Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:19]2[C@@H:15]([O:16]C(C)(C)[O:18]2)[C@@H:14]([C:22]([OH:24])=[O:23])[O:13]1>C(O)=O>[NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:13][C@H:14]([C:22]([OH:24])=[O:23])[C@@H:15]([OH:16])[C@H:19]1[OH:18]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(N)nc(I)nc31)O[C@@H]2C(=O)O
Solvent: O=CO
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](O)[C@H]1O
Yield: 84.9 %

Procedure:
A solution of 1.72 g (3.85 mmol) of (2S,1 R,4R,5R)-4-(6-amino-2-iodopurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]octane-2-carboxylic acid (6.7) in 80 mL of 50% HCOOH was stirred at 80° C. for 1.5 hours. The reaction mixture was evaporated under reduced pressure, dissolved in H2O, and the solution was evaporated again. This process was repeated until there was no odor of formic acid in the residue. Recrystallization from water yielded 1.33 g (85%) 6.8 as a white solid, m.p. 221-223° C. dec. 1H NMR (300 MHz, DMSO-d6) δ8.31 (s, 1H, H-8), 7.68 (s, 2H, NH2), 5.90 (d, J=6.55 Hz, 1H, H-1′), 4.42 (m, 1H, H-2′), 4.35 (d, J=2.31 Hz, 1H, H-4′), 4.22 (m, 1H, H-3′).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12][CH2:13][C:14]#[N:15].C(N(C(C)C)CC)(C)C.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>ClCCl.CN(C1C=CN=CC=1)C>[C:14]([CH2:13][S:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])#[N:15]
Reactant: N#CCSc1ccc(C(F)(F)F)cc1N
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)Nc1cc(C(F)(F)F)ccc1SCC#N
Temperature: 0 °C
Reaction time: 24 h

Procedure:
(2-Amino-4-trifluoromethylphenylsulfanyl)acetonitrile (1.33 g) dissolved in dichloromethane (5 ml) was stirred on an ice bath at 0° C. Diisopropylethylamine (1 ml) and butyric acid chloride (0.9 ml) was added, and the resulting solution was allowed to reach room temperature. After 22 h more butyric acid chloride (0.9 ml) and DMAP (0.70 g) were added at 0° C. and stirring was continued at 40° C. for 24 h. The cold mixture was diluted with dichloromethane (20 ml), extracted with saturated aqueous sodium bicarbonate (10 ml), washed with water (2×50 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/heptane 1:1 as eluent. The title compound was obtained as a sirup. Yield 1.72 g (100%). The compound could be crystallised from ethyl acetate/heptane, mp 88.5-89.5° C.; El SP/MS: 302 (M+). 1H-NMR(CDCl3) δ (ppm): 8.85 (br, 1H), 8.38 (br, 1H), 7.28 (d, 1H), 7.38 (dd, 1H), 3.50 (s, 2H), 2.46 (t, 2H), 1.82 (sextet), 1.03 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C@:6]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[O:14][CH2:13][C:12]2[CH:11]=[C:10]([C:15]#[N:16])[CH:9]=[CH:8][C:7]1=2.[C:24]([OH:33])(=[O:32])[C@@H:25]([C@H:27]([C:29]([OH:31])=[O:30])[OH:28])[OH:26]>CO.O>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C@:6]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[O:14][CH2:13][C:12]2[CH:11]=[C:10]([C:15]#[N:16])[CH:9]=[CH:8][C:7]1=2.[C:29]([C@@H:27]([C@H:25]([C:24]([O-:33])=[O:32])[OH:26])[OH:28])([O-:31])=[O:30]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CNCCC[C@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Solvent: O
Solvent: CO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a desmethylcitalopram (1.2 g) solution in Methanol (15 ML) was added a solution of L-tartaric acid (0.58 g) in water (2 mL). The reaction mixture was stirred at room temperature for 1 h.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:28])[C:13]4[CH:14]=[N:15][N:16]([S:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45](Cl)=[O:46])[N:44]=1.O>C(Cl)(Cl)Cl>[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45]([NH:28][C:12]2[CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:46])[N:44]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1csc(CCl)n1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To solution of 6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-amine (1.5 g) in chloroform (20 ml) at 0° C. was added DIPEA (1.35 ml). 2-(Chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.8 g) in chloroform (20 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h 15 min. The mixture was allowed to warm to RT and stirring continued for 18 h. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (0.2 g) was added to the mixture which was stirred at RT for 30 min. Water (50 ml) was added and the mixture was extracted with DCM (2×100 ml), separating the layers using a hydrophobic frit. The organics were collected and solvent removed in vacuo to give a brown solid which was triturated with ether (10 ml). The solid was filtered and dried in a vacuum oven overnight to afford the title compound, 1.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)[N:3]=1.FC(F)(F)C(O)=O.[O:35]1[CH2:38][C:37](=O)[CH2:36]1.[Na]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:37]3[CH2:38][O:35][CH2:36]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(N3CCC(F)(F)C3)c2)CC1
Reactant: O=C1COC1
Agent: [Na]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CCN(c2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To an ice-cooled solution of tert-butyl 4-(2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyridin-4-yl)piperidine-1-carboxylate (0.220 g, 0.547 mmol, 1 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). After 2 h, the reaction mixture was concentrated in vacuo (25 mm Hg). The resulting residue was dissolved in dichloromethane (10 mL), and the solution was washed with saturated aqueous sodium bicarbonate solution (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in tetrahydrofuran (2 mL). Oxetan-3-one (0.112 mL, 1.10 mmol, 2.00 equiv) and sodium triaetoxyborohydride (366 mg, 1.64 mmol, 3.00 equiv) were sequentially added to the solution at 24° C. After 35 min, the reaction mixture was partitioned between ethyl acetate (10 mL) and saturated aqueous ammonium chloride solution (10 mL). The organic was separated and the aqueous layer was further extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (98:2 dichloromethane/methanol+0.1% ammonium hydroxide) furnished product as a clear oil (166 mg, 85% yield). 1H NMR (CDCl3, 400 MHz), δ: 6.54 (s, 1H), 6.07 (s, 1H), 4.67 (t, J=6.3 Hz, 2H), 4.63 (t, J=6.3 Hz, 2H), 3.82 (t, J=13.2 Hz, 2H), 3.66 (t, J=7.2 Hz, 2H), 3.50 (m, 1H), 2.86 (m, 2H), 2.38-2.52 (m, 3H), 1.72-1.94 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:1][N:2]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNCCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCNC(=O)OCc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl 2-(methylamino)ethylcarbamate (0.05 g, 0.24 mmol) in CH2Cl2 (5 mL was cooled to 6° C. and treated with triethylamine (0.1 mL, 0.72 mmol) and methanesulfonyl chloride (0.02 mL, 0.24 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction was washed with 10% KHSO4, the organic layer was dried over Na2SO4, filtered and evaporated to give the product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])=[O:4]
Reactant: O=C(NCCCCCCO)C(F)(F)F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CCCCCCNC(=O)C(F)(F)F
Temperature: 23 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To 2.1 gm (10.1 mmole) of the 6-trifluroacetamido-1-hexanol in 40 ml of methylene chloride was added 3 gm (10.64 mmole) of pyridinium dichromate and 4.4 gm of 3 Angstrom molecular sieves, and the reaction was allowed to proceed with stirring for 3 hours at 23° C. After addition of 250 ml of ethyl acetate, the reaction mixture was filtered through a small bed of silica gel 60 and concentrated in vacuo. Flash chromatography using 50% (v/v) ethyl acetate in hexane afforded 1.48 gms (70%) of 6-trifluroacetamido-1-hexanal. ##STR17##
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][NH2:7])[CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]3)=[N:17][N:16]2[CH:40]=1)=O)C>>[CH:1]1([CH2:4][CH2:5][CH2:6][NH:7][C:11]([C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C:28]5[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=5[C:35]([F:36])([F:38])[F:37])[CH2:23][CH2:22]4)=[N:17][N:16]3[CH:40]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Reactant: NCCCC1CC1
Product: O=C(NCCCC1CC1)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Yield: 46 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 3-(cyclopropyl)propylamine in place of isoamylamine to react with 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 46% yield (0.079 g). 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=0.6 Hz, 1H), 7.76-7.71 (m, 1H), 7.68 (d, J=9.9 Hz, 1H), 7.30-7.18 (m, 2H), 7.09-7.03 (m, 1H), 6.87 (d, J=9.9 Hz, 1H), 4.04-3.93 (m, 1H), 3.91-3.8 (m, 1H), 3.64-3.54 (m, 2H), 3.51-3.4 (m, 4H), 3.37-3.29 (m, 2H), 1.77-1.65 (m, 2H), 1.32-1.23 (m, 2H), 0.71-0.61 (m 1H), 0.42-0.37 (m, 2H), 0.08-0.03 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 165.9, 162.5, 162.3, 154.7, 138.4, 136.9, 135.6, 129.61, 129.6, 129.5, 126.4, 126.36, 125.0, 123.3, 122.9, 121.4, 118.1, 116.7, 116.5, 114.7, 114.57, 111.8, 46.2, 45.5, 41.2, 38.8, 31.9, 29.7, 10.4, 4.4. MS (ES+) m/z 519 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][N:20]([CH3:32])[C:21](=[O:31])[C:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:28]3[CH2:27][CH2:26][N:25]([C:22]([CH3:24])([CH3:23])[C:21]([N:20]([CH3:32])[CH3:19])=[O:31])[CH2:30][CH2:29]3)=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CN(C)C(=O)C(C)(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.8 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (146 mg, 0.42 mmol) in DMF (5 mL) were added N,N-dimethyl-2-piperazin-1-yl-isobutyramide (100 mg, 0.50 mmol), cesium carbonate (273 mg, 0.837 mmol) and water (23 μL, 1.26 mmol). The resulting mixture was stirred at RT for 17 h. The reaction mixture was loaded directly onto an Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography to give the title compound as an off-white solid (131mg, 67%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2=[O:23])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:24](Cl)(Cl)(=[O:26])=[O:25].CCN([CH:35]([CH3:37])[CH3:36])C(C)C>C(Cl)(Cl)Cl>[CH:1]1([CH2:7][C@H:8]([N:17]2[CH2:22][CH2:21][N:20]([S:24]([C:36]3[CH:35]=[CH:37][C:6]4[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=4)[CH:7]=3)(=[O:26])=[O:25])[CH2:19][C:18]2=[O:23])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CCNCC1=O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1=O

Procedure:
A solution of compound 12F (16.8 mg, 0.05 mmol), sulfonyl chloride (0.06 mmol) and DIEA (17.4 μl, 0.10 mmol) in CHCl3 (200 μl) was maintained at ambient temperature for 30 minutes. Solvents were removed in vacuum. Residue was dissolved in 200 μl of DMSO and subjected to HPLC purification. [Chromolith SpeedRod RP-18e C18 column (4.6×50 mm); flow rate 1.5 ml/min; mobile phase A: 0.1% TFA/water; mobile phase B 0.1% TFA/ACN; gradient elution from 5% B to 100% B over 9.5 min, detection 254 nm]. Fractions containing the desired product were combined and dried to provide trifluoroacetic salt of target product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Si]([C:18]#[N:19])(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-].O=P(Cl)(Cl)Cl>N1C=CC=CC=1.C1C=CC=CC=1>[C:18]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH:7]=1)#[N:19]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cccc2c1CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cccc2c1CCC=C2C#N
Temperature: 25 °C

Procedure:
A solution of 5-methoxy-1-tetralone (52.0 g, 0.29 mole, Aldrich), TMSCN (51 mL, 0.38 mole, Aldrich), 40 mL dry benzene, and catalytic AlCl3 was stirred under N2 at 65° C. for 1 hour. The reaction mixture was cooled and evaporated to dryness. To the residue was added 300 mL pyridine and POCl3 (80 mL, 0.88 mole). The reaction mixture was stirred at reflux for 2 hours, then was cooled to room temperature and was poured onto ice/concentrated HCl. A precipitate was collected, washed with water, and purified by column chromatography (silica gel/CH2Cl2) to obtain 54 g (73%); M+ 185.
Reaction SMILES: O.[OH:2][C:3]1[C:11]2[N:10]=NNC=2C=C[CH:4]=1.CN1CCOCC1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[C:35]([OH:37])=O)(=[O:28])=[O:27])=[CH:22][CH:21]=1.NC(C)CO>C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[C:35]([NH:10][CH2:11][CH:3]([OH:2])[CH3:4])=[O:37])(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Agent: CC(N)CO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(O)CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
Hydroxybenzotriazole hydrate (297 mg), (3-dimethylminopropyl)-3-ethylcarbodiimide (421 mg) and N-methylmorpholine (241 ml) were added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (575 mg) [see Preparation 38]. The reaction mixture was stirred for 15 mins, then 2-aminopropanol (170 ml) was added and stirring continued for 18 hrs at room temperature. The mixture was then diluted with ethyl acetate and washed with 2M aqueous hydrochloric acid, saturated sodium hydrogen carbonate and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-N2-(2-hydroxypropyl)-2-piperidinecarboxamide (555 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:23][C:24]#[N:25]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22](/[C:23](=[CH:5]/[C:4]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:2]([F:1])[CH:3]=2)/[C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COCCOCCl
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COCCOCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1F
Yield: 77.4 %

Procedure:
The hydroxyl group of 3-fluoro-4-hydroxybenzaldehyde (3.92 g) was protected by use of 2-methoxyethoxymethyl chloride (3.49 g) in accordance with (production process 1), to thereby produce an MEM form (4.98 g, yield: 78%). The resultant MEM form (4.98 g) and 3,4-dimethoxybenzyl cyanide (3.87 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (6.55 g, yield: 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-])=O.CC(O)C.Cl.[H][H]>[Pd].CO>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH2:13])[CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CCCCc1ccc(C)c(N)c1

Procedure:
A mixture of 34 parts of 1-(4-methyl-3-nitrophenyl)-1-butanone, 24 parts of 2-propanol saturated with hydrochloric acid and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. Water is added to the residue and the whole is alkalized with ammonium hydroxide. The product is extracted with 2,2'-oxybispropane. The extract is dried, filtered and evaporated, yielding 25.5 parts of 5-butyl-2-methylbenzenamine as a residue.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[CH2:7][CH:8]=[C:9]([F:15])[CH2:10][CH2:11][CH2:12][CH:13]=[O:14].[BH4-].[Na+].CC(C)=O.C(O)(=O)C>CO>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[CH2:7][CH:8]=[C:9]([F:15])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: O=CCCCC(F)=CCC1SCCCS1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: OCCCCC(F)=CCC1SCCCS1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The aldehyde prepared in 2G (0.937 g, 3.77 mmoles) was dissolved in methanol (20 ml) and cooled to 0° C. Sodium borohydride (0.071 g, 1.87 mmoles) was added and the mixture was stirred 30 min. Acetone was added to react with an excess of sodium borohydride and then the reaction mixture was acidified with acetic acid. The solvents were evaporated under reduced pressure. The residue was diluted with ether and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title alcohol as an oil in a quantitative yield. NMR (H1, CDCl3, 60MHz) characteristic peaks 4 (t, JHH =7 Hz, 1), 5.1 (dt, JHF =21 Hz, JHH =8 Hz, 1).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:10][CH2:11][CH2:12][Si:13]([O:17][CH3:18])([O:15][CH3:16])[CH3:14]>C(OCC)C>[CH3:1][C:2]1[CH:6]=[CH:5][CH:4]([CH2:10][CH2:11][CH2:12][Si:13]([O:17][CH3:18])([O:15][CH3:16])[CH3:14])[CH:3]=1
Reactant: CO[Si](C)(CCCCl)OC
Reactant: CC1=CC=CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CO[Si](C)(CCCC1C=CC(C)=C1)OC
Yield: 89 %

Procedure:
33.4 g (417 mmol) of freshly distilled methylcyclopentadiene are added dropwise to a suspension of 10 g (417 mmol) of sodium hydride in 250 ml of absolute diethyl ether at RT over a period of one hour. 76.1 g of (3-chloropropyl)dimethoxy-methylsilane are subsequently added dropwise over a period of 30 minutes. The solution becomes warm during this process. After taking off the solvent, the mixture is fractionally distilled in an oil pump vacuum to give 78.9 g of (3-methylcyclopentadienylpropyl)dimethoxy-methylsilane (yield: 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.[NH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:36]=O)[C:30]=2[CH:29]=[CH:28]1>>[CH3:25][C:22]1([CH3:26])[CH2:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH:1][CH2:36][C:31]5[CH:32]=[CH:33][CH:34]=[C:35]6[C:30]=5[CH:29]=[CH:28][NH:27]6)=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[C:24]=2[O:23]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC1(C)Cc2cccc(N)c2O1
Product: CC1(C)Cc2cccc(Nc3ccc4c(NCc5cccc6[nH]ccc56)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=435.3 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) and indole-4-carboxaldehyde as described in example 26.
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18].[Na].[N-:20]=[N+:21]=[N-:22].[Cl-].[NH4+]>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]4[NH:22][N:21]=[N:20][N:16]=4)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18]
Reactant: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1sc2nc3ccc(-c4nnn[nH]4)cn3c(=O)c2c1C

Procedure:
From 0.43 g (0.0017 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 32), 0.33 g (0.0051 mol) of sodium size azide and 0.3 g (0.0056 mol) of ammonium chloride in 80 ml of dimethylformamide, following the procedure of Example 34, there is obtained 0.14 g of 2,3-dimethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one with pyridine (1:0.6); mp 292°-294° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][P:8](Cl)Cl.Cl.[OH2:12]>>[CH3:7][P:8]1(=[O:12])[CH2:3][CH:2]([CH3:4])[C:1](=[O:6])[O:5]1
Reactant: C=C(C)C(=O)O
Reactant: O
Reactant: CP(Cl)Cl
Agent: Cl
Product: CC1CP(C)(=O)OC1=O
Reaction time: 1 h
Yield: 85.1 %

Procedure:
86 g (1 mol) of methacrylic acid were added dropwise to 117 g (1 mol) of methyldichlorophosphine at a temperature from 40° to 45° C. The mixture was stirred for 1 hour at said temperature. Phosphinic-carboxylic acid dichloride was then decomposed with 18 ml of H2O at a temperature of from 40° to 60° C., whereby a considerable formation of hydrogen chloride occurred. The residual quantity of hydrogen chloride in the reaction mixture was removed in a water-jet vacuum at 150° C. The residue was distilled under reduced pressure. 126 g of 2,4-dimethyl-2,5-dioxo-1,2-oxa-phospholane were obtained, which corresponds to a yield of 85.1% of the theory.