between water and diethyl ether (3 times). The combined ether layer was dried over magnesium sulfate. Rotary evaporation of the ether solution gave a dark liquid. The liquid was added to a silica gel column and eluted with hexane/ethyl acetate (3:1) to give the desired product as tan crystals.
Reaction SMILES: [C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]([NH:15][CH2:16][C:17]2[CH2:18][NH:19][C:20]3[N:21]=[C:22]([NH:24][C:25]([C:27]=3[N:28]=2)=[O:26])[NH2:23])=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6]>[Pt]>[C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:16][CH:17]2[NH:28][C:27]3[C:25](=[O:26])[NH:24][C:22]([NH2:23])=[N:21][C:20]=3[NH:19][CH2:18]2)=[CH:29][CH:30]=1)=[O:10])[C:5]([OH:7])=[O:6]
Reactant: Nc1nc2c(c(=O)[nH]1)N=C(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Agent: [Pt]
Product: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Yield: 65.7 %

Procedure:
Then, 0.112 g of a 5% platinum-activated carbon catalyst (containing the noble metal in an amount of 0.26% by weight based on the dihydrofolic acid) was added to the flask, and hydrogenation was carried out in the same manner as described in Example 1 to obtain 1.439 g (65.7% yield) of tetrahydrofolic acid.
Reaction SMILES: C1(C[O:8][C:9]2[CH:19]=[CH:18][C:12]3[C:13](=[O:17])[CH:14]=[CH:15][O:16][C:11]=3[C:10]=2[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C=CC=CC=1>[Pd].CO.C(OCC)(=O)C>[OH:8][C:9]1[CH:19]=[CH:18][C:12]2[C:13](=[O:17])[CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1ccoc2c(CCCc3ccccc3)c(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCOc2c1ccc(O)c2CCCc1ccccc1
Yield: 44.9 %

Procedure:
Catalytic hydrogenation of 7-(phenylmethoxy)-8-(3-phenylpropyl)-4H-1-benzopyran-4-one, from the preceding example, was carried out over 10% palladium on carbon at room temperature and 1 atmosphere, in 1:1 methanol-ethyl acetate. The crude product was purified by chromatography on silica gel, eluting with ether-dichloromethane mixtures. The title compound, a colorless solid, mp 110°-112° C. (recrystallized from hexane-ether), was obtained in 44.9% yield.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[NH:17][N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH2:26]([N:17]1[N:16]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[C@H:24]2[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[C:18]1=[O:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound 4 and benzylchloride as described for compound 78. Purified by chromatography [petroleum ether (60°-95° C.): ethyl acetate/4:1] and crystallized from petroleum ether (60°-95° C.)/ethyl acetate. M.p. 91°-92° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:24]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[Mg+2].[Cl-].[Cl-]>C(#N)C.CCOC(C)=O>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:15]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24]([O:32][CH2:33][CH3:34])=[O:31])=[O:17])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: O=C(O)C1(c2ccc(C(F)(F)F)cc2)CCOCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(C(F)(F)F)cc2)CCOCC1
Temperature: 23 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A suspension of 4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carboxylic acid (3.749 g, 13.7 mmol) and thionyl chloride (9.97 mL, 137 mmol) was heated at reflux. After 2 hours, the reaction was cooled to 23° C. and concentrated in vacuo, azeotroped with toluene (2×20 mL) and further dried on the vacuum line for 90 minutes. A solution of diethyl malonate (2.17 mL, 14.4 mmol) in ACN (50 mL) in an oven-dried round-bottomed flask, was cooled to 0° C. and treated with MgCl2 (1.30 g, 13.7 mmol), followed by TEA (3.99 mL, 28.7 mmol). The reaction was warmed to 23° C. After 2 hours and 30 minutes, a solution of the crude acid chloride in ACN (10 mL) was added, and the reaction was heated to 50° C. After 15 hours, the reaction was cooled to 23° C., diluted with EtOAc (400 mL), and washed with a 10% HCl solution (300 mL). The aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, and concentrated in vacuo affording 5.50 g of diethyl 2-(4-(4-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate. MS m/e=417.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:22](N)([NH2:25])(=[O:24])=[O:23]>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:22]([NH2:25])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)S(N)(=O)=O)CC1

Procedure:
A solution of 2.05 g of 4-benzylamino-piperidine-1-carboxylic acid tert.-butyl ester and 3.39 g of sulfamide in 100 ml of 1,2-dimethoxy-ethane is refluxed for ca. 10 hours. From the mixture obtained solvent is evaporated, the evaporation residue obtained is treated with EtAc and unsoluble parts are filtered off. The filtrate obtained is subjected to chromatography on silica gel. 4-[N-(Aminosulfonyl)-benzylamino]-piperidine-1-carboxylic acid tert.butylester is obtained. mp 140-142°. 1H-NMR (DMSO) δ: 7.30-7.41 (s/m, 9+2H), 1.64 (m, 2H), 2.53-2.72 (broad, 2H), 3.71 (tt, 1H), 8.83-8.96 (broad, 2H), 4.26 (s, 2H, CH2), 6.86 (bs, 2H, NH), 7.19 (t, 1H), 7.28 (t, 1H), 7.36 (d, 1H). 13C-NMR (DMSO) δ:28.51, 30.13, 43.35, 47.11, 56.52, 79.12, 127.06, 127.48, 128.49, 140.59, 154.156.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:18]OS(C)(=O)=O)=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:24].[Na+]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:18][I:24])=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1cc2c(cc1OCc1ccccc1)CCO2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: ICc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
A flame dried, N2 purged 1-liter, 3-neck round bottom flask equipped with an internal thermometer and mechanical stirrer was charged with 5-benzyloxy-6-(methanesulfonyloxymethyl)-2,3-dihydrobenzofuran (30.60 g, 0.10 moles) and anhydrous acetone (250 ml). The resultant solution was cooled to 0° C. and with efficient stirring sodium iodide (59.90 g, 0.40 moles) in acetone (150 ml) was added in one portion. The reaction mixture was stirred at room temperature for 72 hours and then suction filtered through a bed of celite. The filtrate was concentrated in vacuo to afford the crude product. This was dissolved in ethyl ether (400 ml) and water (200 ml), the layers partitioned, and separated. The organic phase was washed with saturated NaHS03 solution (2×200 ml) and water (1×200 ml), dried over MgSO4, suction filtered, and the filtrate concentrated in vacuo to yield 5-benzyloxy-6-iodomethyl-2,3-dihydrobenzofuran as a yellow solid (33.0 g, 98%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](OC)=[O:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.[O-2].[O-2].[Mn+4]>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1nn(-c2ccccc2)c2ccccc12
Agent: [Mn+4]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1nn(-c2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 46.7 %

Procedure:
To a solution (40 mL) of methyl 1-phenyl-1H-indazole-3-carboxylate (2.25 g) synthesized above in tetrahydrofuran was added dropwise 1.5M diisobutylaluminum hydride toluene solution (26.7 mL) at 0° C., and the mixture was stirred for 1 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a colorless oil. To a solution of the obtained oil in tetrahydrofuran (40 mL) was added active manganese dioxide (8.00 g), and the mixture was stirred at 50° C. for 5 hr. Active manganese dioxide (1.00 g) was additionally added, and the mixture was stirred at 50° C. for 1 hr. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title object compound (926 mg, 47%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][CH2:26][CH2:27][CH3:28]>CO>[NH2:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][CH2:26][CH2:27][CH3:28])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][O:6][N:5]=[C:2]([CH3:4])[CH3:1])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)=O
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON=C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
Acetone (444 mg, 7.65 mmol) was added to a solution of 1-[4-(aminooxy)butyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.53 mmol) in methanol (7 mL), and the reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure and then firther dried under high vacuum to provide 358 mg of acetone O-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]oxime as a white solid, mp 115-117° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]2[CH2:14][C:15](=[CH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][C:29]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)(O)[CH2:28][CH2:27]3)[C:16]3[C:17]([O:22][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[N:18][CH:19]=[CH:20][CH:21]=3)(=O)C.C(OCCOC1C2CC(=CCCN3CCCCC3)C3C(OC=2C=CC=1)=NC=CC=3)(=O)C>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH:29]2[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH:23]=[C:15]3[C:16]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[O:22][C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:13]=4[CH2:14]3)[CH2:31][CH2:30]2)=[CH:34][CH:35]=1
Reactant: CC(=O)OCCOc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: CC(=O)OCCOc1cccc2c1CC(=CCCN1CCCCC1)c1cccnc1O2
Product: OCCOc1cccc2c1CC(=CCCN1CCC(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 51, but replacing the product of example 50 with the product of example 156.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([P:23](Cl)(Cl)=[O:24])=[CH:19][CH:18]=1>>[F:28][C:16]([F:15])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([P:23]2(=[O:24])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: O=P(Cl)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: O=P1(c2ccc(C(F)(F)F)cc2)c2ccccc2CN1c1ccccc1
Yield: 4 %

Procedure:
The procedure of Example 38 was employed utilizing N-benzylaniline and 4-trifluoromethylphenyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation was crystallized from diethyl ether and petroleum ether and recrystallized from diethyl ether to yield 1-[4-(trifluoromethyl)phenyl]-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.5 g, 4% yield) having a melting point of 187°-189° C.