Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][O:19][N:20]1[CH:28]=[N:27][C:26]2[C:25](=[O:29])[NH:24][C:23]([NH2:30])=[N:22][C:21]1=2)([O:11]CC)=[O:10])C>CN(C)C=O>[P:9]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][O:19][N:20]1[CH:28]=[N:27][C:26]2[C:25](=[O:29])[NH:24][C:23]([NH2:30])=[N:22][C:21]1=2)([OH:11])([OH:10])=[O:8]
Reactant: CCOP(=O)(COCCCOn1cnc2c(=O)[nH]c(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2OCCCOCP(=O)(O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Bromotrimethylsilane (0.79 ml, 6 mmol) was added dropwise to a solution of 9-[3-(diethoxyphosphorylmethoxy)propoxy]guanine (0.38 g, 1 mmol) in dry N,N-dimethylformamide (4 ml) and the reaction stirred under nitrogen at 25° C. for 2 h. Concentration in vacuo, followed by co-evaporation three times with methanol gave an off-white solid which on recrystallisation from hot water gave 9-[3-(phosphonomethoxy)propoxy]guanine (267 mg, 83%) as a white crystalline solid; m.p. 247°-250° C.; νmax (KBr) 3320, 1693, 1646, 1370, 1250 cm-1 ; δH [(CD3)2SO] 1.90(2H, m, CH2CH2CH2), 3.57(2H, d, J8.5 Hz, CH2P), 3.67(2H, t, J6 Hz, CH2OCH2P), 4.32(2H, t, J6.6 Hz, NOCH2), 6.60(2H, br.s, D2O exchangeable, NH2), 7.95(1H, s, H-8), 10.63(1H, br.s, D2O exchangeable, NH); Found: C, 33.84; H, 4.60; N, 21.57%; C9H14N5O6P requires: C, 33.86; H, 4.42; N, 21.94%.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1.Br[CH2:39][C:40]1[C:48]2[N:47]=[C:46]([C:49]([O:51][CH3:52])=[O:50])[N:45](COCC[Si](C)(C)C)[C:44]=2[CH:43]=[CH:42][CH:41]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:3][CH:2]2[O:1][CH2:39][C:40]2[C:48]3[NH:47][C:46]([C:49]([O:51][CH3:52])=[O:50])=[N:45][C:44]=3[CH:43]=[CH:42][CH:41]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1nc2c(CBr)cccc2n1COCC[Si](C)(C)C
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COC(=O)c1nc2cccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)c2[nH]1

Procedure:
Analogously to Method D, 1.58 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 10f) and 1.43 g of methyl 4-bromomethyl-1-(2-trimethylsilanylethoxymethyl)-1H-benzoimidazole-2-carboxylate are reacted. The title compound is obtained as a colourless oil. Rf=0.23 (1:1 EtOAc-heptane); Rt=29.5 (II).
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:17](=O)([O-:19])[O-:18].[Ca+2].CO>O>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CO
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4'-methoxyphenyl)-propane (2.89 g; 0.01 mol), calcium carbonate (1 g; 0.01 mol), methanol (7 ml) and water (3 ml) is refluxed for 35 hours. The reaction mixture is then cooled to 25° C. and worked up as described in Example 1a, there is so obtained the title product (1.69 g; 0.0094 mol). Yield, 94%; m.p. 55° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C[Al](C)C.C1(C)C=CC=CC=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[C:22]([C:27](=[O:44])[NH:28][CH:29]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[C:30]([F:33])([F:32])[F:31])[N:23]2[CH3:26])=[CH:19][C:18]=1[C:45](OCC)=[O:46]>ClCCl.O>[CH2:1]([NH:4][C:45]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:17]=1[Cl:16])[N:23]([CH3:26])[C:22]([C:27]([NH:28][CH:29]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=1)[C:30]([F:31])([F:32])[F:33])=[O:44])=[CH:21]2)=[O:46])[CH:2]=[CH2:3]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(C)c2cc1Cl
Reactant: C=CCN
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCNC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(C)c2cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Allylamine (156 mg, 2.73 mmol) was dissolved in 3 ml of dichloromethane and admixed dropwise under argon with a solution of trimethylaluminium in toluene (2 M, 1.37 ml, 2.73 mmol). The mixture was stirred for 30 min, and then ethyl 6-chloro-1-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (165 mg, 0.27 mmol) dissolved in 3 ml of dichloromethane was added dropwise. The mixture was heated under reflux overnight and, after cooling to room temperature, water was added cautiously. The mixture was extracted with ethyl acetate, the organic phase washed with potassium sodium tartrate solution, dried over magnesium sulphate and filtered, and the filtrate concentrated under reduced pressure. The purification was effected by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% EA to 30% EA).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:20]([OH:22])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@H:2]([C:20]([OH:22])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:30]1[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: c1cscn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of Boc-Arg(Tos)-Thiazole (300 mg, 0.6 mmol) in CH2Cl2 (10 mL) at 0° C. was added TFA (10 mL). The solution was stirred at 0° C. for 2 h. The solvent and excess TFA were evaporated to an oily residue which was used directly without further purification in Example 6.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[C:5]1(=[O:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[OH-].[Na+]>CS(O)(=O)=O>[NH:1]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6][C:5]1=[O:15]
Reactant: O=C1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCCc2ccccc2N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
Sodium azide (1.95 g, 30 mmol) was added in small portions to a solution of 3,4-dihydro-1(2H)-naphthalenone (2.92 g, 20 mmol) in CH3SO3H (50 mL) at 0° C. The mixture was stirred at 0° C. for 15 min, 1 hr at room temperature, poured into ice (400 mL), basified until pH>8 with 1N NaOH at 0° C. and extracted with ether (3×100 mL). The combined organic layer was dried (MgSO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:1) gave 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.71 g, 85%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ2.18-2.32 (m, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (td, J=7.6, 1.5 Hz, 1H), 7.22 (d, J=7.0 Hz, 2H), 8.10 (br, 1H) ppm.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:17])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH3:19][NH2:20]>>[CH3:19][NH:20][C:3](=[O:2])[CH:4]([CH3:17])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: CN
Reactant: COC(=O)C(C)CNC(=O)OCc1ccccc1
Product: CNC(=O)C(C)CNC(=O)OCc1ccccc1

Procedure:
2.52 g of 3-benzyloxycarbonylamino-2(R,S)-methylpropionic acid methyl ester and 50 ml of 33% methylamine (in ethanol) are stirred at room temperature for 48 hours. The reaction mixture is concentrated by evaporation and the title compound is obtained from the residue by crystallisation from ethyl acetate: Rf (dichloromethane/methanol=95:5)=0.42; m.p. 128°-129° C.
Reaction SMILES: [C:1]12([C:11]([N:13]3[CH2:17][CH:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:27][CH2:26]4)[CH2:14]3)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]12([CH2:11][N:13]3[CH2:17][CH:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:27][CH2:26]4)[CH2:14]3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(C2CCN(CC3CN(CC45CC6CC(CC(C6)C4)C5)CC3c3ccccc3)CC2)cc1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 1-(1-adamantanecarbonyl)-3-(RS)-((4-phenyl)piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (10 mg, 0.021 mmol) in 2 mL of THF was added lithium aluminum hydride (2 mg, 0.042 mmol). The reaction was heated to reflux. After 2 hours the reaction was quenched with H2O (0.5 mL), 15% NaOH solution (0.5 mL), H2O (1.0 mL) and diluted with a saturated solution of Rochelle salts (50 mL) and CH2Cl2 (50 mL). After stirring for 1 hour the mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo to yield 9 mg of the title compound. Mass Spectrum (NH3 -CI): 469 (M+1).
Reaction SMILES: C([C:5]1[CH:9]=[C:8]([CH3:10])[S:7][C:6]=1[NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])(OC)=O.O.O.[I-].[Li+].CCOCC.Cl>N1C(C)=CC(C)=CC=1C>[CH3:10][C:8]1[S:7][C:6]([NH:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])=[CH:5][CH:9]=1
Reactant: COC(=O)c1cc(C)sc1NC(=O)C(C)C
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(C)C)s1
Yield: 86.7 %

Procedure:
N-(3-Carbomethoxy-5-methyl-2-thienyl)-2-methylpropanamide (4.1 g, 0.017 mol), prepared by the method of Example 48, was dissolved in hot collidine (10 ml) and added to a mixture of lithium iodide dihydrate (10.1 g, 0.06 mol) in collidine (20 ml) kept under nitrogen. The reaction mixture was stirred under reflux for 48 hours, cooled and equilibrated between ether (3 × 50 ml) and 5N-hydrochloric acid (50 ml). The ethereal solution was washed with water (25 ml), dried (Na2SO4) and evaporated to yield the required product as an off-white solid (2.7 g, 47%) m.p. 96°-97° C. The product was identical to the product described in Example 38.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14]#[C:15][Si](C)(C)C)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2.[OH-].[Na+].Cl>C(#N)C>[C:14]([C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:13])#[CH:15]
Reactant: COc1ccc2c(=O)[nH]ncc2c1C#C[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C#Cc1c(OC)ccc2c(=O)[nH]ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A suspension of 6-methoxy-5-trimethylsilanylethynyl-2H-phthalazin-1-one (2.87 g, 10.20 mmoles), prepared as described in example 139, in acetonitrile (50 ml) was added with 32% NaOH (15 ml) and stirred at room temperature for 1 hour. The mixture was neutralised with concentrated HCl and the precipitate filtered off. The aqueous phase was extracted with ethyl acetate, the organic phase was dried and taken up in acetone. The solid was filtered off and joined to the previous precipitate to give 1.99 g of the title compound (yield: 97.3%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:21]([NH:23][C:24]5[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=5)[C:27]([OH:29])=O)=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[NH:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1>>[NH:35]1[CH:39]=[CH:38][C:37]([NH:40][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([N:17]3[CH2:16][C:15]4[CH:14]=[N:13][C:12]5[NH:8][N:9]=[CH:10][C:11]=5[C:20]=4[CH2:19][CH2:18]3)=[O:22])[CH:32]=[CH:31][CH:30]=2)=[O:29])=[N:36]1
Reactant: Nc1cc[nH]n1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)O)c2)CC4)cc1
Product: O=C(Nc1cc[nH]n1)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1

Procedure:
The compound N-[3-(1H-pyrazol-3-ylcarbamoyl)phenyl]-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamide was prepared using 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid and 1H-pyrazol-3-amine as described in general procedure J. The compound was obtained as a solid. LCMS [M+H]: 403.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=O)[S:24][CH:25]=1>[OH-].[K+].CCO>[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])[S:24][CH:25]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2cc(Br)cs2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 43 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.252 g, 0.98 mmol) was reacted with 4-bromothiophene-2-carboxaldehyde (0.282 g, 1.5 mmol) in 5 mL of 4% KOH in EtOH to afford 0.181 g (43%) of the title compound as a light tan powder, mp 164-166° C.: CI-MS m/e 428, 430 (M+); 429, 431 M++1);
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([CH3:9])=[C:7]([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[F:22])OCC)[C:6](=[O:23])[NH:5]1)[CH3:3].CO.Cl.[H][H]>[Pd].C1COCC1.O>[CH3:3][CH:2]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[F:22])[C:6](=[O:23])[NH:5]1)[CH3:1]
Reactant: CCOC(c1ccc(OC)cc1F)c1c(C)n(C(C)C)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cc2c(C)n(C(C)C)[nH]c2=O)c(F)c1

Procedure:
A mixture of 1,2-dihydro-1-(1-methylethyl)-4-[(2-fluor-4-methoxyphenyl)-(ethoxy)methyl]-5-methyl-3H-pyrazol-3-one (294 g; 1.28 mol), methanol (4.5 L), aqueous hydrochloric acid (30%; 11 g) and water (80 mL) is hydrogenated with palladium on charcoal (10%-weight) (65 g) at 50° C. and 3 bar hydrogen pressure until hydrogen uptake ceases. THF (2.3 L) is added to the reaction mixture which is then filtered. The catalyst is washed with THF (1 L) and the solvent is distilled off under reduced pressure to a residual volume of approx. 700 to 800 ml. The resulting suspension is poured into water (1 L) with stirring. The precipitate is isolated by filtration, washed with water (400 ml) and dried at 55° C. to yield crystals (light beige).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]#[N:11])CC2)[CH:2]=1>CC(=O)OCC>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:10]#[N:11])[CH:2]=1
Reactant: Cc1cccc(C2(C#N)CC2)c1
Solvent: CCOC(C)=O
Product: Cc1cccc(CC#N)c1

Procedure:
After silica gel chromatography of the residue (HEP/EA gradient), an approximately 1:1 mixture of 1-m-tolyl-cyclopropanecarbonitrile and the starting compound m-tolylacetonitrile was obtained.
Reaction SMILES: C([O:3][PH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])C.[CH2:12]=[O:13].Cl>>[OH:13][CH2:12][P:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[OH:3]
Reactant: C=O
Reactant: CCO[PH](=O)c1ccccc1
Agent: Cl
Product: O=P(O)(CO)c1ccccc1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
100 g (0.5 moles) of phenylphosphinic acid ethyl ester are heated to 80° C., and 15 g (0.52) of paraformaldehyde are added in small portions. The paraformaldehyde addition is regulated so that the temperature does not exceed 110° C. by virtue of the exothermic nature of the reaction. When the addition is complete, the mixture is kept for about one hour under agitation at 110° C., and the termination of the reaction can be seen by gas chromatography or thin layer chromatography. 100 cc of a 10% HCl solution are then added, and the mixture kept at 80° C. for 30 min. The water and hydrochloric acid are then evaporated under vacuum, and the mixture taken up in isopropanol. On cooling, 69.3 g of hydroxymethylphenylphosphinic acid are obtained with a yield of 80.5% and a melting point of 138°-9° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([OH:16])[CH2:12][N:13]([CH3:15])[CH3:14])=[CH:2]1.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1>CC(C)=O>[CH3:14][N:13]([CH2:12][CH:11]1[O:16][C:17]([CH3:22])([CH3:18])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10]1)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH3:15]
Reactant: CN(C)CC(O)Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CN(C)CC1Cc2c([nH]c3ccccc23)C(C)(C)O1

Procedure:
A mixture of 1-(indol-3-yl)-3-(dimethylamino)propan-2-ol [9.5 g, 0.00435 mole, described by Z. G. Starostina et al., Khim.-Farm. Zh., 6, 14(1972) (Chem. Abstr., 78, 58185 r)] and p-toluenesulfonic acid (10 g, 0.0525 mole) in dry acetone (100 ml), is refluxed for 24 hours. The reaction mixture is evaporated and the residue is dissolved in water. The aqueous acidic solution is extracted with diethyl ether and the aqueous phase is basified with a saturated solution of sodium carbonate. The alkaline aqueous phase is extracted with diethyl ether and the organic extract is dried over magnesium sulfate, treated with charcoal and evaporated to give a residue of 3-[(dimethylamino)methyl]-1,3,4,9-tetrahydro-1, 1-dimethylpyrano[3,4-b]indole, a compound of formula II. The hydrochloride salt of the latter compound is crystallized from acetonitrite, mp 213°-215° C.
Reaction SMILES: [CH:1]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=O)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCc1ccccc1NC2
Yield: 72 %

Procedure:
To a suspension of 11,12-dihydro-5H-dibenzo[b,f]azocin-6-one (2.0 g, 8.96 mmol) in dry THF (20 ml) is added dropwise a solution of LiAlH4 (1.0 N in THF, 8.96 ml) over a period of 10 min. After ceasing of gas evolution, the reaction mixture is kept stirring at reflux overnight, then quenched by the addition of water (0.48 ml). The precipitate is filtered off and the filtrate is extracted twice with EtOAc. The combined organic layers are dried over Na2SO4, the solvent is evaporated and the residue recrystallized from boiling hexane to give off white crystals of the title compound (1.35 g) in 72% yield: tR (LC-2) 1.65 min; ESI-MS(+): m/z 210.70 [M+H]+ (calcd 209.29 for C15H15N).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][NH2:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C#N)cc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CC=C(c2c[nH]c3ccc(CN)cc23)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To an argon purged round bottom flask fitted with a condenser and magnetic stirbar containing 49 (105 mg, 0.442 mmol) was added lithium aluminum hydride (34 mg, 0.896 mmol) followed by absolute THF (5 mL). A small amount of gas was produced. Once no more bubbling occurred, the reaction was transferred to an oil bath heated to 75° C. The reaction was stirred at this temperature for 18 hrs. The reaction was then cooled to room temperature. The reaction was quenched with water (0.1 mL), 3N NaOH (0.1 mL) and water (0.3 mL) sequentially, followed by filtration through a celite plug. The plug was washed with THF and the filtrate concentrated to afford a yellow oil, compound 50 (106 mg, 99%). 1H NMR (DMSO) δ 10.95 (br s, NH), 7.74 (s, 1H), 7.32-7.31 (d, J=2.4 Hz, 1H), 7.30-7.27 (d, J=8.4 Hz, 1H), 7.08-7.05 (d, J=8.1 Hz, 1H), 6.14 (s, 1H), 3.77 (s, 2H), 3.29 (s, 2H), 3.06-3.05 (d, J=2.7 Hz, 2H), 2.57-2.56 (d, J=4.5 Hz, 2H), 2.51-2.50 (d, J=1.2 Hz, 2H), 2.29 (s, 3H), 1.75 (br s, 2NH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[C:6]([OH:12])[CH:5]=1.C(OC(OCC)OCC)C.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>C1C=CC=CC=1.CC(C)=O>[CH2:24]([O:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([OH:10])[C:7]=1[OH:11])[C:3]([O:2][CH3:1])=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCOC(OCC)OCC
Product: COC(=O)c1cc(O)c(O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.1 %

Procedure:
To a solution of methyl-3,4,5-trihydroxybenzoate (10.0 g, 54.3 mmol) and amberlyst (0.2 g) in 40 mL of benzene was added triethylorthoformate (32 mL, 270 mmol). The reaction mixture heated to reflux under Ar for 18 h. The reaction mixture was then filtered while hot and the filtrate was concentrated in vacuo. To the resulting oil was added 20 mL of acetone, benzyl bromide (38.7 mL, 326 mmol), and potassium carbonate (oven dried, 22.4 g, 163 mmol). The reaction mixture was heated to reflux under Ar for 20 h. This mixture was cooled, treated with triethylamine (37.3 mL, 272 mmol) and extracted with EtOAc. The organic layer washed sequentially with 10% H2SO4, H2O, and brine, and dried over Na2SO4. The solvents were removed in vacuo. To the remaining oil was added 20 mL of MeOH and TsOHH2O (100 mg, 0.5 mmol). This solution was stirred at rt under Ar for 20 h. The reaction mixture was cooled, concentrated in vacuo and extracted with EtOAc. The organic layer washed sequentially with NaHCO3, H2O, and brine and dried over Na2SO4. After filtration and concentration, the product was purified by flash chromatography using hexane followed by 25% EtOAc in hexane as eluent to yield 10 g (71%) of methyl 3-benzyloxy-4,5-dihydroxybenzoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/[O:15][CH2:16][CH3:17])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])/[C:5](/[O:15][CH2:16][CH3:17])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CCOC(=O)/C(=C/c1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)/C(=C/c1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 14 b], (Z)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-acrylic acid ethyl ester was reacted with 4-chloromethyl-2-(4-chloro-phenyl)-thiazole (example 14 a]) in the presence of cesium carbonate and potassium iodide to yield (Z)-2-ethoxy-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid ethyl ester as colorless crystals.