Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].N[C@H:14](C(O)=O)[C@H](CC)C>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:7]([CH3:9])[CH2:8][CH3:14])[C:10]([OH:12])=[O:11])=[O:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O

Procedure:
(2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using L-isoleucine instead of L-Valine.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([SH:17])=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:17][CH3:18])=[C:10]([C:13]([F:14])([F:16])[F:15])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(S)c(C(F)(F)F)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1cc2c(cc1C(F)(F)F)N(C(C)=O)CC2
Temperature: 80 °C
Yield: 96.5 %

Procedure:
A mixture of the thiol (D5) (26 g, 99 mmol), anhydrous K2CO3 (15.12 g, 109 mmol) and iodomethane (18.6 ml, 300 mmol) in dry DMF (100 ml) was heated at 80° C. for 1 h. The reaction mixture was cooled, evaporated in vacuo and partitioned between water (200 ml) and dichloromethane (3×200 ml). The combined organics were washed with water (400 ml), dried (Na2SO4) and evaporated to yield the title compound (26.3 g, 97%) as a yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([C@@H:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[C:28](=[O:47])[C@@H:29]([NH:33][C:34](=[O:46])[C@@H:35]([N:37](C)[C:38](=O)OC(C)(C)C)[CH3:36])[CH:30]([CH3:32])[CH3:31])=[O:18]>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH:16][C:17]([C@@H:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[C:28](=[O:47])[C@@H:29]([NH:33][C:34](=[O:46])[C@@H:35]([NH:37][CH3:38])[CH3:36])[CH:30]([CH3:31])[CH3:32])=[O:18]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
TFA (2 mL, 26.0 mmol, Eq: 96.7) was added to a solution of tert-butyl (S)-1-((S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (0.15 g, 269 μmol, Eq: 1.00) in DCM (2 mL) and the resulting solution was stirred at rt for 1 hr. The reaction mixture was concentrated in vacuo and treated with minimal ether/hexanes to give (S)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-indole-2-carboxylic acid (2,6-difluoro-phenyl)-amide as a white solid (0.11 g), m/z=459 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:27]=4)=[O:25])=[N:19][C:18]=3[C:17]([O:38][CH3:39])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[CH3:39][O:38][C:17]1[C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:25])[C:26]3[CH:31]=[CH:30][N:29]=[C:28]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH:27]=3)[S:21][C:22]=2[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Yield: 85 %

Procedure:
0.08 g (0.14 mMol) 4-{4-methoxy-2-[(2-morpholin-4-yl-pyridine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 2 ml 2.5 M HCl/MeOH and heated to reflux for 1.5 h. The reaction mixture was concentrated in vacuo and taken up in 3 ml isopropanol. The suspension formed was filtered and the material on the filter was washed with diethyl ether and dried in vacuo. One obtained 54 mg (71%) N-(4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-2-morpholin-4-yl-isonicotinamide 1:2 hydrochloride as a yellow solid. F.p.: 260-270° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:41])[C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=3[NH:26][C:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[O:28])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:42](Cl)(=[O:44])[CH3:43]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:41])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:42](=[O:44])[CH3:43])=[CH:21][C:20]=3[NH:26][C:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=4)[CH2:31][CH2:30]3)=[O:28])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(NC(=O)c3ccc(N)cc3NC(=O)C3CCN(c4ccncc4)CC3)cc21
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc3ccn(C(=O)OC(C)(C)C)c3c2)c(NC(=O)C2CCN(c3ccncc3)CC2)c1
Yield: 77 %

Procedure:
Using the procedure described in Example 24, Part E, N-(1-tert-butoxycarbonyl-6-indolyl)-2-[1-(4-pyridyl)-piperidin-4 ylcarbonylamino]-4-aminobenzamide (0.18 mmol) was reacted with acetyl chloride to yield 83 mg (77%) of the title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[C:6]([O:14]COC)=[CH:5][N:4]=1.C(Cl)Cl>O1CCOCC1>[Cl:2][C:3]1[N:4]=[CH:5][C:6]([OH:14])=[C:7]([C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1
Reactant: COCOc1cnc(Cl)cc1-c1ncc[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Oc1cnc(Cl)cc1-c1ncc[nH]1
Reaction time: 2 h

Procedure:
Hydrogen chloride in dioxane (4 M, 40 mL) was added dropwise to a solution of 2.06 g (8.60 mmol) of 2-chloro-4-(1H-imidazol-2-yl)-5-(methoxymethoxy)pyridine in Methylene chloride (40 mL, 600 mmol). The suspension was stirred for 2 hours and filtered. The solid was washed with DCM, ether and dried in vacuum. Yield of 6-chloro-4-(1H-imidazol-2-yl)pyridin-3-ol dihydrochloride 2.31 g (100%). MS(ESI+): 196.2. 1H NMR (400 MHz, DMSO) δ 13.20 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.42 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12](Cl)(=[O:14])=[O:13])=[CH:7]2.[NH3:16]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH2:16])(=[O:14])=[O:13])=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cccc2c1
Reactant: N
Product: NS(=O)(=O)c1ccc2c(Cl)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
5-Chloronaphthalene-2-sulfonyl chloride (Toronto, 531 mg, 2.03 mmol) was treated with NH3 (10.2 mL, 5.08 mmol, 0.5M solution in dioxanes) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, redissolved in sat. aq. NaHCO3 solution and extracted with CHCl3 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, 37%). 1H NMR (DMSO-d6) δ 8.53 (d, J=1.8 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.18 (d, J=8.6 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.70-7.62 (m, 1H); MS(ESI−) m/z 240.3 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([O:5]CC)=O.C(O)(=O)C.Cl.Cl.[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([F:33])[C:27]([CH2:28][NH:29][NH2:30])=[C:26]([F:34])[CH:25]=1)[CH3:22]>O1CCOCC1>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([F:34])[C:27]([CH2:28][N:29]2[C:3]([OH:5])=[C:2]([CH3:1])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:30]2)=[C:31]([F:33])[CH:32]=1)[CH3:22]
Reactant: CCOc1cc(F)c(CNN)c(F)c1
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(O)c1C
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4.65 g of diethyl 2-methyl-3-oxobutanedioate (23.0 mmol, 1.00 eq.) were dissolved in 100 mL of dry dioxane under argon atmosphere. 2.1 mL of glacial acetic acid and 6.32 g of (4-ethoxy-2,6-difluorobenzyl)hydrazine dihydrochloride (23.00 mmol, 1.00 eq.) were added. The mixture was stirred for 16 hours at 90° C. bath temperature. The reaction mixture was evaporated in vacuo. The residue was stirred with ethyl acetate. The resulting suspension was filtered off and washed with ethyl acetate. The filter cake was dried in vacuo at 40° C. The filtrate was concentrated in vacuo and purified by flash chromatography (hexane/ethyl acetate-gradient with hexane 0-100%). The filter cake and the received purified compound of the flash chromatography were stirred together in ethyl acetate, filtered off and provided 3.95 g (11.3 mmol, 49%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]4)=[CH:8][O:9][C:5]=2[CH:4]=1.Cl.Cl.Cl.[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1>>[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH:46][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:7]3[C:6]5[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[O:9][CH:8]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:21]([C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[C:18]([F:17])([F:27])[F:28])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1ccccc1C(F)(F)F
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3C(F)(F)F)nc(=O)c1-2
Temperature: 25 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.59 g, 2.65 mmol), 2-trifluoromethylbenzaldehyde (0.5 ml) and glacial acetic acid (25 ml) was refluxed overnight and then 0.5 equivalents of additional aldehyde was added and the mixture was refluxed for about 3 days. The reaction mixture was cooled to room temperature, the acetic acid was stripped and the residue was cooled and rinsed with ether to give a white solid which was collected by filtration and recrystallized from tert-butyl dimethyl ether/hexanes to afford 1-cyclopentyl-3-ethyl-6-(2-trifluoromethylphenyl)-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 201°-202° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([S:25](Cl)(=[O:27])=[O:26])[C:22]([C:29]([F:32])([F:31])[F:30])=[N:21]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:23]2[C:22]([C:29]([F:32])([F:30])[F:31])=[N:21][N:20]([CH3:19])[CH:24]=2)(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Product: Cn1cc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)c(C(F)(F)F)n1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride (0.5 mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 3.8 (s, 3H), 5.7 (s, 1H), 6.0 (dt, 1H), 7.0 (q, 1H), 7.2 (m, 2H), 7.4 (dd, 1H), 7.8 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:16]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[CH3:12].[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[F:27][C:3]1[C:2](/[N:1]=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:16]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: Cc1c(Cc2cccc(N)c2F)c(=O)oc2cc(Oc3nccs3)ccc12
Solvent: CO
Product: Cc1c(Cc2cccc(/N=C\c3ccccc3)c2F)c(=O)oc2cc(Oc3nccs3)ccc12
Temperature: 25 °C

Procedure:
Methanol (4.0 mL) was added to 3-(3-amino-2-fluorobenzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran (compound 1h-3-4) (200 mg), and benzaldehyde (0.053 mL) was added to the resultant suspension while stirring at room temperature. The suspension was heated under reflux for 3 hours. The reaction solution was then cooled to room temperature, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel chromatography (amino gel) (dichloromethane) to yield the title compound (233 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:29])=[O:28]
Reactant: OCCCc1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 11.0 g. of 3-[p-(benzyloxy)phenyl]propanol and 10.4 ml. of triethylamine in 175 ml. of dichloromethane chilled to -10° C. is added dropwise, over 10 minutes, a solution of 3.89 ml. of methanesulfonyl chloride in 10 ml. of dichloromethane. The solution is stirred at -10° C. for 30 minutes, washed with 150 ml. of cold water, 75 ml. of cold 10% HCl, 75 ml. of cold saturated sodium bicarbonate, 75 ml. of cold saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo to give off-white crystals, m.p. 65°-69° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](SC#N)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].[NH2:26][CH2:27][C@@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N+:1]([C:4]1[C:5]([NH:26][CH2:27][C@@H:28]2[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:21])([F:20])[F:22])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CSc1nc(NCc2ccccc2OC(F)(F)F)ncc1[N+](=O)[O-]
Reactant: NC[C@H]1CC[C@@H](O)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@@H](O)CC1
Reaction time: 8 h

Procedure:
(5-Nitro-4-thiocyanato-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine (10 g, 26.9 mmol) was dissolved in DCM (100 ml). cis-4-aminomethyl-cyclohexanol (3.48 g, 26.9 mmol) and diisopropylethylamine (10 mL, 53.8 mmol) were added to the solution and stirred overnight. The reaction mixture was evaporated in-vacuo and purified by column chromatography (1% MeOH/99% CH2Cl2). The resulting solid was washed with cold methanol to give a pale yellow solid as cis-4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexanol (11.3 g, 25.6 mmol, 95.1%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Yield: 81.9 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml ethanol, and 3.75 g (25.8 mmol) 3-chloro-4-fluoroaniline was heated to reflux under N2. Removed heat at 3½ hours and added a solution of saturated sodium bicarbonate until mixture was basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids, washed with water and dried in vacuo. Dissolved solids in 250 ml boiling ethyl acetate, stirred with Darco, and filtered. Stripped solvent and dried in vacuo, giving 6.036 g of yellow solid: mass spectrum (electrospray m/e): M+H=343.1, 345.1.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH3:11][C:12]1([CH3:23])[C:20]2[C:15](=[C:16]([NH2:21])[CH:17]=[CH:18][CH:19]=2)[CH:14]([CH3:22])[CH2:13]1.O>C(Cl)Cl>[CH3:11][C:12]1([CH3:23])[C:20]2[C:15](=[C:16]([NH:21][C:8]([C:4]3[S:3][C:2]([Cl:1])=[N:6][C:5]=3[CH3:7])=[O:10])[CH:17]=[CH:18][CH:19]=2)[CH:14]([CH3:22])[CH2:13]1
Reactant: CC1CC(C)(C)c2cccc(N)c21
Reactant: Cc1nc(Cl)sc1C(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1nc(Cl)sc1C(=O)Nc1cccc2c1C(C)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
252 mg (1.42 mmol) of 2-chloro-4-methylthiazole-5-carboxylic acid and 442 mg (1.42 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidomethiodide were dissolved in 10 ml of methylene chloride and stirred at room temperature for 1 hour. Then, to the solution was added 249 mg (1.42 mmol) of 1,1,3-trimethyl-4-aminoindan and reaction was effected for 6 hours under reflux. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was concentrated and thereafter was purified by column chromatography (eluent; n-hexane:ethyl acetate=50:50 V/V) to obtain 204 mg of N-(1,1,3-trimethyl-4-indanyl)-2-chloro-4-methylthiazole-5-carboxamide (yield 43%).
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>S(=O)(=O)(O)O>[OH:1][CH:2]([CH3:7])[CH2:3][C:4]([O:6][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:5]
Reactant: CC(O)CC(=O)O
Reactant: CCCCCCCCCCO
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCOC(=O)CC(C)O
Temperature: 140 °C
Yield: 57.9 %

Procedure:
A 100 ml one neck round bottom flask equipped with a Dean Stark trap, condenser and nitrogen inlet/outlet was charged with 20.8 g (0.20 moles) 3-hydroxybutyric acid, 63.3 g (0.40 moles) decyl alcohol, and 0.1 g sulfuric acid (based on 0.5 g/mole 3-hydroxybutyric acid). The mixture was heated to 140° C. for 8 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. Approximately 50 ml ether was needed to break the emulsion. The organic layer was collected and dried over magnesium sulfate. Excess decyl alcohol was removed by high vacuum distillation to yield 28.3 g (58% yield) of clear viscous colorless oil. According to GC the product is 89.4% pure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:5]([F:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.CC([O-])(C)C.[K+].CC(O)(C)C>C1COCC1>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:6]1[C:5]([F:17])=[CH:4][N:3]=[C:2]([O:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[N:7]=1
Reactant: OCc1ccc(F)cc1
Reactant: Fc1ccccc1CNc1nc(Cl)ncc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: Fc1ccc(COc2ncc(F)c(NCc3ccccc3F)n2)cc1
Temperature: 80 °C
Yield: 42 %

Procedure:
A solution of (2-chloro-5-fluoropyrimidin-4-yl)-(2-fluorobenzyl)amine* (0.103 g, 0.40 mmol) in 5 mL of dry THF was treated with 4-fluorobenzylalcohol (0.062 g, 0.49 mmol) and a 1.0 M solution of KOtBu in tBuOH (0.4 mL, 0.4 mmol). The mixture was heated at 80° C. in a sealed vial for 18 h, partitioned between CH2Cl2 and water, and the organic phase was washed with brine, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure and the residue purified by flash column chromatography (SiO2, 10→20% EtOAc/petroleum ether) to yield the title compound (0.157 g, 42%) as a white solid: mp 83-84° C.; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=2.8, 1H), 7.45-7.27 (m, 5H), 7.15-6.96 (m, 5H), 5.37 (br s, 1H), 5.29 (s, 3H), 4.74 (d, J=5.9, 3H); MS (ESI) m/z 346 (M+H)+. *Singh, R.; Argade, A.; Payan, D. G.; Clough, J.; Keim, H.; Sylvain, C.; Li, H.; Bhamidipati, S., WO 2004014382 A1 20040219
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[C:19]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:1][CH2:2][C:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])([OH:10])[CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)(=[O:31])=[O:30])=[CH:27][CH:28]=1)(=[O:21])[CH3:20]
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)NCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)cc1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 4-acetamidobenzenesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.Cl[CH2:20][CH:21]1[CH2:23][O:22]1>C1COCC1>[CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH2:5][CH2:20][CH:21]1[CH2:23][O:22]1
Reactant: CC#C[Si](C)(C)C
Reactant: ClCC1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C#CCCC1CO1
Temperature: -75 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a stirred solution of trimethyl(prop-1-ynyl)silane (3 g, 26.7 mmol) in dry THF (100 mL) cooled at −72° C., was added drop by drop 2.5 N nBuLi in hexane solution (10.5 mL, 26.2 mmol). The resulting mixture was stirred at −75° C. for 1 h 30. Then 2-(chloromethyl)oxirane (2.42 g, 26.2 mmol) in dry THF (2 mL) was slowly added. The resulting mixture was stirred at −72° C. for 1 h 30, then warmed up to room temperature for an additional 1 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to afford 4.50 g trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (Yield: 100%) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])=[N:4]1.[O:19]([C:26]([NH:28][C:29]1[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[N:30]=1)=O)C1C=CC=CC=1>C(#N)C>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([O:37][CH3:38])[N:30]=[C:29]([NH:28][C:26]([NH:18][S:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:5]2[O:6][CH2:7][CH2:8][O:3][N:4]=2)(=[O:16])=[O:17])=[O:19])[N:34]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: NS(=O)(=O)c1ccccc1C1=NOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C2=NOCCO2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
0.79 g (0.033 mol) of sodium hydride are added under argon to a mixture of 4.0 g (0.017 mol) of 2-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)benzenesulphonamide and 4.6 g (0.017 mol) of 2-phenoxycarbonylamino-4,6-dimethoxypyrimidine in 20 ml of absolute acetonitrile, and the mixture is stirred at room temperature for 18 hours. The precipitate is filtered off with suction and stirred up with a 20% solution of sodium dihydrogen phosphate. The precipitate is filtered off with suction and dried under high vacuum. 3.9 g (56% of theory) of N-(4,6-dimethoxypyrimidin-2-yl)-N'-(2-(5,6-dihydro-[1,4,2]-dioxazin-3-yl)benzenesulphonyl)-urea are obtained with a melting point of 189° C.