Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20](Cl)[CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH3:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CC(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: C1CNCCN1
Solvent: c1ccccc1
Product: CC(c1ccc(-c2ccc(Cl)cc2)cc1)N1CCNCC1

Procedure:
While stirring, reflux a solution of 90g of anhydrous piperazine, 52g of 4'-chloro-4-(1-chloroethyl)[1,1']biphenyl and 700 ml of anhydrous benzene for 24 hours. Add 300 ml. of water to the reaction mixture, separate the benzene layer and extract with dilute hydrochloric acid. Separate and filter the acidic aqueous phase, basify the filtrate with dilute sodium hydroxide and extract with methylene chloride. Dry the organic extract, concentrate and triturate the resulting solid residue with petroleum ether. Filter and recrystallize the product from methanol to yield 1-[1-(4'-chloro[1,1']biphenyl-4-yl)ethyl] piperazine m.p. 164°-165° C. The dihydrochloride salt (from methanol as hemihydrate) has a m.p. 263°-264°.
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]([NH:17][C:18]([NH:20][C:21]1([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:25]([CH2:26]O)[CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]1)=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:9]([NH:17][C:18]1[S:19][CH2:26][CH:25]2[CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][C:21]2([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[N:20]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2cnccn2)C1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CSC(NC(=O)c3ccccc3)=NC2(c2cnccn2)C1
Yield: 71.4 %

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine (409.71 μL, 3.10 mmol) is added to a stirred solution of tert-butyl 3-(benzoylcarbamothioylamino)-4-(hydroxymethyl)-3-pyrazin-2-yl-pyrrolidine-1-carboxylate (1.09 g, 2.38 mmol) in dichloromethane (30 mL) at room temperature. After stirring the reaction at room temperature for 3 hours a saturated aqueous solution of sodium carbonate (15 mL) is added and the mixture is stirred for 5 minutes. Dichloromethane (80 mL) is added and the layers are separated. The aqueous layer is re-extracted with dichloromethane (70 mL). The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure. The isolated product is dissolved in methanol (60 mL) and is purified by ion exchange column chromatography eluting with methanol (60 mL) then with 7 M ammonia/methanol solution (120 mL). The basic fraction is collected and the resulting product is further purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title product (747 mg, 71%). ES/MS (m/e) 440 (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]#N)[CH:8]=[CH:9][CH:10]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:26]3[CH:31]=C[C:29]([N+:32]([O-])=[O:33])=[CH:28][CH:27]=3)[O:25][CH2:24][CH2:23][O:22]2)=[CH:17][CH:16]=1.O>CO>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2([C:26]3[CH:27]=[CH:28][C:29]4[C:12]([CH:31]=3)=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=3)[O:33][N:32]=4)[O:22][CH2:23][CH2:24][O:25]2)=[CH:19][CH:20]=1
Reactant: COc1cccc(CC#N)c1
Reactant: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(-c2onc3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Yield: 90 %

Procedure:
Sodium hydroxide (16.4 g) and (3 methoxyphenyl)acetonitrile (20.6 ml) were added at room temperature to a solution of interm. (5-a) (25 g) in methanol (100 ml) and the mixture was stirred at room temperature overnight. Water was added, the precipitate was filtered off, washed with cold methanol and dried. The product was used without further purification, yielding 30 g (90%) of 5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-(3-methoxyphenyl)-2,1-benzisoxazole (interm. 5-b).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([OH:11])=[O:10].C([O-])([O-])=O.[Na+].[Na+]>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.CC#N>[Cl:8][C:7]1[C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Clc1cccnc1Cl
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: [Na+]
Solvent: CC#N
Product: O=C(O)c1ccc(-c2ncccc2Cl)cc1

Procedure:
2,3-Dichloropyridine (2.66 g, 18.0 mmol), 4-carboxyphenylboronic acid (2.70 g, 16.3 mmol), and Pd(PPh3)4 (0.965 g, 0.835 mmol) were combined in a degassed solution of 1:1 0.5M aq Na2CO3:MeCN (120 mL), heated to 85° C. for 5 hours, filtered, and the filtrate concentrated under reduced pressure to remove most of the MeCN. The concentrate was extracted with CH2Cl2 (10 mL) and acidified with 1N HCl. The acidified solution was filtered and the filter cake dried under reduced pressure to provide the title compound as a solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:18][CH:17]2[N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:10]([CH2:11][C:12]3[NH:13][N:14]=[CH:15][C:16]=32)[CH2:9]1)=[O:7])C>C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:19]2[CH:10]3[CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:18][CH:17]2[C:16]2[CH:15]=[N:14][NH:13][C:12]=2[CH2:11]3)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (0.5 mL, 3 N solution) was added to a solution 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid ethyl ester (321 mg, 0.783 mmol) in THF (2 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with EtOAc (2×5 mL) and the combined organic phases were dried (Na2SO4), filtered, concentrated and purified by preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid as a white solid. Retention time (min)=1.316, method [1], MS (ESI) 382.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=8.7 Hz, 2H), 7.30-7.22 (m, 3H), 5.30-5.25 (m, 1H), 4.54-4.45 (m, 1H), 2.80 (dd, J=17.0, J=7.7 Hz, 1H), 2.50 (d, J=17.0 Hz, 1H), 2.42-2.30 (m, 1H), 2.24-1.85 (m, 4H).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH:35]([CH3:37])[CH3:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1.CN(C)C=O.Cl>C(N(CC)CC)C.C(Cl)Cl>[C:1]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH:35]([CH3:36])[CH3:37])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=NOC(C)C)c1csc(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(=NOC(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 129.7 %

Procedure:
13.2 g of trityl chloride were slowly added to a cooled mixture of 11 g of the product of Step C, 20 ml of dry dimethylformamide, 40 ml of methylene chloride and 6.2 ml of triethylamine and the mixture was stirred for 21/2 hours, 43 ml of N hydrochloric acid were added thereto and the mixture was stirred and decanted. The organic phase was washed with 40 ml of water and was extracted with methylene chloride. The extracts were dried and vacuum filtered. The filtrate was evaporated to dryness to obtain 27.7 g of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(1-methylethoxyimino)-acetate in the syn configuration.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:24])[C:17](=O)[N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:25])=[CH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].C(Cl)(Cl)Cl.Cl>O1CCOCC1.O>[CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:24])[CH2:17][N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:25])=[CH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2c(nc3n(Cc4ccccc4)c(=O)cc(O)n23)n(C)c1=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)cc(O)n3c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 395 g. (1.12 moles) of 9-benzyl-1,3-dimethyl-6-(hydroxy)pyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione in 10.5 liters of dry 1,4-dioxane, add 68.1 g. (3.14 moles) of lithium borohydride in portions. Maintain the reaction temperature at 20°-25° C. by controlling the rate of addition and by use of a cooling bath as needed. Stir the mixture at room temperature for 0.5 hour, then reflux for 18 hours. Remove solvent under reduced pressure. Allow the residue to cool; then add 4.5 liters of chloroform. To the resultant mixture, cautiously add dropwise 1.1 liters of water. Stir the mixture at room temperature until two clear phases result. Add 3N hydrochloric acid portionwise to bring the pH to 4-5. Separate the layers, and extract the aqueous phase with two 1.1-liter portions of chloroform. Wash the combined extracts with three 1.1-liter volumes of water, and dry over anhydrous sodium sulfate. Filter the drying agent, and remove volatiles from the filtrate under reduced pressure. Crystallize the residue from methanol-ethyl acetate to obtain title compound (I) as a solid with m.p. 176°-182° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=1)#[N:50]>CN(C=O)C>[C:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:58]=1)#[N:50]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.2 %

Procedure:
DIEA (0.015 mL, 0.085 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.016 g, 0.077 mmol) and HATU (0.032 g, 0.085 mmol) in 0.45 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-cyano-biphenyl-3-ylamine (0.015 g, 0.077 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.008 g of product in 26% yield: LCMS (ESI) m/z 383 (MO.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])/[CH:3]=[CH:4]/[C:5]1[C:13]2[O:12][CH:11]([CH2:14][N:15]=[N+]=[N-])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>[Pd]>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][C:5]1[C:13]2[O:12][CH:11]([CH2:14][NH2:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)/C=C/c1cccc2c1OC(CN=[N+]=[N-])C2
Agent: [Pd]
Product: CC(C)(C)CCc1cccc2c1OC(CN)C2
Yield: 38.9 %

Procedure:
Treatment of (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide (1.82 g, 7.07 mmol) with palladium on carbon (0.18 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.642 g (34%) of (±)-1-[7-(3,3-dimethylbutyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 158-160° C.; Anal. calcd. for C15H23NOHCl: C, 66.77; H, 8.97; N, 5.19. Found: C, 66.31; H, 8.56; N, 5.09.
Reaction SMILES: O.O.O.[Cl-:4].F[C:6]1[CH:15]=[CH:14][C:13]2[N+:12]3[CH:16]=[C:17]4[CH:26]=[CH:25][C:24]5[CH:23]=[C:22]([CH3:27])[CH:21]=[CH:20][C:19]=5[N:18]4[C:11]=3[CH:10]=[CH:9][C:8]=2[CH:7]=1.C[N:29]1[CH2:33][CH2:32][CH2:31][C:30]1=O.N1CCCC1>C(OCC)(=O)C>[Cl-:4].[CH3:27][C:22]1[CH:21]=[CH:20][C:19]2[N:18]3[C:11]4[CH:10]=[CH:9][C:8]5[CH:7]=[C:6]([N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)[CH:15]=[CH:14][C:13]=5[N+:12]=4[CH:16]=[C:17]3[CH:26]=[CH:25][C:24]=2[CH:23]=1
Reactant: CN1CCCC1=O
Reactant: Cc1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Agent: [Cl-]
Solvent: C1CCNC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(ccc3c[n+]4c5ccc(N6CCCC6)cc5ccc4n32)c1
Reaction time: 3 h

Procedure:
A stirred mixture of 219.5 g. of 3-fluoro-10-methylimidazo[1,2-a:-3,4-a']diquinolin-15-ium chloride trihydrate and 580 ml. of N-methyl-2-pyrrolidinone is heated to 150° C. and 144 ml. of pyrrolidine is added over a 2 minute period. The mixture is heated and stirred at reflux (132°-140° C.) for 40 minutes, allowed to cool, and then is diluted with 2 l. of ethyl acetate. The precipitated solid is collected by filtration, washed with ethyl acetate, dried and dissolved in 1.6 l. of methanol. The methanol solution is treated with 20 g. of activated charcoal and filtered. The filtrate is passed over a column of 1 l. of IRA-410 anion exchange resin (Cl- form, suspended in methanol) over a period of 3 hours. The eluate is evaporated at reduced pressure to give a residue of 10-methyl-3-(1-pyrrolidinyl)-imidazo[1,2-a:3,4-a']diquinolin-15-ium chloride; m.p. 245°-320° C. (dec.) after crystallization from dimethylformamide and from 2-propanol/acetonitrile.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[CH2:24]([NH2:27])[CH2:25][CH3:26]>C1COCC1>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([NH:27][CH2:24][CH2:25][CH3:26])=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNC(=O)CCn1c(CCC)nc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (3.45 g, 11.1 mmol), n-propylamine (9.1 mL, 110 mmol), and THF (5 mL) was heated at 80° C. for two days in a high-pressure vessel, allowed to cool to ambient temperature, and concentrated under reduced pressure to provide 3.5 g of 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-])=O)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Ni].CO>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:9])[CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCNc2ccccc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CO
Product: Nc1ccccc1NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 100 %

Procedure:
A mixture of 27 parts of (4-fluorophenyl) [1-{3-[(2-nitrophenyl)amino]propyl}-4-piperidinyl]methanone in 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated, yielding 25 parts (100%) of [1-{3-[(2-aminophenyl)amino]-propyl}-4-piperidinyl] (4-fluorophenyl)methanone as a residue.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:16]1[O:18][CH2:17]1>C1(C)C=CC=CC=1>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([O:8][CH:17]([OH:18])[CH3:16])[CH2:7]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: C1CO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(C)O)C1
Temperature: 5 °C
Yield: 96 %

Procedure:
At first, 100.0 g (0.64 mol) of l-menthol and 42.7 g (0.32 mol) of anhydrous aluminum chloride were added into a reaction vessel and after replacement with nitrogen, 500 ml of toluene was further added to the vessel and stirred with the mixture under the ice-cooling condition to cool the resulting mixture to 5° C. And while the temperature of the solution being kept at 5 to 10° C., 57 g of ethylene oxide was further added. On completion of the supply, the mixture was stirred for one more hour at a room temperature to complete the reaction. Next, the reaction solution was cooled again and washed with 150 ml of 10% aqueous hydrochloric acid while being kept at 20° C. or lower. After the reaction solution was washed again with 50 ml of saturated sodium hydrogen carbonate aqueous solution and then with 100 ml of saturated brine, water therein was removed with sodium sulfate and the solvent was recovered under reduced pressure to obtain 123.1 g of crude l-menthyloxyethanol. The obtained product was distilled to isolate and recover 45.7 g of an unreacted raw material, l-menthol, and refine and isolate 60.8 g of an aimed product, l-menthyloxyethanol. Theoretical yield: 47.4% based on l-menthol.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:14]([CH2:27][CH3:28])([P:23]([OH:26])([OH:25])=[O:24])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1)[CH3:13].C(OCC)C>ClCCl>[CH2:27]([C:14]([CH2:12][CH3:13])([P:23]([OH:25])([OH:26])=[O:24])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[CH3:28]
Reactant: CCC(CC)(c1ccc(CO)cc1)P(=O)(O)O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C=O)cc1)P(=O)(O)O
Reaction time: 1.5 h

Procedure:
Pyridinium chlorochromate (110 mmol) in dichloromethane (150 mL) was rapidly stirred while 4-(diethyl phosphonomethyl)benzyl alcohol (73.6 mmol) in dichloromethane (15 mL) was rapidly added. After 1.5 hours, ethyl ether (200 mL) was added to the reaction mixture and the organic solution was decanted from the tarry residue. The residue was washed with 3×50 mL ethyl ether. The combined organic solution was filtered through Florisil chromatographic material and concentrated to a brown oil. The oil was then distilled to give the product as a clear oil (BP 150°-180° C. @0.002-0.005 mm Hq).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=2)[CH:12]=[N:11][C:10]=1[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl.O.[Cu]I>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11][C:10]=1[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1ncc2cc(Br)ccc2c1OCc1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 4-(benzyloxy)-7-bromoisoquinoline-3-carboxylate (372.0 mg, 1.0 mmol), 4-methoxybenzylamine (0.2 mL, 1.5 mmol, TCI), CuI (19.0 mg, 0.1 mmol), proline (23.0 mg, 0.2 mmol) and K2CO3 (276.4 mg, 2.0 mmol) in DMSO (0.6 mL) was stirred at 80° C. for 24 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with CH2Cl2 (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/CH2Cl2) to give the title compound in 137.0 mg. 1H NMR (CDCl3, 200 MHz): δ=8.82 (s, 1H), 7.96 (d, 1H, J=9.0 Hz), 7.54 (d, 2H, J=6.6 Hz), 7.42-7.27 (m, 5H), 7.05 (d, 1H, J=9.0 Hz), 6.93-6.87 (m, 3H), 5.18 (s, 2H), 4.38 (d, 2H, J=5.0 Hz), 4.00 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].Cl.[CH3:14]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([O:9][CH3:14])=[O:8])[CH:10]=[CH:11][CH:12]=1
Reactant: CO
Reactant: O=C(O)C=Cc1cccc(O)c1
Agent: Cl
Product: COC(=O)CCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 ml of 10% hydrogen chloride-methanol was added to 1.64 g (10 mmol) of 3-hydroxycinnamic acid and the mixture was stirred at room temperature for one day. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed twice with water and dried (MgSO4). The solvent was distilled off. The residue was dissolved in 25 ml of methanol, 0.5 g of 10% palladium-carbon was added and the mixture was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1 (v/v)) to obtain 1.75 g (9.71 mmol) of methyl 3-(3-hydroxyphenyl)propionate as a colorless oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14](F)[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][NH:21][CH3:22]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14]([N:21]([CH3:22])[CH3:20])[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CNC
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Solvent: CCO
Product: CN(C)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1

Procedure:
Treatment of 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (see a previous experimental) at 100° C. in a pressure vessel with dimethylamine in ethanol gives 4-(3-bromoanilino)-6-dimethylaminopyrido[3,4-d]pyrimidine. 1H NMR (DMSO) δ 9.71 (1H, s), 8.83 (1H, s), 8.43 (1H, s), 8.21 (1H, brs), 7.94 (1H, brd, J=7.5 Hz), 7.42-7.29 (2H, m), 7.26 (1H, s), 3.17 (6H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH:15]([C:50]([F:55])([F:54])[CH2:51][CH2:52][CH3:53])[CH2:16][CH2:17][CH2:18][C@H:19]1[C@H:23]([O:24]C(=O)C2C=CC=CC=2)[CH2:22][C@H:21]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[C@@H:20]1[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])[Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CO>[O:7]([CH:15]([C:50]([F:55])([F:54])[CH2:51][CH2:52][CH3:53])[CH2:16][CH2:17][CH2:18][C@H:19]1[C@H:23]([OH:24])[CH2:22][C@H:21]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[C@@H:20]1[CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])[Si:8]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10]
Reactant: CCCC(F)(F)C(CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OC2CCCCO2)C[C@H]1OC(=O)c1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCC(F)(F)C(CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OC2CCCCO2)C[C@H]1O)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
Potassium carbonate (0.125 g) was added to a solution of the compound (39) (0.689 g) in methanol, and the resultant mixture was stirred at room temperature for 2 hours. An additional amount (1.75 g) of potassium carbonate was added thereto, and the mixture was left on standing overnight. The crude product obtained after the usual work-up was subjected to silicagel column chromatography to give the monoalcohol (40).