Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C([N:14](CC)CC)C.S(Cl)(Cl)=O>O1CCCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:14])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc(Br)c1F
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a solution of 3-bromo-2-fluorobenzoic acid (3.77 g, 17.2 mmol) in dry tetrahydrofuran (200 ml) was added triethylamine (4.77 ml, 34.4 mmol) and thionyl chloride (1.69 ml, 21.5 mmol). The reaction mixture was stirred for 1 h and then quenched with ammonia in methanol (10 ml, saturated). After an additional hour of stirring the mixture was evaporated and the crude product was purified by flash column chromatography (ethyl acetate/isooctane 1:1) to give the title compound (1.76 g). MS m/z (rel. intensity, 70 eV) 219 (M+, 26), 217 (M+, 26), 203 (62), 201 (70), 94 (bp).
Reaction SMILES: O=C1C2C=CC=CC=2C(=O)[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:20][S:21]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[O:19])=[CH:14][CH:13]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[NH2:3][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:20][S:21]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1

Procedure:
A 74 mg portion (0.21 mmol) of [4-(1,3-dioxobenzo[c]azolidin-2-yl)phenyl]-N-[(5-chloro(2-thienyl))sulfonyl]-carboxamide, 192 mg (0.84 mmol) of tin dichloride dihydrate were combined and dissolved in 1.4 mL of EtOAc. The mixture was refluxed for 4 h, filtered through celite, and concentrated in vacuo to afford a solid which was purified on silica gel eluting with 10% MeOH/CH2Cl2 to give a quantitative yield of the titled compound. ES-MS (M+H)+=317 (Cl).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:19][C:18]2[CH:20]=[CH:21][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(N=Cc2ccc(OC(F)F)cc2)cc1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-difluoromethoxybenzaldehyde and 4-methylthioaniline as starting materials, N-(4-difluoromethoxybenzylidene)-4-methylthioaniline was obtained in a yield of 91%. This aniline compound and trimethylsilyl cyanide were then reacted together in a similar manner to that described in Example 1(ii), to give the title compound as a slightly yellow powder (yield 80%).
Reaction SMILES: FC(F)(F)C1C=CC(CN([C:12]2[CH:17]=[CH:16]C(C#N)=CC=2)N)=CC=1.CO[CH:24]([O:29]C)[CH2:25]N=C=S.[CH2:31]([OH:33])[CH3:32]>>[CH:24]([O:29][CH:17]([CH3:16])[CH3:12])([CH3:31])[CH3:25].[CH2:31]([OH:33])[CH3:32]
Reactant: COC(CN=C=S)OC
Reactant: N#Cc1ccc(N(N)Cc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCO
Product: CC(C)OC(C)C

Procedure:
To a suspension of N1-(4-trifluoromethylphenylmethyl)-N1-(4-cyanophenyl)hydrazine (7.5 g, 0.025 mol) in ethanol (100 ml) was added dropwise 2,2-dimethoxyethylisothiocyanate (4 g, 0.027 mol) and the reaction mixture was heated to reflux for 2 h. After cooling the solvent was evaporated under vacuum, the resulting residue was poured into 2N H2SO4 (20 ml) and the suspension was heated to reflux for 0.3 h. After extraction with ethyl acetate, the organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel (toluene/dioxane: 8/2) and trituration from diisopropyl ether/ethanol afforded a yellow solid (2.7 g, 28%), mp 200° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[C:7]([O:10]C(=O)C)=[CH:8][O:9][C:5]=2[CH:4]=1.CO.Cl>O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: CC(=O)Oc1coc2cc(C(F)(F)F)ccc12
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1COc2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
A mixture of acetic acid 6-trifluoromethyl-benzofuran-3-yl ester (15 g), methanol (100 ml), water (53.8 ml) and 1 N HCl (18.8 ml) was heated at reflux for 6 hrs. Mixture was cooled to room temperature. Crude product was evaporated in vacuo and purified by chromatography to give product 6a (Hexane:EA=18:1).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:16]=1[C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:16]=1[C:25](=[CH2:1])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(=O)c1c(OCOC)cccc1OCOC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)c1c(OCOC)cccc1OCOC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (3.13 g, 8.75 mmol) in dry tetrahydrofuran (30 ml) at 0° C. KHMDS (1.745 g, 8.75 mmol) was slowly added and the reaction mixture was stirred for 15 minutes at 0° C. and for 45 minutes at room temperature. The reaction mixture was cooled to 0° C. and a solution of ethyl (2,6-bis{[(methyloxy)methyl]oxy}phenyl)(oxo)acetate (Intermediate 80, 1.74 g) in dry tetrahydrofuran (10 mL) was slowly added and the reaction mixture was stirred for 2 hours at 0° C. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (20 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound as a colourless oil (1.37 g).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][CH:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 3-hydroxy-6-methylpyridine (5.00 g, 45.8 mmol) was added sodium hydride (2.02 g, 50.4 mmol, 60% in oil), which was stirred for 15 minutes at 0° C. Next, benzyl bromide (5.99 mL, 50.4 mmol) was added to this reaction mixture at 0° C., which was stirred for 3.5 hours at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the tile compound (5.99 g, 66%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>CCOCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[N:3][CH:4]=1
Reactant: COc1ccc(Br)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: COc1ccc(C2(O)CCC3(CC2)OCCO3)nc1

Procedure:
The title compound was prepared as a white solid from 2-bromo-5-methoxy-pyridine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=2[O:6][N:5]=1)[CH3:2].[OH:13]S(O)(=O)=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C(O)(=O)C.C(OCC)C>[CH2:1]([O:3][C:4]1[C:8]2[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:7]=2[O:6][N:5]=1)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOc1noc2c1CCCC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOc1noc2c1C(=O)CCC2
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
To a solution of 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 1a (35 g) in glacial acetic acid (500 mL) at 10° C. was added concentrated H2SO4 (29 mL). A solution of sodium dichromate (71 g) in glacial acetic acid (300 mL) kept at 40-45° C. was added dropwise during one hour at 20-25° C. The mixture was stirred for another 3 hours at 25-30° C. The reaction mixture was poured onto ice and diethyl ether (3 L). pH was adjusted to >10 by addition of concentrated aqueous NaOH. The organic phase was separated and worked up. The remaining crude title compound was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:1). Pure 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one was washed with diisopropyl ether and dried. Yield 27 g. Mp 98-99° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4].Br[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C=O)C>[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][CH2:26][CH3:27])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: CCCCBr
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cc(C2CCN(C(=O)OCC)CC2)c2cccnc21
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, over a suspension of 0.55 g (13.72 mmol) of sodium hydride 60% in paraffin oil in 10 ml of DMF, a solution of 2.5 g (9.1 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester in 10 ml of DMF was added. After 30 minutes, a solution of 1.2 ml of 4-bromobutane in 2 ml of DMF was added. The crude mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the crude was partionated between ethyl acetate and water. The organic phase was dried over sodium sulphate, filtered and the solvent was removed under reduced pressure affording 3.1 g of 4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:21]#[N:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Si:1]([O:8][C@H:9]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][Br:32])=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:21]#[N:22])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)cc(C#N)n2C[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC[C@H](Cn1c(C#N)cc2cc(CBr)ccc21)O[Si](C)(C)C(C)(C)C
Yield: 89.9 %

Procedure:
To a stirred solution of 55 mg of (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-methyl-1H-indole-2-carbonitrile (0.12 mmol) in carbon tetrachloride (0.5 mL) was added 21.3 mg of N-bromosuccinimide (0.12 mmol) and 1.1 mg of AIBN (0.0065 mmol). The mixture was refluxed for 1 h, then cooled, concentrated and filtered through short silica gel plug using hexane-ethyl acetate 10:1 to give 58 mg of crude (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-(bromomethyl)-1H-indole-2-carbonitrile that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CSc1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
1H-NMR: 4.85 (bs, 2H), 6.29 (s, 1H), 7.21-7.39 (m, 3H), 8.64 (s, 1H) To 10 ml of an ethanol solution of 1.5 g of 4,6-dichloropyrimidine was slowly added 0.78 g of sodium thiomethoxide at 0° C., followed by stirring at 0° C. for 7 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture and concentrated under reduced pressure. The residue was extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 1.1 g of 4-chloro-6-methylthiopyrimidine.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:12]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:4]1)[CH3:2].Cl.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37]>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH:12]2[C:10]([N:9]([CH2:8][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)[C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=1)=[O:11]
Reactant: CN(C)CCCl
Reactant: CCn1cc(CN(C(=O)C2CCCc3c(O)cccc32)c2ccc(C(C)C)cc2)cn1
Agent: Cl
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCCN(C)C)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 30.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) as starting materials, 5-[2-(dimethylamino)ethyloxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O:14]=[C:15]([NH:30][CH2:31][C:32](=O)[NH:33][C@@H:34]1[CH2:38]CNC1)[CH2:16][NH:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:33]2[CH2:34][CH2:38][C@@H:31]([NH:30][C:15](=[O:14])[CH2:16][NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:32]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC(=O)N[C@@H]1CCNC1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a mixture of 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone (0.075 g, 0.38 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0.10 g, 0.317 mmol) in 2% AcOH/CH2O2 (10 mL) was added NaB(OAc)3H (0.134 g, 0.634 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed [EtOAc to MeOH/EtOAc (1:9) then to 5% MeOH/EtOAc/Et3N (1:9:0.5)] to give 0.141 g of the title compound in 90% yield. MS (EI) calcd: (M+H)+=497.2; found: 497.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][O:7][SiH:6]([CH3:10])[O:5][CH2:4][CH2:3]1.[CH3:11][Si:12]([CH3:22])([CH3:21])[N:13]([CH2:18][CH:19]=[CH2:20])[Si:14]([CH3:17])([CH3:16])[CH3:15]>[Pt]>[CH3:1][N:2]1[CH2:9][CH2:8][O:7][Si:6]([CH3:10])([CH2:20][CH2:19][CH2:18][N:13]([Si:12]([CH3:21])([CH3:22])[CH3:11])[Si:14]([CH3:17])([CH3:16])[CH3:15])[O:5][CH2:4][CH2:3]1
Reactant: C=CCN([Si](C)(C)C)[Si](C)(C)C
Reactant: CN1CCO[SiH](C)OCC1
Agent: [Pt]
Product: CN1CCO[Si](C)(CCCN([Si](C)(C)C)[Si](C)(C)C)OCC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 11.9 %

Procedure:
To a sealed 300 mL nitrogen purged glass bottle was added 16.2 g (100 mmol) 1,5-dimethyl-1-aza-4,6-dioxa-5-silacyclooctane and 20.1 g (100 mmol) N,N-bistrimethylsilylallylamine and the bottle was heated to 75° C. with stirring. Then, 0.8 mL of a 2 wt % platinum solution of Karsted's catalyst in xylenes was added to the reaction. After 24 hrs, the product was isolated by vacuum distillation at 110° C. and 0.04 mm Hg (4.33 g, 11.9% yield). 1H NMR (300 MHz, C6D6) δ (ppm) 3.72 (4H, t), 2.71 (2H, t), 2.59 (4H, t), 2.41 (3H, s), 1.44-1.42 (2H, m), 0.44 (2H, t), 0.09 (3H, s), 0.06 (18H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24]>>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCCNc1c(N)cnc2ccccc12
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Yield: 66.2 %

Procedure:
The general method described in Step 3 of Example 15 was used to cyclize ethyl 4-(3-aminoquinolin-4-ylamino)butyrate (18.0 g, 65.9 mmol) by reaction with trimethyl orthobutyrate (10.4 g, 70.2 mmol) to provide ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate (14.2 g) as a solid after chromatography on silica gel (elution with 5% methanol in dichloromethane).
Reaction SMILES: C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:34][C:35]1[CH:47]=[CH:46][C:38]([C:39]([C:41]2[CH:45]=[CH:44][O:43][N:42]=2)=[O:40])=[CH:37][CH:36]=1.[Cl:48][C:49]1[CH:59]=[C:58]([O:60][CH2:61][CH:62]=[C:63]([Cl:65])[Cl:64])[CH:57]=[C:56]([Cl:66])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54]O>O1CCCC1>[Cl:48][C:49]1[CH:59]=[C:58]([O:60][CH2:61][CH:62]=[C:63]([Cl:65])[Cl:64])[CH:57]=[C:56]([Cl:66])[C:50]=1[O:51][CH2:52][CH2:53][CH2:54][O:34][C:35]1[CH:47]=[CH:46][C:38]([C:39]([C:41]2[CH:45]=[CH:44][O:43][N:42]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: O=C(c1ccc(O)cc1)c1ccon1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1)c1ccon1
Reaction time: 0.5 h

Procedure:
0.93 ml of azodicarboxylic acid diisopropyl ester is added at 0° C. to 1.26 g of triphenylphosphine in 30 ml of tetrahydrofuran and stirring is carried out for 30 minutes. 0.76 g of 3-(4-hydroxybenzoyl)isoxazole and 1.38 g of 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propan-1-ol in 10 ml of tetrahydrofuran are then added dropwise and stirring is carried out at room temperature for 24 hours. After the reaction mixture has been concentrated and purified over silica gel, (4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-isoxazol-3-yl-methanone is obtained in the form of a colourless oil.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([N:9]1[CH2:12][CH:11]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:14]#[N:15])[CH2:10]1)([CH3:8])[CH3:7].[OH-:28].[Na+]>>[CH:6]([N:9]1[CH2:12][CH:11]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:14]([NH2:15])=[O:28])[CH2:10]1)([CH3:8])[CH3:7]
Reactant: CC(C)N1CC(C(C#N)(c2ccccc2)c2ccccn2)C1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)N1CC(C(C(N)=O)(c2ccccc2)c2ccccn2)C1
Temperature: 70 °C

Procedure:
To 80 ml. of concentrated sulfuric acid preheated to 70° C. was added 15 g. (0.052 mole) of α-(1-isopropyl-3-azetidinyl)-α-phenyl-α-(2-pyridyl)acetonitrile at a rate to maintain 65°-70° C. The solution was heated to 70° C. for 18 hrs. and poured on ice. The mixture was made basic with 50% sodium hydroxide (with ice cooling and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized twice from ethyl acetate-isopropyl ether. Yield 6 g. (37%), m.p. 140°-141° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9]2=N)[CH2:3][CH2:2]1.[OH-:20].[Na+]>Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9]2=[O:20])[CH2:3][CH2:2]1
Reactant: N=C1NN(c2ccccc2)CC1CN1CCOCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C1NN(c2ccccc2)CC1CN1CCOCC1

Procedure:
A solution of 4-morpholinomethyl-1-phenylpyrazolidin-3-imine (29g) in dilute hydrochloric acid (120 ml of 2N) was boiled under reflux for 4 hours. The solution was cooled, neutralised with sodium hydroxide and extracted with chloroform. The chloroform extract was dried and evaporated to dryness. The solid residue was recrystallized from petroleum ether (boiling point 100°-120° C) as colourless plates (melting point 143°-144° C).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH:18]=O)[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH2:18][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: O=CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Reactant: NCCc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: c1ccc([C@]2(CCNCCc3cccnc3)CCOC3(CCCC3)C2)nc1
Reaction time: 8 h

Procedure:
To a solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (50 mg, 0.19 mmole), 5 mL DCM and NA2SO4 (134 mg, 0.95 mmole) was added 2-(pyridin-3-yl)ethan-1-amine (31 mg, 0.25 mmole) and the reaction was stirred overnight. NaBH4 (9.5 mg, 0.25 mmole) added, stir 10 minutes, 2 drops MeOH added, stir 1 h, quenched with water, organics separated off and evaporated. The residue was passed through a Gilson reverse phase HPLC to give {2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}[2-(pyridin-3-yl)ethyl]amine, 65.3 mg (71%). LCMS m/z 367.1 (M+1) observed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[I-:17].[K+].II>>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([I:17])[CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(O)cc1)c1cccc(F)c1
Reactant: [I-]
Agent: II
Agent: [K+]
Product: O=C(c1cccc(F)c1)c1ccc(O)c(I)c1

Procedure:
The product from Example 69A, potassium iodide and iodine were processed as described in Example 68A to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 6.92 (d, 1H, J=8.9 Hz), 7.31-7.59 (m, 4H), 7.67 (d, 1H, J=8.9 Hz), 8.18 (s, 1H); MS (DCI) m/z 343 (M+H)+, 360 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>O>[CH2:23]([C:22]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:25])[CH3:24]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. To 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (188 mg, 1 mmol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and propionyl chloride (101 mg, 1.10 mmol) followed by stirring at 60° C. for 3 hours. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (30/1) as an elution solvent. The yield was 66.4 mg (27%).