Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:42])=[CH:28][C:29]([F:41])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:42])=[CH:28][C:29]([F:41])=[C:30]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: CN(C)CCNS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 mg, 1.0 mmol) and 5-bromo-N-(2-dimethylamino-ethyl)-2,4-difluoro-benzenesulfonamide (example B.36) (446 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (300 mg, 50%). MS (ISP) 600.2 [(M+H)+]; mp 165–166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]1[CH2:11][CH:10]([C:12](OCC)=[O:13])[CH2:9][C:8]1=[O:17].[BH4-].[Na+].[BH4-].C(O)(=O)C>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9][C:8]1=[O:17]
Reactant: CCOC(=O)C1CC(=O)N(Cc2ccc(OC)c(OC)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccc(CN2CC(CO)CC2=O)cc1OC
Reaction time: 0.33 h

Procedure:
8.0 g of 1-(3,4-dimethoxybenzyl)-4-ethoxycarbonyl-pyrrolidin-2-one were dissolved in 100 ml of methanol. Over a period of 20 minutes, at 0°-10° C., a solution of 2.8 g of sodium borohydride in 30 ml of water was added dropwise, while mechanically stirring, and the mixture was stirred for 5 hours more at 0°-10° C. The excess borohydride was then carefully decomposed by the addition of glacial acetic acid up to a pH of 5 and until the development of gas had ceased, and the methanol was distilled off in vacuo. Some water was added, and the reaction product was taken up in methylene chloride. The methylene chloride phase was then washed with water, dried and evaporated. The residue was chromatographed on silica gel (eluant: methylene chloride/methanol 98:2). Finally, 4.8 g (62% of theory) of the title compound were obtained from the eluate.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:10][F:11])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].[OH-:12].[Na+].S(O)(O)(=O)=O.[NH2:19]O>CCO.O>[F:1][CH2:2][C:3]([C:4]1[CH:5]=[C:6]([NH2:7])[O:12][N:19]=1)([CH3:9])[CH2:10][F:11]
Reactant: [OH-]
Reactant: NO
Reactant: CC(CF)(CF)C(=O)CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(CF)(CF)c1cc(N)on1
Temperature: 100 °C
Yield: 17.5 %

Procedure:
To a solution of 5-fluoro-4-(fluoromethyl)-4-methyl-3-oxopentanenitrile (1.00 g, 6.2 mmol) and NaOH (0.272 g, 6.8 mmol) in EtOH (5 mL) and water (5 mL) at room temperature was added a solution of hydroxylamine sulfate (1.12 g, 6.8 mmol) in water (5 mL). To the mixture was added additional NaOH until the pH was about 8. After heating at 100° C. for 2 hours, it was quenched with water and extracted with CH2Cl2. Extracts were washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with with gradient of 0-50% EtOAc/hexane to afford 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-amine as a solid (0.191 g, 17%). 1H NMR (300 MHz, CDCl3) δ 5.16 (s, 1H), 4.63 (q, 2H), 4.5 (q and br, 4H), 1.37 (s, 3H); LC-MS (ESI) m/z 177 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][CH:6]([O:8][C@H:9]([CH3:17])[C:10](OCC(C)C)=[O:11])[CH3:7])[CH3:4].CO.O>ClC1C=CC=CC=1>[CH2:3]([O:5][CH:6]([O:8][C@H:9]([CH3:17])[CH2:10][OH:11])[CH3:7])[CH3:4]
Reactant: CCOC(C)O[C@H](C)C(=O)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Clc1ccccc1
Product: CCOC(C)O[C@H](C)CO
Yield: 78.3 %

Procedure:
1.85 g of sodium borohydride was suspended at room temperature in a solution of 7.52 g of the isobutyl (R)-(+)-2-(1-ethoxyethoxy)propionate (obtained in Reference Example 3) dissolved in 30 ml of chlorobenzene. Thereto was dropwise added slowly 7.3 ml of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 5 hours. to give rise to a reaction. After the reaction, thereto was added 60 ml of water, followed by extraction with 120 ml of ethyl acetate. The water layer was subjected to extraction with 60 ml of ethyl acetate. The two organic layers were combined and washed with a saturated aqueous sodium chloride solution. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 4.0 g (yield: 90.8%) of an oily title compound (diastereomixture).
Reaction SMILES: C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(O)=[O:6].[CH2:30]1[CH2:35][CH2:34][CH:33]([N:36]=[C:37]=[N:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:32][CH2:31]1.ON1C(=O)CCC1=O>CN(C=O)C>[C:37]([NH:36][CH:33]1[CH2:32][CH2:31][CH2:30][CH2:35][CH2:34]1)([NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C

Procedure:
To cholic acid (2 gm, 4.9 mmol) in anhydrous DMF (20 mL), under argon at room temperature, are added DCC (1 gm, 4.9 mmol) and N-hydroxysuccinimide (0.56 gm, 4.9 mmol). The reaction mixture is stirred at room temperature. Dicyclohexylurea starts forming after about 45 min. After 3.5 hours, the dicyclohexylurea is filtered, and the reaction mixture is concentrated under vacuum (using a vacuum pump) overnight to remove DMF. The residue is triturated with Et2O, and the precipitate is filtered. The precipitate is taken up in CH3CN, and the precipitate (left over dicyclohexylurea) is again filtered. Quantitative yield of product is obtained (2.5 gm). TLC (5% MeOH/EtOAc) Rf 0.26. 1HNMR (MeOH-d4): δ(ppm)=0.65 (s, 3H, 10axial CH3); 0.84 (s, 3H, 13axial CH3); 0.97 (d, 3H, CH3 on side chain); 2.78 (s, 4H, NHS protons).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1>C(O)C>[C:11]1([C:10]2[C:3]3[C:2]([C:27]4([CH2:30][OH:31])[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Reactant: OCC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCC1(c2ncnc3scc(-c4ccccc4)c23)CCNCC1
Temperature: 50 °C
Yield: 93.3 %

Procedure:
4-Chloro-5-phenyl-thieno[2,3-d]pyrimidine (1 g, 4.05 mmol) was dissolved in ethanol (15 ml) to give a yellow solution. To this was added triethylamine (1.7 ml, 12.2 mmol) and 4-piperidinemethanol (0.58 g, 5 mmol). The reaction mixture was heated to 50° C. and stirred for 1.5 hours until no 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine was present by TLC. The reaction mixture was allowed to cool to room temperature before being poured over ice water (50:50 mix). The resultant precipitate was collected by filtration to give the product as a pale yellow solid (1.23 g, yield 90%). LCMS: RT=4.05 min, M+1=326.
Reaction SMILES: O1[C:5](=O)[CH:4]=[NH+:3][N-:2]1.[C:7]([Sn:9]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])#[CH:8].[C:22]1(C)[C:23](C)=[CH:24][CH:25]=[CH:26][CH:27]=1>CCCCCC>[CH3:5][C:4]1[CH:8]=[C:7]([Sn:9]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:18][CH2:19][CH2:20][CH3:21])[N:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:3]=1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccccc1C
Reactant: O=c1c[nH+][n-]o1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)nn1-c1ccccc1
Reaction time: 16 h

Procedure:
N-Phenylalanine (825 mg) in 1,2-dimethoxyethane (20 ml) was treated with n-butyl nitrite (0.64 ml) and the mixture was stirred for 2.5 h and then the solvent was removed to leave crude N-nitroso-N-phenylalanine. This was dissolved in dichloromethane (10 ml), cooled in an ice-bath and treated with trifluoroacetic anhydride (1.06 ml). The mixture was stirred for 1 h and then the solvents were removed, toluene was added and removed using a rotary evaporator. The residue was chromatographed on silica gel eluting with ethanol/chloroform mixtures to give the sydnone (1 g), υmax(CH2Cl2) 1803(sh), 1763(sh), 1734, 1485, 1243, and 1065 cm−1; δ(CDCl3) 2.16 (3H,s), 7.51-7.73 (5H, m); Found m/z 176.0590; C9H8N2O2 requires 176.0586. The sydnone in xylene (8 ml) was treated with ethynyltributylstannane and the mixture was heated under reflux for 8 h. After standing for 16 h at room temperature the mixture was diluted with hexane(15 ml) and loaded onto silica gel and eluted with hexane (100 ml) followed by hexane/ethyl acetate mixtures to give 5-methyl-2-phenyl-3-(tri-n-butylstannyl)pyrazole (602 mg), δ(CDCl3) 0.87-1.76 (27H, m), 2.35 (3H, s), 6.25 (1H, s), 7.26-7.47 (5H, m); Found m/z 448.1900. C22H36N2Sn requires 448.1900.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[N:2].[NH2:22][OH:23]>C(O)C>[NH2:2][C:1](=[N:22][OH:23])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[C:5]([CH2:20][CH3:21])[CH:4]=1
Reactant: CCc1cc(C#N)ccc1CN(C)CC(=O)OC(C)(C)C
Reactant: NO
Solvent: CCO
Product: CCc1cc(C(N)=NO)ccc1CN(C)CC(=O)OC(C)(C)C
Yield: 103.4 %

Procedure:
A solution of tert-butyl N-(4-cyano-2-ethylbenzyl)-N-methylglycinate (570 mg, 1.98 mmol) and 50% aqueous hydroxylamine (0.6 mL, 10 mmol) in ethanol (10 mL) was heated at 80° C. for 18 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was passed through a hydrophobic frit and evaporated in vacuo to afford the title compound (658 mg, quantitative). 1H NMR (CDCl3, 400 MHz) δ 7.46 (1H, s), 7.39 (2H, s), 4.85 (2H, br s), 3.73 (2H, s), 3.16 (2H, s), 2.73 (2H, q, J=7.6 Hz), 2.37 (3H, s), 1.47 (9H, s), 1.25-1.19 (3H, m).
Reaction SMILES: CO[C:3]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])(C)C)=[CH:12][C:4]=1CP(=O)(OC)OC.[H-].[Na+].[C:22]1([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:25](C=O)=[CH:24][CH:23]=1.O.CN([CH:42]=[O:43])C>CCOCC>[CH3:42][O:43][C:37]1[C:36]([CH:19]=[CH:16][C:13]2[CH:12]=[CH:4][CH:3]=[CH:15][CH:14]=2)=[CH:35][C:34]([C:13]([CH3:16])([CH3:14])[CH3:12])=[CH:33][C:32]=1[CH:31]=[CH:30][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(C=Cc2ccccc2)cc1
Reactant: CN(C)C=O
Reactant: COc1ccc(C(C)(C)C)cc1CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1c(C=Cc2ccccc2)cc(C(C)(C)C)cc1C=Cc1ccccc1
Yield: 73 %

Procedure:
A suspension of dimethyl 2-methaxy-5-tert-butylbenzylphosphonate (11) (1.01 g, 3.53 mmol) and sodium hydride (60% in oil, 0.17 g, 4.25 mmol) in dry DMF (29 ml) was cooled with stirring co 6° C. under argon. A solution of 4-stilbenecarbaldehyde (12) (0.88 g, 4.23 mmol) in dry DMF (21 ml) was added dropwise with stirring keeping the reaction temperature at 5° C. and then the reaction mixture was stirred at room temperature for 3.75 h under argon. Water (100 ml) and ether (300 ml) were added. The organic layer was separated, washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/hexane; 1:1) and recrystallised from dichloromethane/hexane/methanol to yield a pale yellow solid of (8) (0.95 g, 73%), m.p. 129°-129.5° C.; (Found: C, 88.06; H, 7.62. C27H28O requires C, 88.00; H, 7.66%); λmax /nm (CH2Cl2) 362 (log ε 4.72); 8H (CDCl3) 1.36 (9 H, s, tert-butyl), 3.88 (3 H, s, OCH3), 6.85 (1 H, d, JH4,H3 =8.6 Hz, H3), 7.13 (1 H, d, J=16.5 Hz, vinytic H), 7.125 (1 H, s, vinytic H), 7.26 H, m, H4"), 7.28 (1 H, dd, JH4 =8.6 Hz, JH6,H4 =2.44 Hz, H4), 7.37 (2 H, m, H3" and H5"), 7.53 (7 H, m, H2", H6", H2', H3', H5', H6', and vinylic H), 7.56 (2 H, m, H2' and H6') and 7.62 (1 H, d, JH4,H3 =2.4 Hz, H6); δC (CDCl3) 31.5 (CH3), 34.1 [C(CH3)3 ], 55.6 (OCH3), 110.5, 123.5,124.0, 125.6, 126.5, 126.7, 126.8, 127.5, 128.2, 128.4, 128.7, 136.3, 137.4, 137.5, 143.3 and 154.8; m/z 368.214.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[O:19][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: COC(=O)CCc1c(O)cccc1OCCCCCO
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCOc1cccc(OCCCCCO)c1CCC(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.3 %

Procedure:
A mixture of the 2-hydroxy-6-[(5-hydroxypentyl)oxy]benzenepropanoic acid methyl ester from the preceding example (1.4 g; 4.96 mmol), 1.13 g (5.4 mmol) of ethyl 5-bromovalerate, 1.57 g (11.4 mmol) of anhydrous, granular potassium carbonate, and 12 mL of dimethyl sulfoxide was stirred at room temperature for 6 hr. The resulting slurry was filtered with suction and the solids were washed well with ethyl acetate. The filtrate and washed were combined and treated with water. Work-up with ether in the usual manner gave an oily product which was purified by chromatography on silica gel. Elution with 1:3 hexane-ether afforded 1.0 g (49.3%) of 6-[(5-hydroxypentyl)oxy]-2-(5-ethoxy-5-oxopentyloxy)benzenepropanoic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[N+:27]([O-:30])([OH:29])=[O:28].CCCCCCC>CC(C)=O>[CH3:1][C:2]([O:4][C:5]1[S:9][C:8]2[CH2:10][CH2:11][N:12]([CH:14]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[CH2:13][C:7]=2[CH:6]=1)=[O:3].[N+:27]([O-:30])([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Agent: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Solvent: CCCCCCC
Solvent: CC(C)=O
Product: O=[N+]([O-])[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 251 mg of prasugrel base form I in 3.75 ml acetone at room temperature (20-25° C.), a solution of 50.6 l (1.1 eq) 65% aqueous nitric acid in 1.25 ml acetone was added in portions and the resulting mixture was stirred at room temperature for about 15 minutes. After addition of 5 ml heptane at 0-5° C. (ice bath), the clear reaction mixture turned to an emulsion (clear oil drops on the bottom of the flask). A white precipitate was obtained after storage for 17 hours at about −25° C. The mixture containing the precipitate was stirred for 1 hour at 0-5° C. (ice bath), filtered off, washed with 1 ml cold acetone/heptane (1:1) and dried at 40° C./10 mbar for about 2.5 hours. White crystals (269 mg) of prasugrel nitrate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[Cl:32])[C@H:12]([CH3:24])[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][S:17][CH:16]2CC(O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:33].[K+].[CH3:35][OH:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[Cl:32])[C@H:12]([CH3:24])[CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][S:17][CH:16]2[C:35]([OH:36])=[O:33])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@H](CCN1CCSC1CC(=O)O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CO
Reactant: [OH-]
Agent: [K+]
Product: C[C@H](CCN1CCSC1C(=O)O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a stirring solution of 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(2-carboxymethyl-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide (109 mg, 0.203 mmol) in methanol (20 mL) was added 50% aqueous KOH (1.0 mL) and the mixture was stirred at room temperature for 18 hours. The solvent was removed and the crude mixture was dissolved in CH2Cl2 and washed with 1N HCl. The CH2Cl2 layer was dried over Na2SO4 and evaporated to give crude product. Purification was performed over silica gel using 5-10% methanol in CH2Cl2 with 0.5% NH4OH to afford 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(2-carboxy-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide as a beige foam in 66% yield. IR (KBr) 1467, 1351, 1167, 1094, 753, 622 cm−1; MS (ESI+), 523 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1)=[CH2:2].C1COCC1.[OH-].[K+]>CO>[CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1)=[CH2:2]
Reactant: C=Cc1sc(C(=O)OC)cc1-c1cnc2cccnn12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1sc(C(=O)O)cc1-c1cnc2cccnn12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Methyl 5-ethenyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylate (130 mg, 0.456 mmol) was dissolved in methanol (2.28 mL) and THF (2.28 mL) and 1M KOH in MeOH (1.38 mL, 1.38 mmol) was added to the mixture. The solution was left to stir at 60° C. for 18 h. The reaction was cooled to room temperature and concentrated under reduced pressure. 1N HCl was added to the residue and the precipitate filtered. The precipitate was then dried under high vacuum affording the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 13.37 (s, 1H, br); 8.62 (d, 1H); 8.23 (d, 1H); 8.07 (s, 1H); 7.96 (s, 1H); 7.33 (dd, 1H); 6.91 (dd, 1H); 5.84 (d, 1H); 5.41 (d, 1H). LRMS (APCI) calc'd for (C13H9N3O2S) [M+H]+, 272.0. found 272.0.
Reaction SMILES: [C:1]([S-:3])#[N:2].[Na+].Cl[CH:6]([CH2:10][CH2:11][Cl:12])[C:7](=O)[CH3:8].[Cl-:13].[Na+]>C(OCCCC)(=O)C.O>[Cl:13][C:1]1[S:3][C:6]([CH2:10][CH2:11][Cl:12])=[C:7]([CH3:8])[N:2]=1
Reactant: [Cl-]
Reactant: N#C[S-]
Reactant: CC(=O)C(Cl)CCCl
Agent: [Na+]
Solvent: O
Solvent: CCCCOC(C)=O
Product: Cc1nc(Cl)sc1CCCl
Temperature: 10 °C
Yield: 66 %

Procedure:
83 g (1.024 moles) of sodium rhodanide are added to a solution of 155.5 g (1 mole) of 3,5-dichloro-2-pentanone in 1 litre of butyl acetate. The suspension is stirred for 4 hours in hot water bath. After cooling the sodium chloride formed is filtered off and the filtrate is washed 3 times with water and dried over sodium sulfate. After filtering off the drying agent the light red-brown filtrate is cooled under 10° C. by icy water and saturated with gaseous hydrochloric acid under stirring, keeping the temperature under 10° C. After saturation the reaction mixture is stirred for further 20 minutes under cooling, then the temperature is increased slowly to 40° C. The reaction mixture is stirred at this temperature for 20 minutes and poured onto ice after cooling down to room temperature. The phases are separated, the aqueous phase is shaken with 150 cm3 of butyl acetate. The combined butyl acetate solutions are washed neutral with water and 5% sodium hydrogen carbonate solution, then dried over sodium sulfate. After distilling off the solvent the residue is distilled off under reduced pressure to obtain 121 g (66%) of 2-chloro-4-methyl-5-(2-chloroethyl)-thiazole in the form of pale yellow oil, which is identical in every respect with the product obtained in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[C:8]([O:9][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(O)cccc1-c1nc2ncccc2[nH]1
Product: COc1c(OS(C)(=O)=O)cccc1-c1nc2ncccc2[nH]1

Procedure:
Prepared analogously to Example 1 from 2-(2'-methoxy-3'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and methanesulfonic acid chloride.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[S:3]1.I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C(Cl)Cl>C(N(CC)CC)C>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([C:15]#[C:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[S:3][CH:2]([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[CH:18][CH:19]=1)[CH3:25]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)S2
Reactant: CCOC(=O)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)S3)cc1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
A solution of 55 mg (0.26 mmol) of 2,4,4-trimethyl-6-ethynyl-thiochroman (Compound 55) and 70.5 mg (0.26 mmol) of ethyl 4-iodo benzoate (29) in 1.5 ml of distilled triethylamine was placed in a heavy walled tube. Argon was bubbled through the mixture for 20 minutes under slightly reduced pressure. To the mixture was added 18 mg (0.051 mmol) of bis triphenylphosphine palladium (II) chloride and 9.7 mg (0.051 mmol) of cuprous iodide. The tube was then sealed and the mixture was stirred at 55 degrees C. for 72 hours. The mixture was then cooled to room temperature. The reaction mixture was diluted wth CH2Cl2 and treated with a small amount of silica. The solvent was then removed in-vacuo and the residue was subjected to flash chromatography (silica; 1.5% EtOAc/Hexanes) to give the title compound as a white crystalline solid. PMR(CdCl3): 1.25 (3H, s), 1.35 (3H, d, J=6.6 Hz), 1.37-1.44 (6H, m), 1.75 (1H, t, J=13 Hz), 1.88 (1H, dd, J=13 Hz, 3.5 Hz), 3.40-3.50 (1H, m), 4.38 (2H, q, J=7Hz), 7.17 (1H, dd, J=8.1 Hz, 1.8 Hz), 7.26 (1H, d, J=1.5 Hz), 7.33 (1H, J=8.1 Hz), 7.55 (2H, d, J=8.4 Hz, 8.01 (2H, d, J=8.4 Hz).
Reaction SMILES: CO[C:3](=[O:23])[C:4]([OH:22])=[CH:5][C:6](=[O:21])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:32][N:33](C)[C:34](C1CN(C)C(=O)C=1O)=O>>[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:32][N:33]([CH3:34])[C:3](=[O:23])[C:4]=2[OH:22])=[O:21])=[CH:16][CH:15]=1)(=[O:20])[CH3:19]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(NC(C)=O)cc1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(NC(C)=O)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 43 %

Procedure:
3-[(4-Acetylaminobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 63-D) was treated with paraformaldehyde and methylamine as described in the preparation Compound 12 to give the title compound as a white solid (43% yield); mp 110° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.18 (3H, s, COCH3), 3.1 (3H, s, NCH3), 3.71 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.83 (2H, s, NCH2), 7.29 (2H, d, J=8.6 Hz, aromatics), 7.34 (1H, broad s, NH), 7.50 (2H, d, J=8.6 Hz, aromatics). HRMS (ES+) calculated for C16H20N3O5: [M+H]+: 334.140296. found: 334.139137.