Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]1[CH:22]=[C:21]([CH2:23]Br)[O:20][N:19]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:25]([O:27][C:28](=[O:42])[CH:29]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[CH2:33]([O:32][C:30](=[O:31])[C:29]([NH:35][C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])([CH2:23][C:21]1[O:20][N:19]=[C:18]([CH:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH:22]=1)[C:28]([O:27][CH2:25][CH3:26])=[O:42])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cc(CBr)on1
Reactant: C=CCOC(=O)NC(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A dimethyl formamide (260 mL) solution of 2-(5-Bromomethyl-isoxazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.29 g, 56 mmol) and 2-allyloxycarbonylamino-malonic acid diethyl ester (8.25 g, 32 mmol) was cooled to 0° C. and cesium carbonate (25.41 g, 78 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was then poured into diethyl ether (2 L) and washed with water (5×200 mL) and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with ethyl acetate:hexane (3:7) to afford the title compound as a clear colorless oil (10.95 g; 83%). MS (Cl) m/z 260.1 (M-99).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[OH:12])(=[O:4])=[O:3].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(#N)C>[C:20]([O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CS(=O)(=O)NC1CCCCC1O
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)OC1CCCCC1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
In a nitrogen atmosphere, a mixture of 108 g of 1,2-epoxycyclohexane, 95.1 g of methanesulfonamide, 11.2 g of t-butoxypotassium, and 1,000 g of tetrahydrofuran was heated under reflux for 100 hours. The reaction solution was neutralized with hydrochloric acid and then subjected to conventional aqueous work-up. Purification by column chromatography yielded an alcohol compound, 2-[(methylsulfonyl)amino]cyclohexanol. In a nitrogen atmosphere, the alcohol compound was combined with 111 g of triethylamine and 2,000 g of acetonitrile, to which 105 g of methacryloyl chloride was added dropwise at −20° C. The mixture was gradually warmed to room temperature and then stirred for 10 hours. The reaction mixture was subjected to conventional aqueous work-up and purified by column chromatography, obtaining 165 g of 2-[(methylsulfonyl)amino]-cyclohexyl methacrylate. The yield was 63% based on the methanesulfonamide.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH3:23])[CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH3:23])[C:17]3([CH2:2][CH2:3][OH:4])[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: OCCBr
Reactant: CN(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(c1)OCCO2)C1(CCO)CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.4 %

Procedure:
2-Bromo-ethanol (36 μL, 0.51 mmol, 1.0 eq) is added at room temperature to a stirred solution of (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-piperidin-4-yl-amine (148 mg, 0.51 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by potassium carbonate (70 mg, 0.51 mmol, 1.0 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×8 mL) and water (8 mL). pH of the aqueous layer is neutralized with a 0.1 N hydrochloric acid aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 2-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidin-4-yl}-ethanol as a yellow semisolid (160 mg, 93% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[N:24][CH:23]=[C:22]([CH3:26])[N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[N:24][CH:23]=[C:22]([CH3:26])[N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Reactant: Cc1cncc(Br)n1
Product: Cc1cncc(-c2cc(C)c(Br)c(C)c2)n1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-6-methyl-pyrazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.04 min; Mass spectrum (ESI+): m/z=277/279 (Br) [M+H]+.
Reaction SMILES: C1C[O:4]CC1.C(O[C:14]1[CH:15]=[C:16]2[N:26]([C:27]([C:29]3[NH:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([O:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])=[CH:33][CH:32]=4)=[O:28])[CH2:25][CH:24]([CH2:44][Cl:45])[C:17]2=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)C1C=CC=CC=1>O.[Pd]>[Cl:45][CH2:44][CH:24]1[C:17]2=[C:18]3[C:23](=[CH:14][CH:15]=[C:16]2[N:26]([C:27]([C:29]2[N:30]=[C:31]4[C:36]([CH:37]=2)=[CH:35][C:34]([O:38][CH2:39][CH2:40][N:41]([CH3:42])[CH3:43])([OH:4])[CH:33]=[CH:32]4)=[O:28])[CH2:25]1)[N:22]=[CH:21][CH:20]=[CH:19]3
Reactant: C1CCOC1
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(OCc3ccccc3)c3ncccc43)cc2c1
Agent: [Pd]
Solvent: O
Product: CN(C)CCOC1(O)C=CC2=NC(C(=O)N3CC(CCl)c4c3ccc3ncccc43)=CC2=C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 93 %

Procedure:
THF (8 mL) then HCO2N4 (0.23 g, 3.6 mmol) in H2O (1 mL) were added to cooled (0° C.) mixture of 17b (0.20 g 036 mmol) and 10% Pd/C (0.1 g) under N2. The mixture was stirred at 0° C. for 14 h, and was then filtered through Celite. The Celite was washed with CH2Cl2/H2O. The aqueous layer was extracted with CH2Cl2(×3). The CH2Cl2 extracts were dried (brine, Na2SO4) and passed through a short plug of silica gel to give 18b (0.16 g, 93%) as a yellow solid: mp 209–215° C.; 1H NMR [(CD3)2SO]δ 11.66 (s, 1 H), 10.02 (bs, 1 H), 8.76 (dd, J=4.1, 1.4, 1 H), 8.41 (dd, J=8.5, 1.3, 1 H), 8.07 (s, 1 H), 7.56 (dd, J=8.5, 4.1, 1 H), 7.40 (d, J=8.9, 1 H), 7.17 (d, J=2.2, 1 H), 7.11 (d, J=1.2, 1 H,) 6.93 (dd, J=8.9, 2.3, 1 H), 4.82 (dd, J=10.7, 9.6, 1 H), 4.57 (dd, J=11.0, 2.1, 1 H), 4.29 (m, 1 H), 4.06 (t, J=5.9, 2 H), 4.04 (m, 1 H), 3.91 (dd, J=11.1, 7.2, 1 H), 2.64 (t, J=5.8, 2 H), 2.28 (s, 6 H); 13C NMR [(CD3)2SO]δ 160.3, 153.9, 153.0, 146.4, 142.8, 136.1, 131.6, 130.7, 127.4, 124.8, 124.7, 122.5, 116.0, 114.6, 113.1, 105.5, 103.1, 103.0, 66.1, 57.8, 54.9, 47.7, 45.5, 40.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:29]1[CH2:30][CH2:31][CH:27]([S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH2:28]1)=[O:15]
Reactant: Cc1ccc(S(=O)(=O)C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: Cl
Product: Cc1ccc(S(=O)(=O)C2CCN(C(=O)c3cnoc3-c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-methylphenylsulfonyl)pyrrolidine hydrochloride (15.7 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (13.3 mg). Calcd for C21H19ClN2O4 S: 430.0754, found 430.0753.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:33]>>[OH:24][C:21]([CH3:22])([CH3:23])[C:20]#[C:19][C:16]1[CH:17]=[CH:18][C:11]2[O:10][CH2:9][CH:8]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:7]3[S:6][C:5]([C:3]([NH2:33])=[O:2])=[N:14][C:13]=3[C:12]=2[CH:15]=1
Reactant: COC(=O)c1nc2c(s1)C(N1CCOCC1)COc1ccc(C#CC(C)(C)O)cc1-2
Reactant: N
Solvent: CO
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(N1CCOCC1)CO2
Yield: 64 %

Procedure:
A solution of 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-morpholin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (130 mg, 0.30 mmol) in methanol-ammonia (5 mL) was stirred at room temperature for 0.5 h. Then the reaction mixture was concentrated to afford crude compound which was triturated with EtOAc to afford compound 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-morpholin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (80 mg, 64%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J=1.88 Hz, 1H), 8.41 (s, 1H), 7.86 (s, 1H), 7.27 (dd, J1=8.4 Hz, J2=1.92 Hz, 1H), 7.02 (d, J=8.32 Hz, 1H), 5.43 (s, 1H), 4.40 (m, 3H), 3.54 (m, 4H), 2.65 (m, 4H), 1.46 (s, 6H); LC-MS (ESI & APCI): 414.6 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH2:35][C:36]#[N:37])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH2:35][C:36]#[N:37])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(OCc5ccccc5)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(OCc2ccccc2)C1

Procedure:
3-(Benzyloxy)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.024 g, 0.000046 mol) was treated with trifluoroacetic acid (0.5 mL, 0.006 mol) at rt for 30 min, then evaporated to dry. The residue was dissolved in MeOH (1 mL) and treated with ethylenediamine (0.2 mL, 0.003 mol) at rt for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue purified on prep. HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give 2 isomers of the desired products. First peak retention time 1.406 min; LCMS calculated for C22H21N6O(M+H)+: 385.2; Found: 385.3. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (1H, br s), 8.71 (1H, s), 8.67 (1H, s), 8.38 (1H, s), 7.58 (1H, d, J=3.6 Hz), 7.33 (4H, m), 7.29 (1H, m), 7.05 (1H, d, J=3.6 Hz), 4.43 (2H, s), 4.23 (1H, m), 3.43 (2H, s), 2.78 (2H, m), 2.74 (2H, m) ppm. Second peak retention time 1.474 min, LCMS calculated for C22H21N6)(M+H)+: 385.2; Found: 385.3. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (1H, br s), 8.79 (1H, s), 8.67 (1H, s), 8.39 (1H, s), 7.59 (1H, d, J=3.6 Hz), 7.34 (4H, m), 7.29 (1H, m), 7.06 (1H, d, J=3.6 Hz), 4.44 (2H, s), 4.14 (1H, m), 3.44 (2H, s), 3.16 (2H, m), 2.44 (2H, m) ppm.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[S:14][C:15]([C:18]([O-:20])=O)=[CH:16][N:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[N:22]1[CH:23]=[CH:24][N:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][C:26]=12.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[N:22]1[CH:23]=[CH:24][N:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:18]([C:15]3[S:14][C:13]([CH:10]4[CH2:9][CH2:8][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:12][CH2:11]4)=[N:17][CH:16]=3)=[O:20])=[CH:27][C:26]=12
Reactant: NCc1ccn2ccnc2c1
Reactant: O=C([O-])c1cnc(C2CCN(c3ccccc3)CC2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NCc1ccn2ccnc2c1)c1cnc(C2CCN(c3ccccc3)CC2)s1
Reaction time: 8 h

Procedure:
Lithium 2-(1-phenylpiperidin-4-yl)thiazole-5-carboxylate (28.8 mg, 0.098 mmol), imidazo[1,2-a]pyridin-7-ylmethanamine (17.31 mg, 0.118 mmol), 4-methylmorpholine (49.6 mg, 0.490 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (55.9 mg, 0.147 mmol) were combined in a vial with dichloromethane (2.5 ml) and the reaction was stirred overnight. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate. The organic layers were dried with sodium sulfate, filtered, and concentrated. Trituration of the crude material with dichloromethane provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.21 (t, J=5.9 Hz, 1H), 8.49 (dd, J=7.0, 0.9 Hz, 1H), 8.34 (s, 1H), 7.91-7.88 (m, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.43-7.38 (m, 1H), 7.26-7.16 (m, 2H), 7.01-6.93 (m, 2H), 6.84 (dd, J=7.0, 1.7 Hz, 1H), 6.81-6.72 (m, 1H), 4.48 (d, J=5.9 Hz, 2H), 3.81-3.73 (m, 2H), 3.24-3.01 (m, 1H), 2.90-2.78 (m, 2H), 2.19-2.09 (m, 2H), 1.90-1.73 (m, 2H); MS (ESI(+)) m/e 418 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.4 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (61 mg, 51%).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[C@@H:15]([NH:24]C(OC(C)(C)C)=O)[CH2:16][C:17]2[C:18]([OH:23])=[N:19][O:20][C:21]=2[CH3:22])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:32])[C@@H:15]([NH2:24])[CH2:16][C:17]2[C:18]([OH:23])=[N:19][O:20][C:21]=2[CH3:22])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2c(O)noc2C)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2c(O)noc2C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 146 mg 4-[(S)-2-tert-Butoxycarbonylamino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propionyl]-piperazine-1-carboxylic acid butyl ester in 5 ml dichloromethane were added 0.4 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 156 mg.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[OH:38]/[N:37]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(O)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCC(O)C(F)(F)F)cc1

Procedure:
In analogy to example 151, step 3, 4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=502.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([O:9][C@H:10]2[C@@:15]([OH:17])([CH3:16])[C:14]([CH3:19])([CH3:18])[O:13][C:12]3[CH:20]=[CH:21][C:22]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[C:29]([O:35]C)[CH:28]=4)(=[O:26])=[O:25])=[CH:23][C:11]2=3)=[N:3]1.O>ClCCl.B(Br)(Br)Br>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([O:9][C@H:10]2[C@@:15]([OH:17])([CH3:16])[C:14]([CH3:19])([CH3:18])[O:13][C:12]3[CH:20]=[CH:21][C:22]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([OH:35])[CH:28]=4)(=[O:26])=[O:25])=[CH:23][C:11]2=3)=[N:3]1
Reactant: COc1ccc(S(=O)(=O)c2ccc3c(c2)[C@@H](Oc2ccc(=O)n(C)n2)[C@](C)(O)C(C)(C)O3)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccc(O)c(O)c4)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
(3S,4R)-3,4-Dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-6-(3,4-dimethoxyphenyl)sulphonyl-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.50 g) (see Preparation 26) was dissolved in dichloromethane (12 ml) (under a nitrogen atmosphere) and boron tribromide (4 ml of a 1M solution in dichloromethane) was added. The mixture was stirred at room temperature for one hour and a precipitate was formed. Water (20 ml) and dichloromethane (15 ml) were added, an insoluble gum formed and the solvents were decanted off. The gum was then chromatographed on silica using 1:9 methanol: dichloromethane as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-6-(3,4-dihydroxyphenyl)sulphonyl-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.33 g) as a white foam which was then triturated with diethyl ether and dried to give a white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH2:42]([N:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)[CH3:43]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:50][CH:47]5[CH2:48][CH2:49][N:44]([CH2:42][CH3:43])[CH2:45][CH2:46]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CCN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.2 mL (1.1 mmole) of ethyldiisopropyl amine and 0.034 g (0.26 mmole) of 1-ethyl-piperidin-4-ylamine in 4.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) gave 0.070 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide (I-67) as a white solid.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][CH2:15][C:16](OC)=[O:17].C[O-].[Na+]>COCCOCCOC>[CH3:13][O:14][CH2:15][C:16]([O:12][CH2:11][CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)=[O:17]
Reactant: OCCn1cnc2ccccc21
Reactant: COCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: COCC(=O)OCCn1cnc2ccccc21
Yield: 65 %

Procedure:
In a nitrogen atmosphere, a mixture of crude 2-(1H-benzimidazol-1-yl)ethanol as prepared in Synthesis Example 1, 156 g of methyl methoxyacetate, 3.0 g of sodium methoxide, and 200 g of diglyme was heated under reflux for 20 hours while distilling off the methanol formed during the reaction. The solvent was distilled off in vacuo. The reaction mixture was subjected to conventional aqueous work-up and then purified by column chromatography, obtaining 2-(1H-benzimidazol-1-yl)ethyl methoxyacetate (yield 65%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[CH2:4][O:3][CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1
Reactant: COC(=O)CO
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% NaH (2.66 g) in DMF (20 mL) was added methyl hydroxyacetate (5.00 g) under ice-water cooling, and the mixture was stirred at 0° C. for 0.5 hour. To this was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (12.8 g) under ice-water cooling, and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1-3:1) to give methyl[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate pale yellow oil (4.45 g).
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.CCN(CC)CC>ClCCCl>[CH3:2][C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)[Si](Oc1ccc(C=O)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
At 0° C., tert-butyldiphenylchlorosilane (50 g) was added slowly to a solution of p-hydroxybenzaldehyde (22 g) and Et3N (42 mL) in 1,2-dichloroethane (400 mL) and the mixture was stirred at room temperature a few hours. After the usual work up, the product was purified by flash chromatography on silica using EtOAc:hexane 1:10 and was used as such for Step 2.