Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[N:41]=[CH:40][N:39]=[C:38]2[O:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([O:47][C:38]3[C:37]4[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=4)[N:41]=[CH:40][N:39]=3)[CH:49]=2)=[O:19])[N:7]([CH2:20][CH:21]([CH3:22])[CH3:23])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4CC(C)C)c3)c2cc1OC
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.47 mmol), N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane: methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (60 mg, 38%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.94 (m, 1H), 6.01 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.71 (d, J=7.6 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H), 0.83 (d, J=6.4 Hz, 6H); LC-MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].O.NN>C(O)(C)C.[Ni]>[CH:12]1[C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][NH2:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: [Ni]
Agent: NN
Solvent: CC(C)O
Solvent: O
Product: NCc1ccc(-c2cccc3c2oc2ccccc23)cc1
Yield: 32.1 %

Procedure:
To a solution of 4-(4-cyanophenyl) dibenzofuran (20 g, 0.074 mol) in isopropylalcohol (1.5 L) was added Raney-Nickel (10 g) with stirring. The reaction mixture was heated to reflux, treated with hydrazine hydrate (100 mL) and refluxed for 6 h. The reaction mixture was cooled, filtered through celite and washed with isopropylalcohol. The filtrate was concentrated and crude purified by column chromatography over silica gel (CHCl3/MeOH; 9:1) to give the title compound as a solid (6.5 g, 32%). 1H NMR (THF-d8, 300 MHz) δ 7.30-8.30 (m, 13H), 3.98 (s, 2H)
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[OH-].[Na+]>C(O)(=O)C.C(OCC)C>[Br:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[N:6][CH:7]=1
Reactant: COc1ccccn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of bromine (13.1mL, 256.6 mMol) in glacial acetic acid (45 mL) was added drop wise into a mechanically stirred suspension of 2-Methoxy-pyridine (19 mL, 183 mMol) in glacial acetic acid (88 mL) with the temperature kept at ten degrees. After complete addition the solution was allowed to stir overnight while gradually warming to room temperature. Upon arrival the reaction mixture was poured over ice and the pH adjusted to eight with solid sodium hydroxide. The material was then diluted with diethyl ether (150 mL) and filtered thru Celite. The aqueous layer was extracted with diethyl ether (2×100 mL) and ethyl acetate (2×100 mL) and all the organics combined. The solution was dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator to a dark brown oil. The oil was eluted thru a plug of silica gel with hexanes and concentrated to yield 22.6 g (66% yield) of 5-Bromo-2-methoxy-pyridine as a clear oil. 1H NMR (DMSO-d6): δ=8.29 (dd,1H,J=2.6,0.5 Hz), 7.89 (dd, 1H, J=8.8, 2,6 Hz), 6.84 (dd, 1H, J=8.8, 0.5 Hz), 3.84 (s, 3H). LC/MS (Method A), rt=1.35 mins., purity=76.5%, calculated mass=187,[M+H]+=188/190, [M−H]− 187/189. HPLC (Method C): rt=8.1 mins., purity=88.0% @ 210-370 nm and 88.3% @ 286 nm.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:6]=2[C:5]1=[O:23])[CH:2]=[CH2:3].C12BC(CCC1)CCC2.C1C[O:36]CC1>>[OH:36][CH2:3][CH2:2][CH2:1][N:4]1[CH2:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:6]=2[C:5]1=[O:23]
Reactant: C=CCN1CC(Cc2ccccc2)Oc2ccc(I)cc2C1=O
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: O=C1c2cc(I)ccc2OC(Cc2ccccc2)CN1CCCO
Reaction time: 1 h
Yield: 77 %

Procedure:
To a magnetically stirred solution of 2-allyl-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one (0.9234 grams, 2.2 mmol) in 4 mL THF at room temperature under an atmosphere of nitrogen was added 6.0 mL of a 0.5M solution of 9-borabicylo[3.3.1]nonane in THF (3 mmol) and the mixture stirred for 1 hour. The reaction was quenched with 6 mL of a solution of 2 grams of sodium hydroxide and 22 mL of a 1:1 mixture of ethanol and water. To the resulting solution was added 7 mL of a 30% solution hydrogen peroxide in water. After 30 minutes the mixture was partitioned between diethyl ether and water. The organic layer was washed with 10% citric acid and brine, dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (SiO2, using 1:5 ethyl acetate/methylene chloride as the eluting solvent, Rf (product)=0.22) to yield 0.74 grams (77%) of 2-(3-hydroxypropyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one. 1H NMR (CDCl3, dTMS) 8.08 (1H, d, 4JHH =2 Hz, C9-H), 7.71 (1H, dd, 4JHH =2 Hz, 3JHH =8 Hz, C7-H), 7.4 -7.2 (5H, m, C6H5), 6.78 (1H, d, 3JHH =8 Hz, C6-H), 4.64 (1H, m, ArOCH), 3.70 (2H, m, CH2OH), 3.58 (2H, bt, 3JHH =5 Hz, NCH2CH2), 3.39 (1H, dd, 2JHH =15 Hz, 3JHH =8 Hz, C3-H), 3.24 (1H, dd, 2JHH =15 Hz, 3JHH =3 Hz, C3-H), 3.1 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh), 2.76 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh), 1.68 (2H, m, CH2CH2OH). 13C NMR (CDCl3) 168.3, 152.6, 141.6, 139.4, 136.2, 132.1, 131.9, 129.2, 129.0, 128.8, 128.4, 127.0, 124.7, 86.8, 85.7, 58.0, 49.9, 44.5, 38.8, 30.3. IR (NaCl, cm-1) 3422 (b), 1636, 1463, 1436, 1217, 1064.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([I:17])=[CH:10][CH:9]=2)=O.[OH-].[NH4+:19]>>[I:17][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([C:3]([NH2:19])=[O:2])=[C:14]2[O:15][CH3:16]
Reactant: COC(=O)c1cnc2ccc(I)cc2c1OC
Reactant: [NH4+]
Agent: [OH-]
Product: COc1c(C(N)=O)cnc2ccc(I)cc12
Temperature: 150 °C
Yield: 88 %

Procedure:
A suspension of 6-iodo-4-methoxy-quinoline-3-carboxylic acid methyl ester (example 1d) (1.7 g, 5 mmol) in ammonium hydroxide (28%, 75 mL) was heated at 150° C. for 4 days under pressure tube. After cooling, the solvent was removed by rotary evaporator. The solid was collected by filtration, washed with water and dried to obtain 6-iodo-4-methoxy-quinoline-3-carboxylic acid amide (1.4 g, 88%) as a black solid. LC-MS m/e 329 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(O)C.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCCC2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(3-Cyanophenyl)-N′-(1-benzylpiperidin-4-yl)cycloheptylurea (0.1 g 0.26 mmol) was dissolved in ethanol (10 ml) and cyclohexene (2 ml). Palladium hydroxide catalyst (0.05 g) was added and the reaction was heated at reflux under a nitrogen atmosphere. After 30 min the reaction was allowed to cool to ambient temperature, filtered and concentrated to give a viscous oil. The crude product was purified by flash chromatography on silica gel by eluting with methylene chloride:methanol 85:15 with 3% triethylamine. The product, N-(3-cyanophenyl)-N′-(piperidin-4-yl)cycloheptylurea, was concentrated to give an oil which crystallized from ethyl ether (0.05 g, 48%, mp 157-8° C.); LRMS (M+H)+ m/z 299; 1H NMR (CDCl3): 7.5-7.3(m, 4H), 4.05(m, 1H), 3.60(m, 2H), 3.32(m, 2H), 3.17(m, 2H), 2.72(m, 2H), 2.0-1.6(m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH:11]=[CH:12][CH2:13]C.C1(C)C=CC=CC=1>O>[CH2:12]([C:11]1[C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[C:3]=2[O:9][CH:10]=1)[CH3:13]
Reactant: CCC=CCOc1ccc(F)cc1Br
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1coc2c(Br)cc(F)cc12

Procedure:
Beginning with pent-2-en-1-yl 2-bromo-4-fluorophenyl ether, the title compound was prepared essentially as described in Preparation XVII, except that Amberlyst 15™ resin in refluxing toluene was used in place of sulfuric acid, and water was removed by azeotropic distillation with a Dean-Stark trap.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([NH2:23])[N:9]=2)=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[CH:10]([NH:23][C:25](=[O:26])[O:27][CH2:28][CH3:29])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2N
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a round bottomed flask was added 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-amine (218 mg, 0.67 mmol). The flask was purged with nitrogen, MeCN was added (7 mL), and the solution was cooled to 0° C. Ethyl chloroformate (78 μL, 0.81 mmol) and triethylamine (122 μL, 0.88 mmol) were added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO3:brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated and purified on a Biotage (isocratic elution 25% EtOAc: 75% Hexanes) to provide the title compound as white solid (120 mg). The enantiomers were separated by chrial SFC using a 3.0×25.0 cm RegisPack column, with 35% cosolvent (1:1 MeOH:i-PrOH), 80 mL/min at 100 bar. Rention time peak 1 (compound 253): 1.48 min, 100% ee. Retention time peak 2 (compound 254): 2.96 min, 98.1% ee.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[O:25][CH3:26])(=O)C.C(Cl)(=O)C>CO>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[O:25][CH3:26]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1OC
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
Methyl 4-acetamido-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-methoxypicolinate (209 mg, 0.55 mmol) was dissolved in CH3OH (10 mL), and acetyl chloride (194 μL, 2.73 mmol) was added dropwise to the mixture. The reaction mixture was allowed to stir at 25° C. for 3 h. Additional acetyl chloride (194 μL, 2.73 mmol) was then added, and the reaction mixture was allowed to stir at 25° C. overnight. The reaction mixture was concentrated to dryness and purified by flash chromatography (SiO2; 0-50% EtOAc/hexane gradient) to provide the title compound as an off-white solid (30 mg, 16%): mp 114-118° C.; 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J=8.5, 7.8 Hz, 1H), 7.22 (dd, J=8.6, 1.8 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 4.54 (s, 1H), 3.98 (s, 2H), 3.96 (d, J=0.8 Hz, 2H), 3.92 (s, 2H); ESIMS m/z 341 ([M+H]+), 339 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([NH2:31])[CH2:27][CH2:26]3)=[O:24])[C:17]=2[CH:32]=1.[OH-].[Na+].O>O1CCOCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:26][CH2:27][N:28]([NH:31][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:29][CH2:30]3)=[O:24])[C:17]=2[CH:32]=1
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 4-fluorobenzoyl chloride (761 mg) in dioxane (3 ml) was added dropwise to a mixture of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (872 mg), 1N-NaOH (5.3 ml), dioxane (30 ml) and water (5 ml) at 5° C. The resulting mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue obtained was filtered, washed with water and ethyl acetate, and recrystallized from methanol to give 5-chloro-3-{[4-(4-fluorobenzamido)-1-piperazinyl]carbonylmethyl}-2-benzothiazolinone (0.61 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[OH-].[K+].[CH2:15](Br)[CH3:16]>CS(C)=O>[CH2:15]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[C:2]([CH3:1])=[CH:3]1)[CH3:16]
Reactant: CCBr
Reactant: COc1ccc2c(C)c[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1cc(C)c2ccc(OC)cc21
Yield: 72.2 %

Procedure:
3.12 g of 4.4'-bis-dimethylaminobenzophenone-2-carboxylic acid and 1.9 g of 1-ethyl-3-methyl-6-methoxyindol are stirred at 40° C. in 30 ml of acetic anhydride for 3 hours. The reaction mixture is poured onto ice, the resulting mixture is basified with NaOH and extracted with toluene. The organic phase is separated off, and treated with active carbon, dried and evaporated. The residue is decrystallized once from diethyl ether and once from toluene to give 3.35 g of 3-(4-dimethylaminophenyl)-3-(1-ethyl-3-methyl-6-methoxyindol-2-yl)-6-dimethylaminophthalide of the formula ##STR113## melting point 224°-225° C. On acid clay this compound produces a blue colour. The 1-ethyl-3-methyl-6-methoxyindol used is prepared as follows: 4.6 g of 3-methyl-6-methoxyindole [Chem ber 98, 1727 (1965)]are presented in 29 ml of dimethyl sulfoxide. 6.6 ml of 10 n aqueous KOH are then added, and 3.25 g of ethyl bromide are added dropwise at 20° C. in the course of 30'. 1 hour later the reaction mixture is poured onto water and extracted with toluene. Chromatography over silica gel (hexane/ether 5:1) gives 3.9 g of 1-ethyl-3-methyl-6-methoxyindol in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[CH:18][CH:19]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[CH:18][N:17]([CH2:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[N:16]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1
Reactant: BrCCC1CC1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(-c2ccn(CCC3CC3)n2)sc1C(=O)NCc1ccc(F)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)thiazole-5-carboxylic acid 4-fluoro-benzylamide and (2-bromo-ethyl)cyclopropane as describe in Example 83 and isolated as a white solid (0.045 g, 38% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J=2 Hz, 1H), 7.29-7.35 (m, 2H), 7.05 (t, J=8 Hz, 2H), 6.80 (d, J=2 Hz, 1H), 5.96-6.01 (bm, 1H), 4.57 (d, J=4 Hz, 2H), 4.23 (t, J=7 Hz, 2H), 2.75 (s, 3H), 1.78 (q, J=7 Hz, 2H), 0.58-0.68 (m, 1H), 0.40-0.48 (m, 2H), 0.0-0.04 (m, 2H); MS (M+H)+=385.2; Rt=1.48 min; HRMS (M+H)+=385.15.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:5]([NH2:20])=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:20][C:21](=[O:22])[N:8]([CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])[C:6]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1cc(Br)ccc1N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCn1c(=O)[nH]c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
5-Bromo-N1-(3-((tert-butyldimethylsilyl)oxy)propyl)benzene-1,2-diamine (1.8 g, 5.14 mmol) was dissolved in dry THF (50 mL) and 1,1′-carbonyl-diimidazole (0.92 g, 5.65 mmol) was added. The dark brown solution was stirred at room temperature under nitrogen overnight. The mixture was diluted with ethyl acetate and washed with water then brine and dried over anhydrous magnesium sulfate. After filtration and concentration the crude product was chromatographed on silica gel eluting with 5-50% ethyl acetate in hexanes to give 6-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-benzo[d]imidazol-2(3H)-one as a purple oily foam (1.14 g, 2.96 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=S)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C(OCCO)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: S=C1Nc2ccc(Cl)cc2Nc2ccccc21
Reactant: NCc1cccnc1
Solvent: CCOCCO
Product: Clc1ccc2c(c1)Nc1ccccc1C(NCc1cccnc1)=N2
Yield: 59 %

Procedure:
A solution of 0.41 g (1.57 mmol) of 7-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL 2-ethoxyethanol was treated with 0.32 mL (3.14 mmol) of 3-(aminomethyl)pyridine and heated at reflux for 22 hours. The solvent was removed under reduced pressure and the residue mixed with EtOAc and filtered to give 0.31 g of product. The filtrate was concentrated and chromatographed on silica gel, eluting with EtOAc to give an additional 0.16 g of product. The material was combined and recrystallized from EtOAc/hexane to give 0.3 g (56.6% yield) of the product as a pale yellow solid, mp 218-220° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =335.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH:7]1[CH2:12][CH2:11][C:10]([OH:16])([C:13]([OH:15])=O)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH:28][C:13]([C:10]2([OH:16])[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[O:15])[CH3:27])=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)(C(=O)O)CC1
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)C1(O)CCC(O[Si](C)(C)C(C)(C)C)CC1)c1ccc(F)cc1
Yield: 44 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-1-hydroxy-cyclohexanecarboxylic acid (Intermediate 79, 1.15 g) and with (R)-1-(4-Fluoro-phenyl)-ethylamine (640 mg) were coupled using the standard HATU coupling procedure as described in Example 1 to yield a 3:2 mixture (A:B) of diastereomers the title compound (44%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:14])=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1.CC(O)=O.[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[CH2:20]>CO>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:19][CH2:20][NH:1][C:2]1[C:3]([F:14])=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1c(F)ccc(N)c1F
Reactant: C=Cc1ccccn1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1c(F)ccc(NCCc2ccccn2)c1F

Procedure:
A solution of 402 mg (2.0 mmol) of methyl 3-amino-2,6-difluorophenylacetate (prepared in step 3 of example 24) in 15 mL of MeOH was treated with 1.1 mL (20.0 mmol) of HOAc and 0.28 mL (2.6 mmol) of 2-vinylpyridine. The reaction mixture was stirred at reflux for 16 h. The mixture was cooled and the acetic acid was removed in vacuo. The residue was dissolved in EtOAc and washed with saturated NaHCO3 (4×5 mL), water (1×10 mL) and brine. Column chromatography (1:4 EtOAc/Hex) afforded methyl 3-(2-pyridylethyl)amino-2,6-difluorophenylacetate.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>ClCCl.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]=2[CH:5]=1
Reactant: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(N)ccc21

Procedure:
To a solution of 2-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (79.0 g, 0.339 mol) in dichloromethane as added 1 g of 10% palladium on carbon and the mixture was hydrogenated at 40–50 psi of hydrogen for 20 hrs. The catalyst was removed by filtration and the organic and the aqueous layers were separated. The aqueous layer was made alkaline by addition of 1N NaOH and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated to give 2-amino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene as a red-orange solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[CH:20]=[CH:19][CH:18]=[C:17]([C:22]#[N:23])[C:16]=4[C:15]([CH:24]=[O:25])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.[OH:26]O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[C:17]([C:22]#[N:23])[CH:18]=[CH:19][CH:20]=4)[C:15]([C:24]([OH:26])=[O:25])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: OO
Reactant: N#Cc1cccc2c1c(C=O)nn2Cc1cc(-c2ccc(Cl)s2)on1
Product: N#Cc1cccc2c1c(C(=O)O)nn2Cc1cc(-c2ccc(Cl)s2)on1

Procedure:
The title compound was prepared analogously to example 1 (iii) with the difference that 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3-formyl-1H-indazole-4-carbonitrile was used instead of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3-formyl-1H-indazole-5-carboxylic acid methyl ester and that a modified oxidation procedure described by E. Dalacanale et al. J. Org. Chem. (1986) 51, 567 employing H2O2 instead of 2-methylbutene was utilized.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([S:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15])[CH2:8][CH2:9][CH3:10].O>C1COCC1>[CH2:7]([S:11][C:12]1[C:13]([CH2:14][OH:15])=[CH:17][CH:18]=[CH:19][N:20]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCSc1ncccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCSc1ncccc1CO
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Anhydrous THF (30 mL) in dried flask was cooled to 0° C., LAH (1.14 g, 30 mmol) was added slowly thereto, and the mixture was stirred for 30 minutes. 2-Butylsulfanyl-nicotinic acid (1.27 g, 5.58 mmol) obtained in Step A which is dissolved in anhydrous THF (10 mL) was added slowly thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, water (10 mL) was added slowly thereto at 0° C., and the mixture was stirred for 30 minutes. The reactant was extracted with EtOAc, and the organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.85 g, 77%).