Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[N:11]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:10]1[N:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1
Reactant: COCCCO
Reactant: Nc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1cccc(N)n1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Into a 250 mL round bottom flask was added 3-methoxy-propanol (5.26 g, 58.4 mmol) and DMF (156 mL). Sodium hydride (60%, 4.67 g, 3 eq) was added slowly to the solution. After addition the mixture was heated to 90° C. for one hour. 2-chloro-6-amino-pyridine was added and the mixture was heated to reflux for four hours. LCMS showed conversion to product. The reaction was cooled to room temperature and solvent was removed under vacuum. The residue was partitioned between water and ethyl acetate. Organic layer was separated and the aqueous was extracted three times with ethyl acetate (3×50 mL). Organic layer dried over sodium sulfate and filtered; the solvent was removed under vacuum. The residue was dissolved with 2N HCl in MeOH and stirred for five hours at room temperature; the solvent was removed and the residue was purified by column chromatography with 20% ethyl acetate in hexanes yielding 3.12 g (45%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:25]=[O:26])=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].CC(=CC)C.[O-:32]Cl=O.[Na+]>CC(O)(C)C.CC#N.O>[CH2:15]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:14]=2)[C:10]([C:25]([OH:32])=[O:26])=[C:11]1[CH:22]([CH3:23])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure D. To a solution of ethyl1-benzyl-3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 35, 220 mg, 0.63 mmol) in t-BuOH (6 ml), CH3CN (1 ml), and 2-methyl-2-butene (1.76 ml) was added a solution of NaH2PO4 (1.51 g, 12.6 mmol) and NaClO2 (80%, 1.13 g, 12.6 mmol) in H2O (6 ml). The mixture was stirred at room temperature fro 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([NH:8][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:7])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(N)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(N)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-amino-(S)-α-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 518 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:7]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=O)=[CH:18][CH:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:6]([CH2:35][CH3:36])[CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[C:26]([C:27]3[NH:31][C:30]([O:32][CH2:33][CH3:34])=[N:29][N:28]=3)=[CH:25][C:7]([C:8]([N:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:24]=[CH:23][C:19]([C:20]#[N:22])=[CH:18][CH:17]=4)[CH2:14][CH2:15]3)=[O:9])=[C:6]([CH2:35][CH3:36])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C(N)=O)cc4)CC3)c(CC)cc2C2CC2)[nH]1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(CC)cc2C2CC2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of 4-(1-(4-cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide (compound 228.4, 80.0 mg, 0.160 mmol, 1.00 equiv) in dichloromethane (10 mL). Trifluoroacetic anhydride (34.0 mg, 0.160 mmol, 1.00 equiv) and triethylamine (33.0 mg, 0.330 mmol, 2.00 equiv) were added dropwise to the stirred mixture. The resulting solution was stirred for 2 h at 25° C., then washed with 1×10 mL of brine. The aqueous layer was extracted with 2×20 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (42% CH3CN up to 57% in 8 min, up to 100% in 1.5 min, down to 42% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 15 mg (20%) of the title compound as a an off-white solid. m/z (ES+) 470 (M+H)+. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.64 (d, 2H), 7.46-7.28 (m, 3H), 7.02-7.01 (m, 1H), 4.89-4.80 (m, 1H), 4.40-4.33 (m, 2H), 3.58-3.56 (m, 1H), 3.27-3.25 (m, 1H), 3.04-2.90 (m, 2H), 2.73-2.58 (m, 2H), 2.31-2.29 (m, 1H), 1.94-1.96 (m, 1H), 1.82-1.78 (m, 3H), 1.45 (t, 3H), 1.32-1.12 (m, 3H), 0.98-0.88 (m, 2H), 0.71-0.68 (m, 2H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:40][CH2:41][CH3:42])[C:34]=1[C:35]1[CH:36]=[N:37][O:38][CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:44]1[C:48]([C:49]2[CH:50]=[C:51]3[C:61](=[CH:62][CH:63]=2)[O:60][C:54]2([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][C:52]3=[O:64])=[N:47][N:46]=[N:45]1>O.CN(C=O)C.CCN(CC)CC>[CH2:41]([O:40][C:33]1[CH:32]=[C:28]([C:29]([N:57]2[CH2:58][CH2:59][C:54]3([CH2:53][C:52](=[O:64])[C:51]4[C:61](=[CH:62][CH:63]=[C:49]([C:48]5[NH:47][N:46]=[N:45][N:44]=5)[CH:50]=4)[O:60]3)[CH2:55][CH2:56]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][O:38][CH:39]=1)[CH3:42]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnoc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1cnoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (104 μL), HOBT (57 mg) and WSC hydrochloride (71 mg) were added to a DMF (4 mL) solution of 3,5-diethoxy-4-isoxazol-4-yl-benzoic acid (86 mg) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (119 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and washed with water and ether. The resulting solid was purified through high-performance preparative liquid chromatography (0.1% TFA, water/acetonitrile) to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 9.18 (1H, s), 8.96 (1H, s), 8.42 (1H, d, J=4.0 Hz), 8.21 (1H, dd, J=8.0, 4.0 Hz), 7.33 (1H, d, J=8.0 Hz), 6.74 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz). MS [M+H]+=545.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11]>>[OH:8][C:4]1[CH:3]=[C:2]([C:11]#[C:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1cccc(I)c1
Reactant: C#CC(=O)OCC
Product: CCOC(=O)C#Cc1cccc(O)c1
Yield: 73.1 %

Procedure:
According to the method of (Reference Example 3), from 3-iodophenol (1.18 g) and ethyl propiolate (1.0 g), the subject compound (746 mg) was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]([F:44])=[CH:31][N:30]=1>>[Cl:28][C:29]1[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:33][C:32]([F:44])=[CH:31][N:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cc(F)cnc2Cl)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cc(F)cnc2Cl)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 287 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a slightly rose powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=513.2/515.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.67-1.96 (m, 2H) 2.86-3.50 (m, 4H) 4.14-4.29 (m, 1H) 7.33 (d, J=8.78 Hz, 2H) 7.85 (d, J=9.15 Hz, 2H) 7.97-8.02 (m, 1H) 8.02-8.21 (m, J=8.42, 2.93 Hz, 1H) 8.55 (t, J=3.11 Hz, 1H) 8.81 (dd, J=7.68, 2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.C([O-])(=O)C.[Na+].[H][H]>CCOCC.[Pd]>[F:9][C:7]1[CH:8]=[C:3]([CH3:2])[CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: [H][H]
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(F)cc(F)c1
Yield: 98.1 %

Procedure:
A mixture of 1-bromomethyl-3,5-difluoro-benzene (75 g, 0.362 mol), Pd/C (5%, 5 g), and sodium acetate (208 g, 2.54 mol) in ether (300 mL) was treated with hydrogen gas (50 psi) in a Parr shaker for 2 days. The mixture was filtered through Celite and the organic solution washed three times with saturated aqueous sodium bicarbonate solution. The aqueous layers were washed with ether and the combined organic layers dried (MgSO4), filtered, and partially concentrated by evaporation using a cold water bath. The volatile product was obtained as a mixture with ether and the ratio (˜3:2, ether:product, g:g) calculated based on 1H NMR integration to determine actual yield (45.5 g, 0.355 mol, 98%) of product for scaling reagents in the ensuing reaction. 1H NMR (400 MHz, CDCl3) δ2.25 (s, 3H), 6.51-6.56 (m, 1H), 6.58-6.60 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([NH:22][NH2:23])=[O:21]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][C:9]([S:12][CH3:13])=[N:8][C:7]=1[NH:23][NH:22][C:20]([C:16]1[O:15][CH:19]=[CH:18][CH:17]=1)=[O:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NNC(=O)c1ccco1
Product: CCOC(=O)c1cnc(SC)nc1NNC(=O)c1ccco1

Procedure:
Compound ee was obtained using 5-ethoxycarbonyl-4-chloro-2-methylthiopyrimidine and 2-furoic hydrazide in the same manner as in Reference Example 19.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:14]1[C:22]2[C:17](=[C:18]([C:23]3[S:24][C:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[C:30]([C:38]#[N:39])[CH:29]=4)=[N:26][N:27]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([C@@H:14]1[C:22]2[C:17](=[C:18]([C:23]3[S:24][C:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:36])[CH3:37])=[C:30]([C:38]#[N:39])[CH:29]=4)=[N:26][N:27]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N(CC(=O)O)C(=O)OC(C)(C)C)s2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a stirred solution of (S)-methyl 2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate (120 mg, 0.21 mmol) in MeOH (2 mL) was added 6N solution of sodium hydroxide (180 μL) and the mixture was stirred at room temperature for overnight. The solvent was evaporated and the residue was dissolved in water (5 mL) and acidified with 1N HCl. The mixture was extracted with EA (3×5 mL) and the organic layers washed with brine, dried over MgSO4, and concentrated to afford 108 mg (92%) of (S)-2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1yl)amino)acetic acid as white solid which was used in the next experiments without purification. LCMS-ESI (m/z) calculated for C28H30N4O5S: 534.2; found no M+, tR=3.81 min.
Reaction SMILES: [CH3:1][CH:2]([OH:13])[C:3]#[C:4][CH:5]([OH:12])[CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH3:11].N1C2C(=CC=CC=2)C=CC=1>[Pd]>[CH3:1][CH:2]([OH:13])[CH2:3][CH2:4][CH:5]([OH:12])[CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH3:11]
Reactant: CCC=CCCC(O)C#CC(C)O
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Product: CCC=CCCC(O)CCC(C)O

Procedure:
Undec-8-en-3-yne-2,5-diol (obtained as detailed above) was hydrogenated under hydrogen and 10 percent palladium on barium sulphate and quinoline. The rush over process provided the product undec-8-ene-2,5-diol.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([CH2:18][CH2:19][O:20][CH3:21])[CH:6]=[CH:7][CH:8]([CH2:14][CH2:15][O:16][CH3:17])[C:9]([O:11]CC)=[O:10])C.[OH-].[Na+].Cl>C1COCC1>[CH3:17][O:16][CH2:15][CH2:14][CH:8]([CH:7]=[CH:6][CH:5]([CH2:18][CH2:19][O:20][CH3:21])[C:4]([OH:22])=[O:3])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(C=CC(CCOC)C(=O)OCC)CCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCC(C=CC(CCOC)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a stirred solution of 1.29 g (4.08 mmol) mixture of (E)-(2R,5S)- and -(2RS,5SR)-2,5-bis-(2-methoxy-ethyl)-hex-3-enedioic acid diethyl ester in 10 ml THF was added 33 ml (33 mmol) of 1 M sodium hydroxide solution. After stirring for 18 h at room temperature, the reaction mixture was acidified to pH 3 by addition of 1 M hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were washed successively with water and with saturated brine, dried over sodium sulphate, and concentrated in vacuo to afford 894 mg (84%) of the title compound as a yellow oil. MS m/e (%): 259 ([M−H]−, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:28])[NH2:27])[CH:21]=2)=[C:16]([F:29])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]>COC(OC)N(C)C>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:28])[N:27]=[CH:6][N:7]([CH3:13])[CH3:8])[CH:21]=2)=[C:16]([F:29])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCN(Cc1ccc(-c2cccc(C(N)=O)c2)c(F)c1)C(=O)OC(C)(C)C
Agent: COC(OC)N(C)C
Product: CC(C)CCN(Cc1ccc(-c2cccc(C(=O)N=CN(C)C)c2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 120 °C

Procedure:
(3′-Carbamoyl-2-fluoro-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-5e; 0.8 g, 1.92 mmol) was dissolved in dimethylformamide dimethyl acetal (10 ml) and heated to 120° C. for 2 hours. The reaction mixture was then cooled to room temperature and volatiles were removed under reduced pressure. The crude residue (0.9 g) used in the next reaction without purification. Mass Spec.: (m/z+1=470).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].O>ClCCl.C(O)C.C(OCC)(=O)C>[C:29]1([O:28][C:26](=[O:27])[NH:12][C:10]2[S:11][C:7]3[C:6]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine (26.5 g, 100 mmol) in dichloromethane (56 ml) and pyridine (56 ml, 700 mmol) is added phenyl chloroformate (15.7 ml, 125 mmol) at 0-5° C. and the reaction mixture is warmed to ambient temperature. After 1 h, water (7.2 ml, 400 mmol) was added and the reaction mixture is heated for 1 h to 45° C. Then ethyl acetate (250 ml) and 2M HCL (125 ml) were added and the organic phase separated. After removal of the solvent and recrystallization from tert.butyl-methyl ether and finally from ethanol the title compound was obtained as white solid (80% yield), mp 166-168° C. MS: m/e=386(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]([O:23][CH3:22])=[O:25])[CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(COC3CCCNC3)cc2)cc1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(OCc3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Yield: 33.7 %

Procedure:
Using 3-[(4′-chlorobiphenyl-4-yl)methoxy]piperidine (220 mg, 0.729 mmol) and 3-(methoxycarbonyl)phenylboric acid (263 mg, 1.46 mmol), the same procedure was followed as in Example 2 to give 107 mg (34%) of the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:10]1([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:16][Br:19])[CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1cc(OCc2ccccc2)ccc1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(OCc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a solution of 4-chloro-3-(hydroxymethyl)phenol (for as preparation see Intermediate 12) (3.3 g, 20.8 mmol) in ethanol (30 ml) was added 2 M sodium hydroxide (10 ml, 20 mmol). To the mixture was added dropwise a solution of benzyl bromide (2.48 ml, 20.8 mmol, Aldrich) in ethanol (30 ml). The reaction was stirred under nitrogen overnight at ambient temperature. The ethanol was removed in vacuo to leave a cream solid and the residue partitioned between water (80 ml) and dichloromethane (60 ml). The phases were separated and the aqueous phase extracted with dichloromethane (40 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (40 ml) and the solvent removed in vacuo to leave a white solid (4.6 g). The sample was loaded in dichloromethane and purified on silica (2×100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give {2-chloro-5-[(phenylmethyl)oxy]phenyl}methanol as a clear oil (4.12 g). To a solution of {2-chloro-5-[(phenylmethyl)oxy]phenyl}methanol (1.22 g, 4.91 mmol) in DCM (25 ml) at −10 to −15° C., under nitrogen, was added a solution of phosphorus tribromide (0.463 ml, 4.91 mmol, Aldrich) in DCM (10 ml) dropwise. The solution was allowed to warm to ambient temperature and stirred for 3 h under nitrogen. To the reaction mixture in an ice-bath was added dropwise saturated aqueous sodium hydrogen carbonate (15 ml). The mixture was diluted with water (80 ml) and DCM (100 ml). The phases were separated and the aqueous phase washed with DCM (60 ml). The combined organic extracts were washed with water (50 ml). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to give 3-(bromomethyl)-4-chlorophenyl phenylmethyl ether as a colourless gum (1.11 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:6]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([C:34](=[O:36])[CH3:35])[C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:6]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN[C@H]2CCc3ccccc32)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-((S)-indan-1-ylaminomethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [H-].[Na+].C(S)C.C[O:7][C:8]1[C:16]2[O:15][C:14]([CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[O:19]1[CH2:20][CH2:21][CH:17]([C:14]2[O:15][C:16]3[C:8]([OH:7])=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=2)[CH2:18]1
Reactant: COc1cccc2cc(C3CCOC3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: Oc1cccc2cc(C3CCOC3)oc12
Temperature: 140 °C
Yield: 79.1 %

Procedure:
Sodium hydride (0. 19 g, 60% in mineral oil) was added to a stirred solution of ethane thiol (0.34 ml) in N, N-dimethylformamide (6 ml) at room temperature under a dry nitrogen atmosphere. After stirring for 15 minutes 7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran (0.5 g) in N,N-dimethylformamide (6 ml) was added and the reaction heated to 140° C. for 2 hours. After cooling to room temperature the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic extract was dried over magnesium sulphate, filtered and preadsorbed onto silica. Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a brown oil (0.37 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12)[NH2:5].[C:19]1([CH2:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:29]([NH:28][C:26](=[O:27])[CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[S:30])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (0.105 g, 0.403 mmol) in THF (1 mL) was added 2-phenylethanoyl isothiocyanate (0.257 g, 1.45 mmol; prepared according to the procedure described by J. Org. Chem. 1964, 29, 1115-1119). The reaction was stirred for 4 hours at room temperature. The reaction mixture was partially purified by Biotage Flash 40 silica gel chromatography, eluting with a gradient of 10-50% EtOAc in hexanes. The product was further purified by preparative TLC (10% MeOH in CH2Cl2). Yield: 18 mg (9%). 1H NMR (400 MHz, CDCl3) δ 12.55 (s, 1H), 9.00 (s, 1H), 8.53 (d, J=5 Hz, 1H), 7.94 (m, 1H), 7.75 (d, J=5 Hz, 1H), 7.58 (d, J=5 Hz, 1H), 7.08-7.50 (m, 7H), 6.54 (d, J=5 Hz, 1H), 3.75 (s, 2H). LRMS (APCI neg) m/e 436 (M−1).