Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[CH2:20]([O:19][C:17]1[CH:16]=[CH:15][C:14]([S:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1ccnc2ncccc12
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (100 mg, 0.559 mmol) was reacted with 4-(2-amino-4-benzyloxy-phenylsulfanyl)-phenol (224 mg, 0.559 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (mg, %). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.14 (s, 2H), 6.31 (d, J=6.99 Hz, 1H), 6.61-6.69 (m, 2H), 7.08-7.23 (m, 5H), 7.32-7.46 (m, 5H), 7.92 (dd, J=8.46, 4.41 Hz, 1H), 8.47 (d, J=6.99 Hz, 1H), 9.10-9.21 (m, 2H), 9.77 (s, 1H), 11.14 (s, 1H); MS (ESI+) m/z 452 (M+H−TFA)+; (ESI−) m/z 450 (M−H−TFA)−.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=[O:4])=[O:3].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].C(O)(=O)C.[Na]BCC(O)=O.C(OOC(=O)C)(=O)C>CO>[CH3:1][S:2]([O:5][CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:30]5[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]5)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(=O)CC4)c3c21
Reactant: O=C1CNCCN1
Agent: CC(=O)OOC(C)=O
Agent: O=C(O)CB[Na]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of [(3S)-12-[(4-oxocyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate (500 mg, 1.26 mmol, 1.00 equiv) in methanol (10 mL) was added piperazin-2-one (126 mg, 1.26 mmol, 1.00 equiv) and acetic acid (1 mL). The solution was stirred for 1 h and then acetyl ethaneperoxoate sodioboranyl acetate (534 mg, 2.52 mmol, 2.00 equiv) was added. Stirring was continued for 2 h at 0° C. The mixture was then quenched with saturated aqueous sodium bicarbonate, extracted with DCM (60 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The desired [(3S)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate (450 mg, 74%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:17]=1
Reactant: Cc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(Cl)c3ccccc3n2)cc1
Temperature: 0 °C

Procedure:
To a mixture of 7 g of 2-(4-methylphenyl)quinazolin-4(3H)-one and 50 ml of thionyl chloride was slowly added 2.16 g of dimethylformamide and the mixture was heated under reflux for 75 minutes. The mixture was poured into 250 ml of ice and the ice allowed to melt. The precipitate was collected to give 6.7 g of 4-chloro-2-(4-methylphenyl)quinazoline which melted at 113°-115° after recrystallization from petroleum ether (30°-60° fraction); ir and nmr spectra were consistent with the assigned structure. Calcd. for C15H11ClN2 : C, 70.73; H, 4.35; N, 11.00. Found: C, 70.92; H, 4.39; N, 11.09.
Reaction SMILES: O[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.S(Cl)([Cl:12])=O.N1C=CC=CC=1>ClCCCl>[Cl:12][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: CC1(CO)COC(=O)N1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC1(CCl)COC(=O)N1
Temperature: 110 °C
Yield: 70.6 %

Procedure:
To a suspension of 4-(hydroxymethyl)-4-methyloxazolidin-2-one (1.89 g, 14.4 mmol) in 1,2-dichloroethane (10 ml) was added thionyl chloride (5.0 ml, 69 mmol) dropwise over 10 min. Pyridine (5.0 ml, 62 mmol) was added, and the solution heated to 110° C. for 2 h. The solution was cooled to RT, concentrated, and the residue purified by flash chromatography (30%→100% EtOAc in hexanes) to give the title compound as a white solid (1.52 g, 10.2 mmmol, 71%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 3H), 3.55 (s, 2H), 4.12 (d, J=9.2 Hz, 1H), 4.33 (d, 8.8 Hz, 1H), 5.8 (br s, 1H). ESI/APCI calculated for C5H8ClNO2: 149.02. Found: 150 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=O)[S:7][CH:8]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([NH2:36])=[O:35])[C:29](=[O:37])[CH2:28]2.Cl>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([NH2:36])=[O:35])[C:29](=[O:37])[CH:28]2[C:9](=[O:11])[C:6]1[S:7][CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CC(=O)c1csc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Temperature: 25 °C
Yield: 22 %

Procedure:
A 0.78 g (4.59 nmuoles) sample of 4-acetyl-2-thio-phenecarboxylic acid (prepared according to Satonaka, H., Bull. Chem. Soc. Japan 56:2463 (1983)) was combined with 0.95 g (5.85 mmoles) of 1,1'-carbonyldiimidazole in 10 ml of N,N-dimethylformamide and stirred at room temperature under argon atmosphere. After two hours the reaction contents were transferred to an addition funnel and slowly added to a slurry of 0.88 g (4.18 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 1.38 g (11.28 mmoles) of 4-(N,N-dimethylamino)pyridine in 30 ml of N,N-dimethylformamide stirring at 5° C. (ice bath) under an inert atmosphere. The reaction contents were stirred for fifteen minutes at 5° C. after complete addition followed by twenty-four hours at room temperature. Pouring the reaction mixture into 110 ml of 0.3N hydrochloric acid cause the precipitation of a greenish-yellow solid. Filtration followed by sequential washing with 3N hydrochloric acid and water, provided the crude product which was recrystallized twice from acetic acid to give 0.34 g (0.94 mmoles, 22% yield) of pure 5-chloro-3-(4-acetyl-2-thenoyl)-2-oxindole-1-carboxamide as a greenish-yellow solvated complex with 0.2 equivalents of acetic acid, m.p. 230-233° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH2:21].C(Cl)Cl.CO.[NH4+].[OH-]>>[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and Nε-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=119-121° C.). The reaction was monitored by tlc (Rf=0.46 in 90:10:1 CH2Cl2\MeOH\NH4OH).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C@@H:13]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[N+:29]([O-:31])=[O:30])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@@H:13]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[N+:29]([O-:31])=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=C[C@H](CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CC[C@H](CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1[N+](=O)[O-]
Yield: 95.9 %

Procedure:
A solution of 2.75 g (6.17 mmol) of (S)-2-t-butyl-5-(3-t-butyldimethylsilyloxy-4-cyclohexyl-1-butenyl)-1-nitrobenzene [prepared as described in step (v) above] in 30 ml of diethyl ether was vigorously stirred for 20 minutes at 0° C. in a stream of hydrogen and in the presence of 303 mg of 10% w/w palladium-on-charcoal. The reaction mixture was then worked up in a similar manner to that described in step (iii) above, to give 2.65 g (yield 96%) of the title nitrobenzene derivative as a colorless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:29])[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1.[CH:30](I)([CH3:32])[CH3:31]>C1COCC1>[CH3:11][O:12][C:13](=[O:29])[CH:14]([C:15]1[CH:16]=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)I
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium bis(trimethylsilyl) amide (1.0M in THF—177 μL) was added drop-wise to a solution of (3,5-bis-trifluoromethyl-phenyl)-acetic acid methyl ester (389 mg) in dry THF (2 mL) at 0° C., under nitrogen atmosphere. After ten minutes, isopropyl iodide (143 μL) was added and the reaction mixture was stirred at 0° C. for 30 min. Further isopropyl iodide (143 μL) was added and the solution stirred at r.t. for 1 hour. The reaction was quenched with a 2N hydrochloric acid solution (2 mL) and the product was extracted with Et2O (2×). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified by flash chromatography (CH/AcOEt 95:5) to give the title compound (184 mg) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14]1[NH:15][CH2:16][CH2:17][CH2:18][C:19]=1[N+:20]([O-:22])=[O:21]>C(O)C>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]1[NH:15][CH2:16][CH2:17][CH2:18][C:19]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSC1=C([N+](=O)[O-])CCCN1
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC1=C([N+](=O)[O-])CCCN1
Yield: 74 %

Procedure:
A solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.51 g, 0.003 mol) and 2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.49 g, 0.003 mol) in ethanol (50 ml) was refluxed for 6 hours. The mixture was cooled, and the solvent was removed in vacuo. The residue was dissolved in hot propan-2-ol and the product crystallised on cooling. Recrystallisation of the product from propan-2-ol/methanol gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitro-1,4,5,6-tetrahydropyridine (0.66 g, 82%) m.p. 205.5°-206.5°. Found: C, 48.6; H, 6.5; N, 23.6; S, 10.8; C12H19N5O2S requires: C, 48.5; H, 6.4; N, 23.55; S, 10.8%.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:12])[CH3:11].[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:40][CH3:41])=[CH:30][C:31]=3[O:33][CH2:34][C@H:35]3[CH2:39][CH2:38][CH2:37][NH:36]3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[F:21]>C(Cl)Cl>[C:10]([N:36]1[CH2:37][CH2:38][CH2:39][C@@H:35]1[CH2:34][O:33][C:31]1[CH:30]=[C:29]([O:40][CH3:41])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:22][C:17]1[CH:18]=[CH:19][C:20]([F:21])=[C:15]([Cl:14])[CH:16]=1)=[N:24][CH:25]=[N:26]2)(=[O:12])[CH3:11]
Reactant: COc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC[C@H]2CCCN2C(C)=O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reaction time: 1 h
Yield: 83 %

Procedure:
N,N-Diisopropylethylamine (52 μl) and acetyl chloride (21 μl) were added sequentially, each in one portion, to a stirred mixture of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (100 mg) in DCM (2 ml) at room temperature. The reaction mixture was stirred for 1 hour and then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow solid, which was purified by column chromatography using 24% methanol in DCM as eluent, followed by trituration with ether to give the title compound as a white solid (92 mg, 83%); NMR Spectrum (DMSO-d6) 9.90 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.40 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.25 (m, 1H), 3.95 (s, 3H), 3.50 (m, 1H), 3.30 (s, 3H), 2.0-1.85 (m, 5H); Mass spectrum MH+ 445.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH3:18])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: COc1ccccc1B(O)O
Product: COC(=O)c1c(O)c2ccc(-c3ccccc3OC)cc2sc1=O

Procedure:
4-Hydroxy-7-(2-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 2-methoxyphenylboronic acid under conditions analogous to Example 7(a). MS ESI(−) m/e: 341.07 (M−1).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].[OH:11]C1C=C(C=CC=1)C#N.P(S)(OCC)(OCC)=S>O>[OH:11][C:7]1[CH:2]=[C:3]([C:8](=[S:10])[NH2:9])[CH:4]=[CH:5][CH:6]=1
Reactant: NC(=S)c1ccccc1O
Reactant: N#Cc1cccc(O)c1
Agent: CCOP(=S)(S)OCC
Solvent: O
Product: NC(=S)c1cccc(O)c1
Yield: 57 %

Procedure:
The procedure used for the preparation of 3a was repeated with 3-hydroxybenzonitrile (5.48 g, 46.1 mmol), (EtO)2P(S)SH (7.72 mL, 46.1 mmol) and water (9.2 mL) at 80° C. for 36 hr to give 3d (4.04 g, 57%) as a yellow solid after chromatographic purification on silica gel (gradient EtOAc/CH2Cl2 : 6-12%) and crystallization from EtOAc/hexane. mp 139.0°-140.0° C.; IR (KBr) 3340, 3280, 3165, 1629, 1590, 1462 cm-1 ; 1H NMR (DMSO-d6) δ 6.83 (1H, br d, J=7.0 Hz, Ar), 7.10-7.25 (2H, m, Ar), 7.27 (1H, s, Ar), 9.33 (1H, br s, NH), 9.58 (1H, s, OH), 9.72 (1H, br s, NH); FDMS m/z 153 (M+); Anal. Calcd for C7H7NOS: C, 54.88; H, 4.60; N, 9.14. Found: C, 55.01; H, 4.53; N, 9.02.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]2[CH:61]=[CH:60][N:59]=[C:58]([NH2:62])[N:57]=2)=[CH:51][CH:50]=1>ClCCCl>[NH2:62][C:58]1[N:57]=[C:56]([NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][CH2:47][NH:46][C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:50][CH:51]=2)[CH:61]=[CH:60][N:59]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCCc1ccc(Nc2ccnc(N)n2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4ccnc(N)n4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (51 mg, 0.31 mmol), DIPEA (0.134 mL, 0.76 mmol) and N4-[4-(2-aminoethyl)phenyl]pyrimidine-2,4-diamine (49 mg, 0.15 mmol) in DCE (1 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([Cl:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](OB(O)O)=[CH:19][CH:18]=1>>[Cl:15][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)COc1ccc(Br)cc1Cl
Reactant: OB(O)Oc1ccc(Cl)cc1
Product: CCOC(=O)COc1ccc(-c2ccc(Cl)cc2)cc1Cl

Procedure:
Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and 4-chlorophenylboric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Solvent: CC(C)=O
Product: COc1cccc(S(=O)(=O)N2CCOCC2)c1

Procedure:
3-Methoxybenzenesulfonyl chloride (0.20 g, 0.968 mmol) in acetone (2 mL) at 0° C. was treated with excess morpholine (0.253 mL, 2.9 mmol) with stirring. After 0.5 hr the reaction mixture was partitioned between CH2Cl2 (1 mL) and 1N HCl, the organic layer separated, washed with brine, dried (Na2SO4), filtered and concentrated to dryness to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[N:13]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][N:15]=[N:14]1>>[N:13]1([CH2:18][CH2:19][NH:20][C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH:17]=[CH:16][N:15]=[N:14]1
Reactant: NCCn1ccnn1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Yield: 97.6 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g, 11.96 mmol) reacted with 2-[1,2,3]triazol-1-yl-ethylamine (2.66 g, 14.36 mmol) to give 3.05 g (98%)of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:21])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27].[Na+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([O:29][C:25](=[O:28])[CH2:26][CH2:27][C:12]([C:11]1[CH:14]=[C:15]([I:21])[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:13])[CH3:31]
Reactant: CCCOc1c(I)cc(C=O)cc1OCc1ccccc1
Reactant: C=CC(=O)OCC
Agent: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1c(I)cc(C(=O)CCC(=O)OCC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.1 %

Procedure:
To a solution of 3-benzyloxy-4-propoxy-5-iodo benzaldehyde (25.5 g, 0.064 mol) in DMF (155 ml) was added sodium cyanide (0.78 g, 0.016 mol) and stirred at room temperature for 45 min under nitrogen atmosphere. Ethyl acrylate (5.21 g, 0.057 mol) in DMF (30 ml) was added slowly and stirred at room temperature for 30-40 mints. Ethyl acetate (185 ml) and 15% NaCl solution were added to the reaction mixture and the two layers were separated. The aqueous phase was extracted with ethyl acetate (250 ml). The combined organic extracts were washed with saturated aqueous NaHCO3 (125 ml) followed by 5% aqueous NaCl (180 ml). The ethyl acetate layer was dried Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using ethyl acetate:light petroleum (1:12) as eluent to give ethyl-4-(3-benzyloxy 4-propoxy-5-iodophenyl)-4-oxo-1-butanoate as a syrup (23.80 g, 74%). TLC: Ethyl acetate:light petroleum (1:9), Rf=0.4; 1H NMR (CDCl3, 200 MHz): δ 1.05 (t, J=7.4 Hz, 3H), 1.3 (t, J=6.97 Hz, 3H) 1.78 (m, 2H), 2.7 (t, J=6.5 Hz, 2H), 3.1 (t, J=6.5 Hz, 2H), 4.06 (t, J=5.6 Hz, 2H), 4.18(q, J=7.1 Hz, 2H), 5.12 (s, 2H), 7.33-7.43 (m, 5H), 7.58 (d, J=1.62 Hz, 1H), 7.97 (d, J=1.62 Hz, 1H); IR (neat): 2970, 2930, 1735, 1690, 1585, 1550 cm−1
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10]CC2C=CC=CC=2)=O)[CH:4]2[CH2:18][CH2:19][N:20]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH:3]12.Br.C(O)(=O)C.C1CCN2[C:38](=[N:39]CCC2)[CH2:37]C1.C(CC(OC)=O)#N>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH2:37][C:38]#[N:39])[CH:4]2[CH2:18][CH2:19][N:20]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH:3]12
Reactant: CC1CCN(C(=O)OCc2ccccc2)C2CCN(c3ncnc4[nH]ccc34)C12
Reactant: C1CCC2=NCCCN2CC1
Agent: Br
Agent: COC(=O)CC#N
Solvent: CC(=O)O
Product: CC1CCN(C(=O)CC#N)C2CCN(c3ncnc4[nH]ccc34)C12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product of Example 20 (30 mg, 0.077 mmol), was added HBr in acetic acid (1.5 mL, 0.10 mmol) and the reaction was stirred at room temperature for 2 hours before being concentrated in vacuo and azeotroped with heptanes (×4) and MeOH/heptanes (×3). The solid was dried under high vacuum and was then dissolved in methanol and passed through a Varian StratoSpheres™ SPE PL-HCO3 MP SPE resin and concentrated in vacuo. The solid was dissolved in MeOH (0.4 mL) and DBU (5.8 μL, 0.038 mmol) and methyl cyanoacetate (15.2 mg, 0.153 mmol) were added and the reaction was stirred at 40° C. for 16 hours. The reaction was concentrated in vacuo and the residue was purified by mass triggered reverse phase HPLC. Lyophilization of the desired fractions gave the title product (TFA salt) as a off-white solid. LRMS calc'd for C17H21N6O [M+H]+, 325; found 325. Jak1 activity: +.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:18])=[C:11]([CH3:17])[C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1.Cl.[N:20](=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[OH:21].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:17][C:11]1[C:12](=[O:16])[O:13][C:14]2[C:9]([C:10]=1[CH3:18])=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][C:22](=[N:20][OH:21])[CH2:23][CH2:24]1)[CH:15]=2
Reactant: Cc1c(C)c2ccc(OCCCBr)cc2oc1=O
Reactant: ON=C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(C)c2ccc(OCCCN3CCC(=NO)CC3)cc2oc1=O

Procedure:
By the reaction of 7-(3-bromopropoxy)-3,4-dimethylcoumarin with 4-oximino-piperidine hydrochloride in dioxane solution in the presence of a Hunig base, there is obtained 3,4-dimethyl-7-[3-(4-oximino-piperidino)-propoxy]-coumarin (m.p. 198°-200° C.), from which, by catalytic hydrogenation over Raney nickel in ammoniacal methanol, there is obtained 7-[3-(4-amino-piperidino)-propoxy]-3,4-dimethyl-coumarin; m.p. 92°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24]
Reactant: Cc1n[nH]c(=O)c(-c2cc(F)c(F)cc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2cc(F)c(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
2.09 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,5-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.10 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2,4,5-trifluorophenyl)pyridazine (hereinafter, referred to as compound (vii) of the present invention).