Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[Cl:17]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:8])=[CH:12][C:11]=1[Cl:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)ccc1Br
Temperature: 90 °C
Yield: 85.4 %

Procedure:
Add NBS (5.266 g, 23.9 mmol) and benzoyl peroxide (49 mg, 0.2 mmol) to a solution of 4-bromo-3-chlorotoluene (4.925 g, 23.9 mmol) in carbon tetrachloride (49 mL) and heat overnight at 90° C. Cool to 0° C. and filter the mixture. Concentrate the filtrate in vacuo to obtain the desired intermediate as a yellow oil (5.807 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[CH:18][CH:17]=1.Cl>CCCCCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([C:28]2([OH:31])[CH2:27][CH2:26][N:25]([CH2:24]/[CH:23]=[CH:22]/[C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[CH:7]=1
Reactant: O=C1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A solution of n-buthyllithium in hexane (47.0 ml of a 1.6M solution) was added dropwise to a solution of N-(4-chloro-phenyl)-2,2-dimethyl-propionamide (6.35 g) in dry THF (100 ml) at −5° C. under a N2 atmosphere over 15 min. The resulting solution was stirred at 0° C. for 2 hours, and then a solution of 1-[(E)-3-(4-chloro-phenyl)-allyl]-piperidin-4-one (7.49 g) in THF (15 ml) was added dropewise to the above solution of the dianion at 0° C. over a 1 hour period. The reaction mixture was stirred for 2 hours at 0° C. and then overnight at r.t. The solution was then poured into ice water, made acidic with conc. HCl and extracted with ethyl acetate. The water layer was made basic and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (hexane:ethyl acetate:triethyl amine 49:49:2) to afford the title product (6.2 g). M.p. 177-179° C.; Retention Time HPLC 2.19 min; MS (ES+) 461 (M+H+).
Reaction SMILES: [K].[NH:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.Cl[C:8]([O:10][CH3:11])=[O:9].CS(C)=O>C1CCCCC1>[C:8]([N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1)([O:10][CH3:11])=[O:9]
Reactant: c1cc[nH]c1
Reactant: COC(=O)Cl
Agent: [K]
Solvent: C1CCCCC1
Solvent: CS(C)=O
Product: COC(=O)n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Potassium (5.85 g, 0.15 mol) was added to a solution of 10 ml pyrrole (0.145 mol) in 80 ml hot cyclohexane in several portions. The mixture was refluxed for 1 hour. To this cold solution was added 15 g (0.16 mol) methyl chloroformate slowly. After addition, the mixture was stirred at room temperature for 30 minutes. During this period, 2.5 ml dimethyl sulfoxide was added for catalysis. After quenching with ice-water, the organic layer was separated and the aqueous layer extracted with ether. The combined organic layer was washed with 10% sodium bicarbonate, sat. sodium chloride and dried over magnesium sulfate. Removal of solvent yielded 17.4 g of a liquid. Bulb to bulb distillation gives 16.5 g N-carbomethoxy pyrrole 21 as a colorless liquid, yield 91%. The product requires storage at −20° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:15][CH2:14][CH2:13][Br:12])[CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: BrCCCBr
Reactant: Fc1ccc2c(c1)OCCN2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)OCCN2CCCBr
Temperature: 70 °C
Yield: 47.3 %

Procedure:
A mixture of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, 1 eq, 8.49 mmol) obtained in step (iii) above, 1,3-dibromo propane (8.6 ml, 10 eq, 84.9 mmol) and anhydrous sodium carbonate (2.7 g, 3 eq, 25.4 mmol) in dry DMF (85 ml) was heated at 70° C. for 16 h. The reaction was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound (1.1 g, yield 47%) as viscous oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>C(#N)C>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:34]([NH:33][CH2:31][CH3:32])=[O:35])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: CCN=C=O
Solvent: CC#N
Product: CCNC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50 mg (0.125 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 4 ml of dry acetonitrile is added at RT 16 μl (0.2 mmol) of ethyl isocyanate (Fluka, Buchs, Switzerland). After stirring for 16 h at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to provide trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-ethyl-urea. Analytical HPLC: tR=6.77 min (Grad 2); ES-MS: m/eo=471.1.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.O[NH:42][C:43]([C:45]1[C:46]2[CH:47]=[CH:48][NH:49][C:50]=2[CH:51]=[CH:52][CH:53]=1)=[NH:44]>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:18][N:44]=[C:43]([C:45]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:46]=4[CH:47]=[CH:48][NH:49]5)[N:42]=3)[S:10][C:11]=2[C:12]([F:13])([F:14])[F:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N=C(NO)c1cccc2[nH]ccc12
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: FC(F)(F)c1sc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.6 %

Procedure:
4-Phenyl-5-(trifluoromethyl)-2-thiophenecarboxylic acid (310 mg), HOBT (170 mg) and EDCI.HCl (242 mg) were dissolved in DMF (3 ml) and stirred at room temperature for 20 mins. D9 (200 mg) was dissolved in DMF (3 ml) and added to the above solution and stirring continued at room temperature for two hours. The reaction mixture was then heated to 90° C., cooled to RT, stood overnight, re-heated to 80° C. and stirred for 3 hours, cooled to room temperature and evaporated to dryness. The residue was re-dissolved in H2O and extracted with EtOAc (×3) and the combined organic extracts evaporated to dryness. The residue was purified by flash silica chromatography, eluting with a 25-75% mixture of diethyl ether in hexane to give the title compound (265 mg) as a brown solid. A sample of this compound (100 mg) was purified by MDAP to give the title compound (62 mg) as an off white solid. δH (CDCl3, 400 MHz): 7.33-7.36 (2H, m), 7.41-7.42 (1H, m), 7.46-7.52 (5H, m), 7.61 (1H, d), 7.94 (1H, s), 8.06 (1H, d), 8.46 (1H, br s). MS (ES): C21H12F3N3OS requires 411; found 412 (MH+).
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH:10]([CH3:13])[CH2:11][OH:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[Cl:30]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:30][C:22]1[CH:23]=[C:24]([N:9]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH:10]([CH3:13])[CH2:11][OH:12])[CH:25]=[CH:26][C:21]=1[F:20]
Reactant: CC(CO)NC(C)c1ccccc1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(CO)N(c1ccc(F)c(Cl)c1)C(C)c1ccccc1
Reaction time: 24 h

Procedure:
2-[(1-phenylethyl)amino]propan-1-ol (5-5, 0.027 g, 0.151 mmol) in CH2Cl2 (1.0 mL) was treated with Cu(OAc)2 (0.041 g, 0.227 mmol), pyridine (0.024 mL, 0.302 mmol), and 4-fluoro-3-chloro-phenylboronic acid (0.026 g, 0.149 mmol). 4 A MS (20 mg) were added and the resulting solution stirred 24 h. Upon completion, the reaction mixture was filtered and the filtrate was purified by reverse phase liquid chromatography (Semi-prep YMC C-18 Column 5% CH3CN/H2O up to 95% CH3CN/H2O) to give 2-[(3-chloro-4-fluorophenyl)(1-phenylethyl)amino]propan-1-ol (5-6) as a brown oil. MS 308.3 found 308.8 (M+H+) required.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH3:14].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:20]([NH2:22])[CH:21]=1.Cl.O1CCOCC1>CO>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[C:20]([NH:22][C:2]2[C:11]3[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:13])[C:3]=2[CH3:14])[CH:21]=1
Reactant: Cc1nc2c(Cl)cccc2c(Cl)c1C
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2c(Cl)cccc2c(Nc2cc(Br)ccc2N2CCOCC2)c1C

Procedure:
Prepared according to Procedure K, Method 1 using 4,8-dichloro-2,3-dimethylquinoline (104 mg, 460 μmol), 5-bromo-2-morpholinobenzenamine (118 mg, 460 μmol) and 4N hydrochloric acid solution in dioxane (0.050 mL, 200 μmol) in MeOH (1.00 mL) to afford a colorless solid upon purification by chromatography on silica gel, eluting with a Et2O gradient in toluene. 1H NMR (400 MHz, chloroform-d) δ ppm 7.69 (1H, dd, J=7.4, 1.2 Hz), 7.55-7.63 (1H, m), 7.23-7.30 (1H, m), 6.92-6.98 (1H, m), 6.85-6.92 (1H, m), 6.83 (1H, s), 6.18 (1H, d, J=2.3 Hz), 3.80-3.91 (4H, m), 2.92-3.08 (4H, m), 2.71-2.78 (3H, m), 2.23 (3H, s).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([N:31]([C:33]1([C:38]#[CH:39])[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:32])[CH:29]=[CH2:30]>>[CH2:28]([N:31]([CH3:32])[C:33]1([C:38]#[C:39][C:16]2[CH:15]=[CH:14][C:13]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:8][CH:7]=4)=[N:10][S:11][C:12]=3[CH:17]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1)[CH:29]=[CH2:30]
Reactant: C#CC1(N(C)CC=C)CCCC1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: C=CCN(C)C1(C#Cc2ccc3c(-c4ccc(C(F)(F)F)cc4)nsc3c2)CCCC1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and Allyl-(1-ethynyl-cyclopentyl)-methyl-amine were converted to yield Allyl-methyl-{1-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ylethynyl]-cyclopentyl}-amine as light yellow oil, MS: 441 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.O(Cl)[Cl:24].O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([Cl:24])=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: ClOCl
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Di-cyclopropylmethyl-8-nitro xanthine (6 g, 0.023 mol) was dissolved in dimethylformamide (20 ml) and reacted with phosporous oxychloride (14 g) for 1 hour at 120° C. The mixture was then treated with water and stirred for 1 hour at room temperature. The precipitate was filtered off, dissolved in ethyl acetate, dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yield 2.5 g (40%), m.pt. 220° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:32])[C:15]([NH:17][C:18]2[N:22](C(OCCCl)=O)[N:21]=[C:20]([CH:29]3[CH2:31][CH2:30]3)[CH:19]=2)=[O:16])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].CO>CN(C)C=O>[CH:29]1([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([C:11]3[CH:10]=[CH:9][C:8]([N:7]4[CH2:2][CH2:3][O:4][C:5]4=[O:6])=[CH:13][CH:12]=3)[CH3:32])[NH:22][N:21]=2)[CH2:31][CH2:30]1
Reactant: CC(C(=O)Nc1cc(C2CC2)nn1C(=O)OCCCl)c1ccc(NC(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C(=O)Nc1cc(C2CC2)n[nH]1)c1ccc(N2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.9 %

Procedure:
431 mg (0.89 mmol) of 2-chloroethyl 5-{[2-(4-{[(2-chloroethoxy)carbonyl]amino}phenyl)propanoyl]amino}-3cyclopropyl-1H-pyrazole-1-carboxylate were dissolved in 3 ml of N,N-dimethylformamide and 124 mg (0.89 mmol) of potassium carbonate were added and the mixture stirred at room temperature for 19 hours. The reaction mixture was poured into 30 ml of methanol and stirred for 40 minutes, evaporated under vacuum, diluted with 40 ml of methanol and washed with a saturated aqueous ammonium chloride solution. The organic layer was further extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness. The crude was purified by chromatography on a silica gel column to afford 233 mg (77% yield) of the title compound. Analogously, but employing the suitable bisacylated amide derivatives, the following compounds can be prepared:
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].C[O-].[Na+].CS(O)(=O)=O.N[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[NH:22][CH2:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:17]#[N:18]>CO.O>[Cl:1][CH2:2][C:3]1[N:22]([CH2:23][C:24](=[O:32])[NH:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:21]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[N:4]=1
Reactant: N#CCCl
Reactant: N#Cc1ccc(NCC(=O)NC2CCCCC2)c(N)c1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(c1)nc(CCl)n2CC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of chloroacetonitrile (3.9 ml) in methanol (166 ml) was added sodium methoxide (3.29 g), and the mixture was stirred at room temperature for 40 min under a nitrogen atmosphere. Methanesulfonic acid (7.91 ml) and 3-amino4-(cyclohexylcarbamoylmethylamino)benzonitrile (8.3 g) were added, and the mixture was stirred for 3 hours. After completion of the reaction, water (166 ml) was added and the precipitated solid was collected by filtration, and washed with a small amount of water. The obtained solid was stirred in a mixture of hexane and tetrahydrofuran, collected by filtration and dried under reduced pressure to give the title compound (9.30 g).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>>[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccc(Cl)c2C)c1Br
Yield: 34 %

Procedure:
3-Chloro-2-methyl-N-(4-Bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-chloro-2-methylbenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 185-187° C., yield 34%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:5]([NH:7][C:8]1[CH:37]=[CH:36][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][C:14]=2[CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+]>CO.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:5]([NH:7][C:8]1[CH:37]=[CH:36][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[CH:10][CH:9]=1)=[O:6]
Reactant: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNS(=O)(=O)c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNS(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 30.6 %

Procedure:
Methyl 2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-((4-fluorophenyl-sulfonamido)methyl)phenyl)acetate (40 mg, 0.065 mmol) was diluted with MeOH (1 mL) followed by the addition of NaOH (0.32 mL, 1.3 mmol). After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a 0.5 mm preparative plate eluting with methylene chloride:MeOH:AcOH (90:9:1) to yield 12 mg of the title compound as a solid. 1H NMR (400 MHz, CDCl3/CD3OD) 8.1 (m, 1H), 7.85 (m, 1H), 7.8 (m, 2H), 7.7 (d, 1H), 7.6 (d, 1H), 7.25 (s, 1H), 7.2 (m, 3H), 6.85 (d, 2H), 6.7 (d, 1H), 4.15 (s, 2H), 3.55 (s, 2H).
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Li].O>CCOCC>[C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH3:26])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (0.59 g, 1.79 mmol) in Et2O (25 mL) under Ar at −70° C., was added methyl lithium (1.4 M in Et2O; 1.88 mL, 2.63 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 min and then allowed to warm to RT over 15 min and stirred at this temperature for 1 h. The mixture was cooled to 0° C. to which was slowly added H2O (25 mL) and the solution was extracted between Et2O (100 mL) and H2O (100 mL). The aqueous phase was extracted with more Et2O (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo to afford the title compounds as a light yellow oil (0.58 g, 94%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.42-0.57 (m, 3H, —NHCH(CH2CH3)CH(CH3)OH), 0.97-1.15 (m, 5H, —NHCH(CH2CH3)CH(CH3)OH+—NHCH(CH2CH3)CH(CH3)OH), 2.01 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 3.26 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 4.39 (d, 1H, J=4.10 Hz, —NHCH(CH2CH3)CH(CH3)OH), 7.13-7.50 (m, 15H, 3×Bz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:39])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:13]=2)=[CH:6][C:5]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[CH:4][N:3]=1>C(O)(=O)C>[NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:39])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[CH:6][C:5]([C:40]2[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=2)=[CH:4][N:3]=1
Reactant: Cc1cc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: CC(=O)O
Product: Cc1cc(N)nc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)c1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
405 mg of N-[2-amino-5-(4-chloro-phenyl)-pyridin-3-yl]-3-[4-methyl-6-(trityl-amino)-pyridin-2-yl]-propionamide (compound B8) are dissolved in 24 ml of aqueous acetic acid (50% strength) and heated at 80° C. for 3 h. Subsequent workup according to the procedure described herein for example B5 yields 36 mg of the title compound as an oil. ESI-MS: 382.2/384.2 (MH+, 100%/360%). TLC: Rf=0.40 (dichloromethane/methanol 10:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+]>CN(C)C=O>[C:9]1([S:15][C:2]2[N:3]=[C:4]([Cl:8])[CH:5]=[N:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cncc(Sc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2,6-dichloropyrazine (0.100 mol) and freshly distilled thiophenol (0.100 mol) in 200 ml. N,N-dimethylformamide is treated with five grams of sodium hydride (50% dispersion in Nujol) gradually with vigorous stirring under nitrogen at room temperature. After 3 hr. the mixture is concentrated in vacuo, and the residue partitioned between water and benzene. The benzene extract is washed with water, dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil which is the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[S:11])[CH:3]=1.S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:8][C:6]1[N:5]2[S:11][C:10](=[N:12][S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:14])=[O:15])[N:9]=[C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=S)Nc2cc(C)cc(C)n2)cc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N=c2nc3cc(C)cc(C)n3s2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a mixture of 1-(4,6-dimethyl-2-pyridyl)-3-(4-methylphenyl)sulfonyl-2-thiourea (2.90 g) and chloroform (50 ml), sulfuryl chloride (1.28 g) was added. After being stirred at room temperature for 15 minutes, the mixture was refiuxed with heating for 30 minutes. The reaction mixture was concentrated, and the resulting crystal was collected by filtration and suspended in water. After pH adjustment to 7 by the addition of saturated aqueous sodium bicarbonate, the suspension was stirred at room temperature for 1 hour. The separating crystal was collected by filtration and recrystallized from chloroform-methanol to yield 5, 7-dimethyl-2-(4-methylphenyl) sulfonylimino-2H-[1,2,4]thiadiazolo[2,3- a]pyridine (2.40 g, yield 83%) as a colorless needle.