Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[C:6]([F:11])[CH:5]=1)(=[O:3])[CH3:2].Cl.[N+:13]([O-])([O-])=O.[Na+].[S:18](=[O:20])=[O:19]>O.C(O)(=O)C.O.O.[Cu](Cl)Cl>[C:1]([C:4]1[CH:10]=[CH:9][C:7]([S:18]([NH2:13])(=[O:20])=[O:19])=[C:6]([F:11])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)c1ccc(N)c(F)c1
Reactant: O=S=O
Agent: Cl[Cu]Cl
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc(S(N)(=O)=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a solution of 4-acetyl-2-fluoroaniline (5.0 g, 32.6 mmol, Krueger, G et al., Arzneim Forsch, 34, 11a, 1612 (1984)) in conc-HCl (24.0 mL), sodium nitrate (2.9 g, 42.4 mmol) in water (10 mL) was added at 0° C. After stirring for 1 h, the resultant yellow solution was added slowly to the suspension of copper (II) chloride dihydrate (1.7 g, 9.8 mmol) and sulfur dioxide (10 g, 156 mmol) in acetic acid (25 mL) at 0° C. The mixture was stirred for 30 min at 0° C. and poured into ice water (200 mL) and extracted with CH2Cl2 (80 mL×2). The extracts was cooled to 0°0 C. and 25% aqueous ammonia (70 mL) was added slowly and stirred for 1 h at room temperature. The mixture was concentrated and the residual solid was suspended with ether and collectted by filteration to give the title compound (3.3 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[C:12]([N:14]1[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:17]=2[CH:16]=[CH:15]1)=[O:13])[C:5]([OH:7])=[O:6]
Reactant: CCC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of methyl 3,5-dichloro-4-{[4-(propanoylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoate (250 mg, 0.59 mmol) and sodium hydroxide (23 mg, 0.59 mmol) in tetrahydrofuran and water (1:1) was stirred at room temperature for about 1 hour. Tetrahydrofuran was removed in vaccuo and aqueous layer was diluted with water (5 mL) and acidified with hydrochloric acid (2N, up to pH 2). The solid thus obtained was filtered and dried to afford 3,5-dichloro-4-{[4-(propanoylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoic acid (170 mg, 70%). The material was taken as such for the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:46][C:47]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:48]=1[NH2:49]>CN(C=O)C>[CH3:46][C:47]1[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:48]=1[NH:49][C:10]([C:8]1[S:7][C:3]2=[N:4][CH:5]=[CH:6][N:1]=[C:2]2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1cc2nccnc2s1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)c1cc2nccnc2s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (250 mg, 1.387 mmol), HATU (633 mg, 1.665 mmol) and DIPEA (0.459 mL, 2.77 mmol) in DMF (5 mL) was stirred for 15 min. 2-methyl-5-nitroaniline (211 mg, 1.387 mmol) was added and stirred at 60° C. for 4 h. Quenched in citric acid solution and the resulting precipitate was collected to give N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carboxamide 75 (400 mg, 92%). (m/z)=315 (M+H)+.
Reaction SMILES: C1(S([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[N:11]=2)(=O)=O)C=CC=CC=1.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:25]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:17])=[O:18])[N:11]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(c1ccccc1)c1cccc(S(=O)(=O)c2ccccc2)n1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1cccc(-c2ccccc2)n1
Yield: 80 %

Procedure:
To a stirred solution of bis-(phenylsulfonyl)pyridine 4d (1.0 g, 2.78 mmol) in 10 mL THF at room temperature is charged 1.0 M PhMgBr (5.56 ml, 2.0 equiv) slowly over a period of 10 min. The progress of the reaction is monitored by LC-MS. Upon complete consumption of the starting material (about 2 h), the mixture is quenched with MeOH (2 mL). The crude mixture is then evaporated to dryness, and the product is isolated by flash column chromatography (silica gel, 15% ethyl acetate in hexanes) and dried to yield 656 mg of 3e as a white solid, 80% yield. 1H NMR (400 MHz, CDCl3) δ 8.14-8.08 (m, 3H), 7.95-7.91 (m, 3H), 7.83-7.86 (m, 1H), 7.62-7.51 (m, 3H), 7.46-7.40 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 158.0, 138.9, 138.7, 137.1, 133.7, 130.0, 129.2, 128.9, 128.8, 127.0, 123.1, 119.8.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[CH:16]1([C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH:16]2[CH2:18][CH2:17]2)[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)C1CC1
Product: CCOC(=O)C1=C(C2CC2)Nc2n[nH]cc2C1c1ccccc1Cl

Procedure:
To a solution of 2-oxazolydone (20.8 g) in tetrahydrofuran (750 ml) was added n-butyllithium (1.56 M hexane solution, 153 ml) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of cyclopropanecarbonyl chloride (25 g) in tetrahydrofuran (50 ml) at −78° C. over 30 minutes. The mixture was stirred for 14 hours while gradually raising the temperature to room temperature. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give white crystals (26 g). A mixture of the obtained white crystals (10 g), ethyl bromoacetate (21.5 ml) and zinc powder (25.3 g) in tetrahydrofuran (300 ml) was ultrasonicated for 2 hours and heated under reflux for 2 hours. To the reaction mixture was added 10% hydrochloric acid and the insoluble material was filtered off through Celite. The filtrate was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give ethyl 3-cyclopropyl-3-oxopropionate (5.7 g) as a yellow oil. Subsequently, the title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-cyclopropyl-3-oxopropionate in the same manner as in Example 275.
Reaction SMILES: [CH:1]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:26]([C:29]([OH:38])([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])[CH:27]=[CH2:28]>CS(C)=O>[CH:1]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:26]([C:29]([OH:38])([C:30]([F:32])([F:33])[F:31])[C:34]([F:35])([F:36])[F:37])[CH:27]=[CH2:28]
Reactant: O=S(=O)([O-])C=Cc1ccccc1
Agent: C=CCC(O)(C(F)(F)F)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Solvent: CS(C)=O
Product: O=S(=O)(O)C=Cc1ccccc1

Procedure:
19 g of sodium styrenesulfonate (SSNa) (available from Sigma-Aldrich Corp.) and 1 g of 2-Allylhexafluoro-isopropanol are fully dissolved in 0.24 L of dimethylsulfoxide (DMSO) with heating. Then, 0.1 g of azobisisobutyronitrile (AIBN) is added dropwise to the DMSO solution. The monomers are polymerized for 24 hours or more. The polymerization is carried out varying the content of the allylhexafluoro-isopropanol (2, 5, 10, and 20 wt %).
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2>ClCCl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]([C:29]2[C:28]3[C:32](=[C:24]([CH2:23][S:22][CH3:21])[CH:25]=[CH:26][CH:27]=3)[NH:31][CH:30]=2)([CH:1]2[CH2:3][CH2:2]2)[CH3:5])=[CH:8][CH:9]=1
Reactant: CC(O)(c1ccc(Cl)cc1)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (3.05 mmol) of the compound from Example 138A and 0.28 ml (3.66 mmol) of trifluoroacetic acid were added to 541 mg (3.05 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified three times by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). 441 mg (41% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C(O)(=[O:12])C.OO>O1CCCC1>[NH2:9][C:4]1[N:3]([OH:12])[C:2](=[NH:1])[N:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: CC(=O)O
Reactant: Nc1cc(Cl)nc(N)n1
Agent: OO
Solvent: C1CCOC1
Product: N=c1nc(Cl)cc(N)n1O
Reaction time: 4 h
Yield: 63 %

Procedure:
1.5 g (10 mmoles) of 2,6-diamino-4-chloropyrimidine are dissolved in 20 ml of anhydrous tetrahydrofuran. A mixture of 10 ml of acetic acid and 2 ml of a 70% aqueous hydrogen peroxide solution is added in 30 minutes under stirring and reflux. The reaction mixture is boiled for four hours, evaporated in vacuo to third of its volume, and a 40% aqueous sodium hydroxide solution is added to the residue until reaching a pH value of 8. The mixture is allowed to stand in refrigerator for a night. The crystals are filtered, washed with water and dried. In this way 1.0 g (63%) of the aimed compound is obtained.
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[S:13](Cl)(=[O:15])=[O:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:25]2[CH2:28][CH:27]([NH2:29])[CH2:26]2)=[CH:20][CH:19]=1>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:25]2[CH2:26][CH:27]([NH:29][S:13]([C:9]3[S:8][CH:12]=[CH:11][CH:10]=3)(=[O:15])=[O:14])[CH2:28]2)=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccs1
Temperature: 25 °C
Reaction time: 68 h
Yield: 66.2 %

Procedure:
69.3 mm3 of triethylamine and 110 mg of thien-2-ylsulfonyl chloride are successively added, at room temperature and under an argon atmosphere, to a solution of 61.4 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 3 cm3 of dichloromethane. After stirring for 68 hours at room temperature, the reaction mixture is introduced into a Bond Elut® SCX cartridge (3 cm5/500 mg) , eluting successively with twice 2 cm3 of dichloromethane and then twice 2 cm3 of a 1 M solution of ammonia in methanol. The ammoniacal fractions are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is dissolved in 5 cm3 of dichloromethane, washed with three times 3 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 60 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}thien-2-ylsulfonamide are thus obtained in the form of a cream-colored foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.77 (split t, J=7 and 2 Hz: 2H); 3.40 (split t, J=7 and 2 Hz: 2H); 4.06 (mt: 1H); 4.21 (s: 1H); from 4.85 to 5.25 (broad unresolved complex: 1H); 7.06 (t, J=4.5 Hz: 1H); from 7.15 to 7.35 (mt: 8H); 7.58 (mt: 2H)].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[O-].[Li+].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[C:29][C:30]1[C:31]([O:40][CH3:41])=[CH:32][C:33]([O:38][CH3:39])=[C:34]([CH:37]=1)[CH:35]=O>CN(C=O)C.CO>[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[C:29][C:30]1[C:31]([O:40][CH3:41])=[CH:32][C:33]([O:38][CH3:39])=[C:34](/[CH:35]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH:37]=1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Reactant: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)NCC(=O)O)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 23 h
Yield: 35.8 %

Procedure:
Ex-51A: A solution (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A, 238 mg, 1.01 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (153 mg, 4.04 mmol), followed by the addition of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 300 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 23 h under nitrogen. It was quenched with water (10 mL) and extracted with ethyl acetate (25 mL). The aqueous phase was acidified with 6N HCl to pH3 and was extracted with (3:1) ethyl acetate/THF (5×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (0–7.5% MeOH in dichloromethane) to give (4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamino)acetic acid (188 mg, 36%) as an orange solid. 1H-NMR (300 MHz, DMSO-d6) 8.23 (d, 2H, J=8.7), 8.19 (s, 1H), 7.99 (d, 1H, J=15.9 Hz), 7.92 (d, 2H, J=7.80 Hz), 7.82 (d, 1H, J=16.5 Hz), 7.16 (d, 1H, J=6.6 Hz), 7.05 (t, 1H, J=8.1 Hz), 6.76 (s, 1H), 6.71 (d, 1H, J=7.8 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.72 (s, 1H), 5.45 (br s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.41 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([CH3:11])[C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>>[CH2:17]([O:16][C:12]([CH2:13][CH2:14][NH:1][CH:2]([CH3:11])[C:3]([CH3:9])([CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:15])[CH3:18]
Reactant: CCOC(=O)C(C)(C)C(C)N
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCNC(C)C(C)(C)C(=O)OCC

Procedure:
In the second stage of the reaction, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is reacted with ethyl acrylate to obtain the corresponding ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate derivative 5--which in the case of the preparation of BIII 277 might be, for example: ethyl 3-(2-ethoxycarbonylethyl)amino-4-(3-methoxyphenyl)-2,2-dimethylbutanoate (R2 =CH3O): ##STR4##
Reaction SMILES: BrC1C=CC(C2N([C:13]3C=C[C:16]([S:19](N)(=O)=O)=[N:17][CH:18]=3)N=C(C(F)(F)F)C=2)=CC=1C(F)(F)F.Br[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[N:42]([C:43]3[CH:44]=[CH:45][C:46]([S:49]([NH2:52])(=[O:51])=[O:50])=[N:47][CH:48]=3)[N:41]=[C:40]([C:53]([F:56])([F:55])[F:54])[C:39]=2Cl)=[CH:34][CH:33]=1>>[S:19]1[CH:13]=[C:18]([C:32]2[CH:33]=[CH:34][C:35]([C:38]3[N:42]([C:43]4[CH:44]=[CH:45][C:46]([S:49]([NH2:52])(=[O:50])=[O:51])=[N:47][CH:48]=4)[N:41]=[C:40]([C:53]([F:56])([F:55])[F:54])[CH:39]=3)=[CH:36][C:37]=2[C:53]([F:56])([F:55])[F:54])[N:17]=[CH:16]1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)c(C(F)(F)F)c2)cn1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)c(C(F)(F)F)c2)cn1

Procedure:
The title compound was prepared according to the procedure of step 3, 4 in the example 4 using 5-{5-[4-bromo-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide, instead of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=O)[CH3:26]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:31][C:30]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=1
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1cc(C=C(Br)Br)ccc1OC
Yield: 90.4 %

Procedure:
According to the General Procedure F, carbon tetrabromide (3.70 g, 11.10 mmol), triphenylphosphine (5.82 g, 22.20 mmol) and 3-Ethoxy-4-methoxybenzaldehyde (2.00 g, 11.10 mmol) are converted to give after workup and chromatography (SiO2, CH2Cl2, Rf=0.55) the title compound (3.37 g, 10.03 mmol) as a pale yellow solid. M.p. 41-42° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[CH:13][C:12]=1[S:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(O)c(Cl)c1
Product: O=S(=O)(Nc1ccc(O)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3-chloro-4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide was synthesized (92%) from 4-amino-2-chlorophenol (Aldrich) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride in a similar manner as described in Example 421. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.17 (s, 1H), 8.14 (d, J 1.0 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.88 (dd, J=8.5, 1.4 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.88 (dd, J=8.7, 2.5 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H). MS (EI): m/z 384 (M+H).
Reaction SMILES: [CH3:1][C:2]([N:9]([CH3:11])[CH3:10])([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]#[N:4].O>CCOCC>[CH3:1][C:2]([N:9]([CH3:10])[CH3:11])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][NH2:4]
Reactant: CCCCC(C)(C#N)N(C)C
Solvent: CCOCC
Solvent: O
Product: CCCCC(C)(CN)N(C)C
Temperature: 0 °C

Procedure:
A solution of 2-methyl-2-dimethylamino-hexanenitrile (7.70 g.,) in dry ether (100 ml.) was added dropwise to a stirred solution of sodium dihydro-bis(2-methoxy-ethoxy)aluminate (43.3 g., 70% solution in benzene, 25% excess) in dry ether (100 ml.) under nitrogen with ice water cooling. The solution was refluxed overnight under nitrogen and allowed to cool. Ether (200 ml.) was added, followed by dropwise addition of excess water with ice-water cooling to destroy excess reducing reagent. The mixture was filtered on hyflo and the filtrates extracted with ether (4 × 100 ml.). The combined ether extracts were washed with water (4 × 200 ml.), dried (Na2SO4) and evaporated leaving a colourless oil. Distillation of the oil afforded 2-methyl-2-dimethylamino-hexylamine as a colourless liquid (4.808 g., 61%) b.p. 86-88/12 mm..
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[ClH:10]>O>[Cl:10][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1
Reactant: Cl
Reactant: Fc1cnc(F)c(F)c1
Solvent: O
Product: Fc1cnc(Cl)c(F)c1
Temperature: 25 °C

Procedure:
To a microwave tube is added 2,3,5-trifluoropyridine (2.0 g, 15 mmol), concentrated HCl (12.5 mL, 150 mmol). The mixture is irradiated with microwave for 30 min at 130° C. The reaction mixture is cooled to ambient temperature, diluted with 100 mL of water, extracted with dichloromethane three times. The organic phase is further washed with brine, dried over Na2SO4 and dried to give 2-chloro-3,5-difluoropyridine as a greenish solid. The compound is used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39]O)[CH2:34][CH2:33]1.O1C2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[O:31][CH2:39][CH2:38][N:35]5[CH2:36][CH2:37][O:32][CH2:33][CH2:34]5)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: OCCN1CCOCC1
Agent: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN1CCOCC1)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(2-morpholinoethoxy)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-morpholinoethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][OH:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1
Reactant: CC1CCNCC1
Reactant: OCCBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.9 %

Procedure:
A mixture of 4-methylpiperidine (10 g, 0.10 mol), 2-bromoethanol (12.5 g, 0.10 mol), and triethylamine (15 g, 0.15 mol) in CHCl3 (100 mL) was stirred at room temperature for two days. The mixture was concentrated, and the residue was purified on a silica gel column (eluting with NH3—H2O/MeOH/DCM=1/6/300) to give 2-(4-methylpiperidin-1-yl)ethanol (3 g) as a colorless oil. 1H NMR (CDCl3): δ 3.57 (m, 2H), 3.24 (br s, 1H), 2.84 (m, 2H), 2.47 (m, 2H), 2.00 (dt, 2H), 1.58 (m, 2H), 1.35 (m, 1H), 1.21 (dt, 2H), 0.89 (d, 3H); LCMS: 144 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH:7](=O)[CH2:8][CH3:9].N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[CH2:8]([CH:9]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]1[C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:7]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CNC(=S)NN
Reactant: CCC=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC1SC(NC)=NN1C(=O)C(C)(C)C

Procedure:
A 10.5 g. portion of 4-methylthiosemicarbazide was reacted with 5.8 g. of propionaldehyde in the presence of 7.9 g. of pyridine and 200 ml. of toluene, and 12.1 g. of pivaloyl chloride was added to produce 13.8 g. of the desired product, m.p. 78.5°-80°.