Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+].CN(C)C=O.Br[C@@H:15]1[CH2:41][C@@:40]2([CH3:42])[C@@H:18]([CH2:19][CH2:20][C@@H:21]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:43])[C@H:22]3[CH2:23][C@@H:24]3[O:29][C@@:28]4([O:35][CH2:34][C@H:32]([CH3:33])[CH2:31][CH2:30]4)[C@@H:26]([CH3:27])[C@@H:25]32)[CH2:17][C:16]1=[O:44]>C(OCC)(=O)C>[CH3:27][C@@H:26]1[C@:28]2([O:35][CH2:34][C@H:32]([CH3:33])[CH2:31][CH2:30]2)[O:29][C@H:24]2[CH2:23][C@@H:22]3[C@@:36]([CH3:43])([C@@H:25]12)[CH2:37][CH2:38][C@H:39]1[C@H:21]3[CH2:20][CH2:19][C@@H:18]2[C@:40]1([CH3:42])[CH:41]=[CH:15][C:16](=[O:44])[CH2:17]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)[C@H](Br)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)C=C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 95 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of lithium bromide (0.700 g, 8.06 mmol), lithium carbonate (1.20 g, 16.24 mmol) and anhydrous N,N-dimethylformamide (30 mL) were heated under nitrogen atmosphere to 95° C. To this mixture, (2α,5α,25R)-2-bromospirostan-3-one (4.00 g, 8.11 mmol) was added. The reaction mixture was stirred at 130° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (3×), brine (1×), dried (sodium sulfate), filtered and concentrated in vacuo to afford 3.31 g, (98%) of the title compound.
Reaction SMILES: I[C:2]1[C:10]([N+]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:28][O:27][C:23](=[O:26])[CH:24]=[CH:25][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2
Reactant: C=CC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC(=O)/C=C/c1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (545 mg, 1.49 mmol) (Starting Material 2 supra) in DMF (8 mL) and TEA (3 mL) was added methyl acrylate (0.26 mL, 2.98 mmol) (Aldrich), tri-o-tolylphosphine (361 mg, 1.19 mmol) (Aldrich) and Pd(OAc)2 (67 mg, 0.30 mmol) (Aldrich). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 3-[2,3-dihydro-(Z)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-(E)-2-propenoic acid methyl ester as a yellow solid. (Yield 371 mg, 77%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[CH2:28]([O:30][C:31](=[O:46])[C@@H:32]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:33][CH2:34][C:35](O)=[O:36])[CH3:29].CN1CCOCC1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O>O.C(#N)C>[CH2:28]([O:30][C:31](=[O:46])[C@@H:32]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:33][CH2:34][C:35](=[O:36])[NH:25][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:26]=[CH:27][C:9]([CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:29]
Reactant: CCOC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Reactant: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-ethyl ester (390 mg, 0.67 mmol; 63% purity) described in Manufacturing Example 4-1 and ethanol (4 mL) was added palladium-carbon (40 mg, 0.19 mmol; 50% water content) at room temperature, which was stirred overnight under a hydrogen atmosphere (1 atm) at room temperature. The reaction mixture was replaced with nitrogen and filtered through a Celite pad. The solvent was evaporated from the filtrate under a reduced pressure, so as to obtain (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-ethyl ester (330 mg) in a crude form. The crude product thus obtained was used directly in the next reaction. To a mixture of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (150 mg, 80.42 mmol) described in Reference Example 1 and acetonitrile (3 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-ethyl ester (crude, 230 mg), N-methylmorpholine (46 μL, 0.42 mmol), and 180 mg (0.46 mmol) of 047-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (180 mg, 0.46 mmol) were added in this order at 0° C., which was stirred overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1), so as to obtain the titled compound (47 mg).
Reaction SMILES: C(O[K])(C)(C)C.C1COCC1.[C:12]1([CH3:34])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[C:20]1[C:21]([CH3:33])=[N:22][N:23]2[C:28]3[NH:29][CH2:30][CH2:31][C:27]=3[C:26]([CH3:32])=[N:25][C:24]=12.O>C1COCC1>[C:12]1([CH3:34])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[C:20]1[C:21]([CH3:33])=[N:22][N:23]2[C:28]3[NH:29][CH:30]=[CH:31][C:27]=3[C:26]([CH3:32])=[N:25][C:24]=12
Reactant: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCN4)c(C)c1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2c(C)nn3c2nc(C)c2cc[nH]c23)c(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
1.0 M tert-BuOK/THF (0.29 mL, 0.29 mmol) was added to a solution of 3-mesityl-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (80 mg, 0.261 mmol) prepared in Example 72 in THF (4 mL), which was at room temperature, followed by stirring at room temperature for 15 hours. Water was added, and the mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4 and the solvent was evaporated. The residue was subjected to silica gel column cromatography (25% ethyl acetate/hexane), to give the title compound (50 mg, 63%) as white crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1CCN2C(=NCCC2)CC1>>[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]([N:1]3[CH:5]=[C:4]([C:6]4[C:7]5[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=5[N:9]=[CH:10][N:11]=4)[CH:3]=[N:2]3)[CH2:39][C:40]#[N:41])[CH:35]=[N:36][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=Cc1cncc(N2CCOCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(N5CCOCC5)c4)c3)ncnc21
Reaction time: 8 h
Yield: 125.6 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E & Z)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (70 mg, 0.0003 mol) (mixture of isomers), DBU (50 μL, 0.0003 mol) was added and the resulting mixture was stirred overnight. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-morpholin-4-ylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (200 mg, 100%) as a crude product; LC/MS=531 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.C(N(CC)CC)C.O.Br[C:28](Br)([CH3:30])[CH3:29]>>[CH3:1][N:2]1[CH2:30][CH2:28][CH2:29][N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[CH:4]2[CH2:3]1
Reactant: CNCC1Nc2ccccc2Cc2ccccc21
Reactant: CC(C)(Br)Br
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCCN2c3ccccc3Cc3ccccc3C2C1
Reaction time: 2 h

Procedure:
4.76 g 5,6-dihydro-6-methylaminomethyl-11H-dibenzo[b,e]azepine is dissolved in 125 ml dibromopropane and 5 ml triethylamine is added to the solution. The mixture is boiled under reflux with stirring for 2 hours, after which it is cooled. 150 ml Water is then added and the whole is shaken for a little while, after which the aqueous layer is separated from the dibromopropane layer. The organic layer is subsequently dried over sodium sulphate and evaporated to dryness under vacuum. The residue is further purified chromatographically on a silica gel column with methanol:acetone (9:1) as eluent.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:6][C:5]1=[O:22].C([O-])(O)=O.[Na+].[O:28]=[C:29]1[CH2:34][S:33][C:32]2[CH:35]=[CH:36][C:37]([CH:39]=O)=[N:38][C:31]=2[NH:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[CH3:21][O:20][C:17]1[N:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][CH2:39][C:37]2[CH:36]=[CH:35][C:32]3[S:33][CH2:34][C:29](=[O:28])[NH:30][C:31]=3[N:38]=2)[C:5](=[O:22])[CH2:6]1
Reactant: COc1ccc2nccc(N3CCN(CCN)C(=O)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc(N3CCN(CCNCc4ccc5c(n4)NC(=O)CS5)C(=O)C3)c2n1
Reaction time: 12 h
Yield: 66.7 %

Procedure:
To a solution of 1-(2-aminoethyl)-4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone (46 mg, 0.15 mmol) in DCM-EtOH (2 mL, 1:1) were added NaHCO3 (32 mg, 0.38 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (29 mg, 0.15 mmol). After 12 h, NaBH(OAc)3 (38 mg, 0.15 mmol) was added. After an additional 2 h the solution was partitioned between NaHCO3 (sat)-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 0-7% MeOH in DCM (1% NH4OH)) yielding the title compound (48 mg, 67%) as a yellow solid: LCMS (ES) m/e 480 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.44 (d, J=5.3 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 6.96 (d, J=5.2 Hz, 1H), 4.21 (s, 2H), 4.19-4.22 (m, 2H), 4.03 (s, 3H), 3.82 (s, 2H), 3.69-3.74 (m, 4H), 3.67 (s, 2H), 2.90-2.93 (m, 2H).
Reaction SMILES: [N:1]([C@@H:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:5]([OH:13])[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])=[N+:2]=[N-:3]>C(Cl)(Cl)Cl>[N:1]([C@@H:4]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:5]([O:13][CH2:4][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)COC(=O)[C@@H](O)[C@@H](N=[N+]=[N-])c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)[C@@H](OCc1ccccc1)[C@@H](N=[N+]=[N-])c1ccccc1

Procedure:
Compound 11 (12.6 g, 47 mmol) was benzoylated, as described for 10, to yield (+)-12 (16 g, 88%):[a]D20=+54° (c 2, CHCl3); 1H NMR d 0.93 (d, J=9 Hz, 6 H), 1.75-1.91 (m, 1 H), 3.84-3.90 (m, 2 H), 5.15 (d, J=6 Hz, 1 H), 5.60 (d, J=6 Hz, 1 H), 7.34-7.61 (m, 8 H), 7.99-8.03 (m, 2 H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([CH2:22][C:23](OCC)=[O:24])[N:14]1[CH2:28][CH2:29][CH3:30]>O>[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([CH2:22][C:23]([NH:10][C:9]([NH2:11])=[NH:8])=[O:24])[N:14]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCN1C(=O)c2ccccc2C1CC(=O)OCC
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCCN1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
N-[(3-Oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 3.9 g of potassium tert-butoxide, 3.3 g of guanidinium chloride and 1.8 g of ethyl (3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 1 hour, followed by addition of 60 cm3 of water. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate and is then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. The residue is taken up in water, triturated and filtered. The solid is taken up in methanol and the solvent is then evaporated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. 0.6 g of N-[(3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl)acetyl]-guanidine is thus obtained in the form of a pale yellow cottony solid melting at 229° C. Mass spectrum EI: m/e 274 (M+), m/e 187, m/e 86 (base peak).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C:23](O)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC(C)(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoic acid (60 g, 274 mmol) in anhydrous THF (700 mL) at 0° C. was added DMF (2 mL) followed by oxalyl chloride (48 mL, 548 mmol) portionwise over 1 hour. The mixture was stirred at 0° C. for 30 min, and then at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue dissolved in DCM (700 mL). tert-Butyl alcohol (97 g, 1315 mmol) and pyridine (150 mL) were added, and the reaction mixture was stirred at room temperature for 64 h. The mixture was transferred to a separating funnel and washed with water (400 mL), 2 N NaOH aqueous solution (400 mL) and brine (2×200 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0 to 5% ethyl acetate in heptane over 30 min) to give tert-butyl 4-bromo-2-fluorobenzoate (60 g, 80%) as an oil. LCMS (m/z): 218/220 (MH+ (−tBu)), 1.11 min; 1H NMR (500 MHz, CDCl3) δ ppm 7.81-7.71 (m, 1H) 7.39-7.30 (m, 2H) 7.29 (s, 1H) 1.68-1.55 (m, 9H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:15]([Cl:35])=[CH:16][C:17]([F:34])=[C:18]([C:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[N:22]([CH3:33])[N:21]=2)[CH:19]=1>O1CCCC1>[Cl:35][C:15]1[C:14]([N:13]([S:9]([CH3:8])(=[O:11])=[O:10])[S:9]([CH3:8])(=[O:11])=[O:10])=[CH:19][C:18]([C:20]2[C:24]([C:25]([F:26])([F:27])[F:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[N:22]([CH3:33])[N:21]=2)=[C:17]([F:34])[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nc(-c2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Reaction time: 16 h

Procedure:
1 g (10 mmol) of triethylamine and 0.8 g (6.6 mmol) of methanesulfonyl chloride were added in succession to a solution of 1.2 g (3.3 mmol) of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-4,5-di(trifluoromethyl)-1H-pyrazole in 30 ml of tetrahydrofuran. The reaction mixture was subsequently stirred for 16 hours, whereupon it was concentrated. The residue was treated with water and ethyl acetate. The organic phase which had been separated off was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally concentrated. Yield: quantitative.
Reaction SMILES: [Br:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([N+:24]([O-])=O)[CH:17]=[C:16]([Br:27])[C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:14])=[C:7]([CH3:15])[CH:6]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].CCCCCCC.CCOC(C)=O>CCO.CCOC(C)=O>[NH2:24][C:18]1[CH:17]=[C:16]([Br:27])[C:3]([O:4][C:5]2[CH:10]=[C:9]([CH:11]([CH3:12])[CH3:13])[C:8]([OH:14])=[C:7]([CH3:15])[CH:6]=2)=[C:2]([Br:1])[C:19]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Cc1cc(Oc2c(Br)cc([N+](=O)[O-])c(C(F)(F)F)c2Br)cc(C(C)C)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cc(Oc2c(Br)cc(N)c(C(F)(F)F)c2Br)cc(C(C)C)c1O
Yield: 81 %

Procedure:
4-(2,6-Dibromo-4-nitro-3-trifluoromethylphenoxy)-2-methyl-6-isopropylphenol of Part 11E (120 mg, 0.23 mmol) was dissolved in EtOH (5 mL) and sodium hydrosulfite (204 mg, 1.2 mmol) was added. The reaction mixture was heated at reflux for 48 hours. The reaction progress was monitored by TLC (n-heptane/EtOAc 65:35) and when complete diluted with EtOAc. The organic phase was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified on column (silica gel, gradient elution with n-heptane/EtOAc) to give 90 mg (81%) of 4-(4-amino-2,6-dibromo-3-trifluoromethylphenoxy)-2-methyl-6-isopropylphenol.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21]O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:25]([NH:27][CH2:28][CH2:29][OH:30])[CH3:26]>>[CH2:25]([N:27]([CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:1])[F:23])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:28][CH2:29][OH:30])[CH3:26]
Reactant: OCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CCNCCO
Product: CCN(CCO)CCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 19.1, 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and 2-Ethylaminoethanol were converted to yield 2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amino)-ethanol as light yellow oil, MS: 419 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([N:8]([CH2:10][CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH3:9])=[O:7])=[C:4]([O:23]C)[CH:3]=1.B(Cl)(Cl)Cl.CO.N>ClCCl>[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[O:7])=[C:4]([OH:23])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N(C)CCO[Si](C)(C)C(C)(C)C
Agent: ClB(Cl)Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CN(CCO)C(=O)c1cc(Cl)c(N)cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
4-Amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-2-methoxy-N-methylbenzamide (2.0 g, 5.3 mmol) was stirred in dichloromethane (100 mL) at −10° C. under an atmosphere of nitrogen and a 1M solution of boron trichloride in dichloromethane (10.68 mL, 10.7 mmol) was added dropwise. The reaction was allowed to warm to room temperature then left to stir at this temperature for 18 h. The reaction was cooled to −10° C. and a further 1 equivalent of boron trichloride solution was added dropwise, then the reaction was allowed to warm to room temperature and stirred for 3 h. After this time analysis by LCMS indicated that the reaction was complete. The reaction was cooled in a ice bath and methanol (20 mL) was added drop-wise to the reaction followed by 7N methanolic ammonia solution (17 mL) and then a further portion of MeOH (˜80 mL) until all the solids had dissolved. The solution was stirred for 1 h at room temperature then concentrated. The resulting residue was stirred with saturated aqueous NaHCO3 (150 mL) for 30 min then the aqueous phase was extracted with ethyl acetate. The combined extracts were washed with brine then passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford a green gum (1.00 g, 77%). This material was taken through to the next step with no further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].O1CCCC1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(I)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(I)ccc1F
Reaction time: 8 h
Yield: 88 %

Procedure:
Dissolve 2-fluoro-5-iodobenzaldehyde, (prepared essentially as described in Tet. Lett., 33, 7499, (1992)), (6.54 g, 26.1 mmol) in 4:1 tetrahydrofuran:methanol (200 mL) and treat with sodium borohydride (1.98 g, 52.3 mmol) and stir overnight. Concentrate the reaction mixture, then partition between ethyl acetate and water. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter, and concentrate. Purify the crude oil by silica gel chromatography, eluting with 85:15 hexanes:ethyl acetate, to give the title compound as a white crystalline solid (5.8 g, 88%).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:21]=[C:20]([CH3:28])[N:19]=1>O1CCOCC1>[F:16][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:17][C:18]1[N:23]=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:21]=[C:20]([CH3:28])[N:19]=1)=[O:15])(=[O:12])=[O:11]
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Reactant: Cc1cc(OC(F)F)nc(N)n1
Solvent: C1COCCO1
Product: Cc1cc(OC(F)F)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of 2.5 g of 2-difluoromethoxyphenylsulfonyl isocyanate, 1.75 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine and 30 ml of absolute dioxane is stirred at a temperature of 70°-75° C. for 2 hours. The solution is evaporated and the residue is crystallised from ether to give 4.0 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-difluoromethoxy-6-methyl-pyrimidin-2-yl)-urea of melting point 163°-164° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32].[I-].[Na+]>COCCOC>[OH:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][OH:35])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: OCCNCCO
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN(CCO)CCO
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 525.7 mg (5.0 mmol) of diethanolamine and 75.0 mg (0.5 mmol) of sodium iodide in 6 mL of DME was heated at 135° C. for 15 hr. The work up gave 109.1 mg (47.2%) of the product as a yellow solid, m.p. 150° C. (dec.), mass (electrospray, m/e): M+H 463.0.