Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.[C:25]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)(=O)[CH3:26].C([BH3-])#N.[Na+].CO.C(O)(=O)C>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH3:26])[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: CC(=O)c1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(c1ccncc1)N1CCC(CNc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a small sample of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.03 g, 0.1 mmol) weighed out in a 1 mL sealable vial, excess 4-acetylpyridine was added (100 μL, ca. 1 mmol) followed by sodium cyano-borohydride (360 μL of a 1 M solution in tetrahydrofuran) and methanol-acetic acid (95:5). The vial was capped and placed in a shaker at 50° C. for several days until reasonable conversion by TLC was evident. The reaction mixture was then diluted with methanol, shaken well for several minutes, and allowed to stand for 0.5 h before applying it to a 2 g SCX column. After washing well with methanol, the product was gravity-eluted from the column with 2 M ammonia in methanol. The product fractions were combined and concentrated in vacuo to a residue which was triturated in acetonitrile, giving rise to the title compound as a powdery solid (0.03 g, 74%) in >98% purity by HPLC.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>O>[CH3:34][O:33][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (52 mg), potassium carbonate (53 mg), and morpholine (33 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][S:18]2(=[O:24])=[O:23])=[N:11][C:10]=1[C:25]([OH:27])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].ClC=[N+](C)C.[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl>[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:25]([C:10]2[N:11]=[C:12]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][S:18]3(=[O:24])=[O:23])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])=[CH:37][CH:36]=1
Reactant: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)O)c(OCc2ccccc2)c1=O
Reactant: Nc1ccc(F)cc1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)Nc2ccc(F)cc2)c(OCc2ccccc2)c1=O
Reaction time: 0.25 h
Yield: 108.8 %

Procedure:
A solution of 5-benzyloxy-2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid (0.200 g, 0.51 mmol) in dichloromethane (20 ml) was treated at 25° C. with (chloromethylene)dimethylammonium chloride (0.080 g, 0.62 mmol) and the resulting mixture was stirred for 15 min. Then a solution of 4-fluoroaniline (0.117 g, 1.06 mmol) and pyridine (0.1 ml, 1.2 mmol) in dichloromethane (2 ml) was added and the reaction mixture was stirred for another 45 min. The mixture was quenched by addition of ethyl acetate and pH 6 phosphate buffer. The organic phase was then washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 7:3) gave 0.270 g (88% yield) of the title amide as white crystals; mp 201–202° C.(ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.65–1.69 and 2.35–2.7 (1H and 3H, 2 m, 2×CH2), 3.2–3.25 (1H, m, CH), 3.59–3.73 (2H, m, CH2), 3.68 (3H, s, NCH3), 3.99–4.07 (1H, m, CH), 5.47 (2H, AB system, JAB=10.8 Hz, Δν=49.8 Hz, OCH2), 6.93 (2H, m, aromatics), 7.22 (2H, m, aromatics), 7.39–7.52 (5H, m, aromatics) Anal. Calcd for C23H23FN4O5S: C, 56.78; H, 4.77; N, 11.52. Found: C, 56.83; H, 4.58; N, 11.53.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C>C(O)(=O)C>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:12]2([C:1]#[N:2])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C1CCCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC2(C#N)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
Sodium cyanide (0.147 g, 3 mmol) was added to a mixture of p-toluidine (0.214 g, 2 mmol) and cyclohexanone (0.294 g, 3 mmol) in acetic acid 90% (3 ml). The reaction mixture was stirred at room temperature for 12 h and then 20 ml of ethyl acetate was added. The organic layer was washed with water (3×10 ml), dried over magnesium sulfate and concentrated under vacuum to dryness to yield 1-(4-methylphenyl)aminocyclohexanenitrile, 9a (0.398 g, 1.86 mmol, 93%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[OH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([N:41]5[CH2:42][CH2:43][CH:38]([OH:37])[CH2:39][CH2:40]5)=[O:34])=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a mixture of 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoic acid (150 mg), 4-hydroxypiperidine (33.2 mg) and 1-hydroxybenzotriazole monohydrate (60 mg) in N,N-dimethylformamide (3 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg) and triethylamine (0.208 mL) at room temperature and the mixture was stirred overnight at room temperature. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=80:20), and crystallized from diisopropyl ether to give the title compound (168 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15](=O)[CH2:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)=[CH:30][NH:29][N:28]=1>>[CH3:38][C:34]1[CH:33]=[C:32]([C:31]2[CH:30]=[N:29][N:28]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:25])([F:24])[F:1])[CH:6]=4)=[N:26][C:27]=23)[CH:37]=[CH:36][N:35]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)ccn1
Yield: 53.8 %

Procedure:
Reaction of 1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (140 mg, 54%). MS (ISP) 521.4 [(M+H)+]; mp 201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[F:11][C:12]([F:19])([F:18])[C:13]([F:17])([F:16])[CH:14]=O.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:20]1([CH:14]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:13]([F:17])([F:16])[C:12]([F:19])([F:18])[F:11])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: O=CC(F)(F)C(F)(F)F
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(NC(n1nnc2ccccc21)C(F)(F)C(F)(F)F)c1ccc(Cl)cc1

Procedure:
4-Chlorobenzamide, pentafluoropropanal, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.O1CCOCC1.C(OC([N:34]1[CH:38]=[CH:37][CH:36]=[C:35]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[C:35]2[NH:34][CH:38]=[CH:37][CH:36]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(Cc2nc(-c3ccncc3)sc2Br)cc1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2ccc[nH]2)cc1
Temperature: 130 °C
Yield: 28.8 %

Procedure:
To a solution of 5-bromo-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole (94.0 mg, 0.257 mmol) in 4:1 dioxane:water (3.0 mL) was added 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (57 mg, 0.27 mmol), cesium carbonate (251 mg, 0.771 mmol), and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). The solution was degassed with argon and heated in a microwave reactor at 130° C. for 105 minutes. The reaction was concentrated in vacuo and the residue taken up in DCM (25 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→80/20) followed by HPLC purification (formic acid method) to give 26 mg of the title compound as a yellow solid (29% yield). LC/MS (FA) ES+ 352. 1H NMR (300 MHz, d4-MeOH) δ: 8.62-8.60 (m, 2H), 7.90-7.88 (m, 2H), 7.66-7.55 (m, 1H), 7.26-7.24 (m, 2H), 7.20-7.17 (m, 2H), 6.92 (dd, 1H, J=2.7, 1.5 Hz), 6.32 (dd, 1H, J=3.5, 1.5 Hz), 6.21 (dd, 1H, J=3.5, 2.7 Hz), 4.28 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:10]=2[N:11]=1.[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:19][C:20]1[C:25]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])(=[O:29])=[O:28])=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:10]=3[N:11]=2)=[CH:22][N:21]=1
Reactant: Clc1ccc2ncnc(NC3CCOCC3)c2n1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CCOCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A mixture of 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine (0.026 g, 0.098 mmol) (Intermediate 17), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-3-yl)-2,4-difluorobenzenesulfonamide (Intermediate 3) (0.051 g, 0.118 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.802 mg, 0.982 μmol) and sodium bicarbonate (0.196 ml, 0.196 mmol) in dioxane (0.491 ml) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (only EtOAc) to give N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.015 g, 29%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.68-1.83 (2H, m), 2.13-2.20 (2H, m), 3.58-3.65 (2H, m), 4.05-4.12 (2H, m), 4.41-4.50 (1H, m), 6.94-7.02 (2H, m), 7.18 (1H, d, J=8.0 Hz), 7.84-7.90 (1H, m), 8.09 (1H, d, J=8.8 Hz), 8.24 (1H, d, J=8.4 Hz), 8.65 (1H, s), 8.74 (1H, d, J=2.0 Hz), 8.84 (1H, d, J=2.4 Hz). NH peak was not observed. m/z=533.4 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[O:9]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:14]([C:13]2[O:9][C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH:12]=2)(=[O:15])=[O:16])[O:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Cc1noc(N)c1C
Product: Cc1noc(NS(=O)(=O)c2cc3ccccc3o2)c1C

Procedure:
N-(3,4-Dimethyl-5-isoxazolyl)benzo[b]furan-2-sulfonamide was prepared, in the same manner as described in Example 34B, from 3,4-dimethyl-5-amino isoxazole (78 mg, 0.70 mmol) and benzo[b]furan-2-sulfonyl chloride (0.46 g, 2.1 mmol). Flash chromatography (30% ethyl acetate/hexanes) provided 0.186 g of a light yellow solid, which was treated with 31 mg of NaOH in 10 ml of methanol at 25° C. for 30 minutes. Recrystallization from CHCl3/hexanes yielded a light tan solid (90 mg, 44% yield), m.p. 160.5-163° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:25])[NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[N:13]=1)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][NH:15][C:14]([C:12]2[N:13]=[C:9]([CH2:8][NH2:7])[S:10][CH:11]=2)=[O:25])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Reaction time: 12 h

Procedure:
To a solution of {4-[2-(3-Chlorophenyl)ethylcarbamoyl]thiazol-2-ylmethyl}carbamic acid tert-butyl ester (0.73 g, 1.8 mmol) in methanol (10 mL) was added HCl in dioxane (4M solution, 10 mL). The mixture stirred for 12 hours. The methanol and dioxane were removed in vacuo and the resulting solid was vigorously mixed with 0.1 N NaOH and methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a solid. 1H NMR (400 MHz, d6-DMSO): 8.39 (br s, 1H), 8.08 (s, 1H) 7.25 (m, 4H), 4.00 (s, 2H), 3.48 (m, 2H), 2.84 (t, 2H), 2.41 (br s, 2H); MS (ESI-LCMS) for C13H14ClN3OS: 296 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1>CC(=O)CC>[Cl:7][C:8]1[N:9]=[N:10][C:11]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: C1CNCCN1
Solvent: CCC(C)=O
Product: Clc1ccc(N2CCNCC2)nn1
Temperature: 62 °C
Yield: 80.9 %

Procedure:
Piperazine (20.0 g, 232 mmol) and 3,6-dichloropyridazine (34.6 g, 232 mmol) were mixed with 2-butanone and heated at 62° C. for 16 h. The reaction mixture was cooled to room temperature and the precipitated product filtered and washed with 2-butanone. The solid was redissolved in DCM (250 mL), filtered and the filtrate evaporated. The solid was dried in vacuo to yield 37.3 g, 81% 3-chloro-6-piperazin-1-ylpyridazine.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[CH3:8].[Na].[Cl-].[Na+].C(#[N:14])C>>[ClH:1].[NH2:14][CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[CH3:8]
Reactant: Cc1nnsc1CCl
Reactant: CC#N
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: Cc1nnsc1CN
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To 50 ml of acetonitrile were added 7.0 g (47 mmol) of 5-chloromethyl-4-methyl-1,2,3-thiadiazole and 9.0 g (94 mmol) of sodium formimide. After stirring the resulting mixture for 16 hours with heating under reflux, the reaction mixture was cooled to the room temperature, a saturated aqueous solution of sodium chloride was added, the objective product was extracted with ethyl acetate, the organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. Then, while stirring the resulting crystalline product together with 40 ml of water, 30 ml of concentrated hydrochloric acid was added. After ten minutes, water and hydrochloric acid were distilled off, and the residue was washed with ethyl acetate. Thus, 6.6 g of the objective compound was obtained.
Reaction SMILES: [Mg].C(I)C.II.[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:26]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:37]=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1.CCOCC>[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:37]([C:36]1[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:35]=1)[OH:38])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCCCCCCCCCOCc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCI
Product: OC(CCCCCCCCCCOCc1ccccc1)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a mixture of 1 ml of anhydrous ether and 0.6 g of metallic magnesium were added 0.1 ml of ethyl iodide and a piece of iodine crystal followed by heating to initiate the reaction and then a mixture of 6.7 g of 10-benzyloxy-1-chlorodecane and 10 ml of anhydrous ether was added dropwise to the aforesaid mixture. After the reaction was over, the reaction mixture was refluxed for 2 hours. After cooling, the reaction mixture was added dropwise to a solution of 6 g of 3,4-dibenzyloxybenzaldehyde dissolved in 30 ml of tetrahydrofuran at 0° to 5° C. Thereafter, the mixture was stirred for 30 minutes at room temperature and after adding 300 ml of an aqueous 1% hydrochloric acid solution to the reaction mixture, the product was extracted with 100 ml of toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 30 ml of ethanol, the solution was allowed to stand overnight under cooling to 0° to 5° C., and the crystals thus precipitated were collected by filtration. By drying the crystals, 5 g of 11-benzyloxy-1-(3,4-dibenzyloxyphenyl)-1-undecanol was obtained. Melting point 50°-52° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.[Cl:31][C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[CH:48]=[C:47]([CH3:49])[O:46][N:45]=1>C(Cl)(Cl)Cl.O>[ClH:31].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:43][C:44]2[CH:48]=[C:47]([CH3:49])[O:46][N:45]=2)=[O:34])=[CH:18][C:17]=1[F:23]
Reactant: Cc1cc(N)no1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)on4)cc3F)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (800 mg) was dissolved in chloroform (20 ml) and triethylamine (1.0 ml) to prepare a solution. A solution of triphosgene (378 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 3-amino-5-methylisoxazole (294 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Iced water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine and was then dried over anhydrous sodium sulfate. The dried organic layer was filtered and was then concentrated. Ether was added to the residue for crystallization, and the crystal was collected by filtration. The collected solid was purified by chromatography (chloroform:acetone=2:1). A 10% solution of hydrogen chloride in methanol was added to the purification product, followed by concentration. The resultant crystal was washed with ether to give 598 mg of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]([NH2:18])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.I[CH2:20][C@@H:21]([C:30]1[C:31](Cl)=[C:32]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=1)[O:22][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25].BrCC(C1C=CC([Cl:52])=C(NS(C)(=O)=O)C=1)=O>>[CH2:24]([Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[O:22][C@H:21]([C:30]1[CH:35]=[CH:34][C:33]([Cl:52])=[C:32]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:31]=1)[CH2:20][NH:18][CH:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:25]
Reactant: N[C@H](Cc1ccccc1)c1ccc2c(c1)OCO2
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1cccc(NS(C)(=O)=O)c1Cl
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1Cl
Product: CC[Si](CC)(CC)O[C@@H](CNC(Cc1ccccc1)c1ccc2c(c1)OCO2)c1ccc(Cl)c(NS(C)(=O)=O)c1

Procedure:
The title compound was prepared by coupling (R)-α-(1,3-benzodioxol-5-yl)benzeneethanamine (preparation described in Step B of Example 60) with (R)-N-[3-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-chlorophenyl]methanesulfonamide (prepared from 2-bromo-1-[4-chloro-3-[(methylsulfonyl)amino]phenyl]ethanone, preparation described in Example 69, utilizing the procedures described in step A-C of Example 19) following the procedure described in steps D and E of Example 19 with the following modifications. 1) Chromatography on silica gel using 25% EtOAc/hexane yielded (R), (R)-N-[5-[1-(triethylsilyl)oxy-2-[[1-(1,3-benzodioxol-5-yl)-2-phenylethyl]amino]ethyl]-2-chlorophenyl]methanesulfonamide. 2) In step E the title compound was eluted from silica gel using 1:1 EtOAc/hexane prior to final preparative HPLC purification (see Example 1 for HPLC protocol) eluting with 52% solvent B.