Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH2:19][O:20]C)[N:17]=[CH:18][C:13]=3[CH2:12][CH:11](C)[C:10]2=[O:23])=[CH:4][CH:3]=1.N1C=CC=C[CH:25]=1.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH2:19][OH:20])[N:17]=[C:18]([CH3:25])[C:13]=3[CH2:12][CH2:11][C:10]2=[O:23])=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: COCc1ncc2c(n1)N(Cc1ccc(Br)cc1)C(=O)C(C)C2
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc(CO)nc2c1CCC(=O)N2Cc1ccc(Br)cc1

Procedure:
To a solution of 8-[(4-bromophenyl)methyl]-6-methyl-2-methoxymethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.70 mmol) and pyridine (0.11 g, 1.30 mmol) in CHCl3 (9 mL) was added iodotrimethylsilane (0.77 g, 3.80 mmol). The mixture was heated under reflux for 30 h and MeOH (0.5 mL) was added. The mixture was concentrated, taken up in CH2Cl2, washed with aqueous Na2SO3 and brine, dried (MgSO4), and concentrated. Purification by flash chromatography (5% MeOH/CH2Cl2) gave o.54 g (56%) of product as a colorless foam.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[F:44][C:45]([F:57])([F:56])[C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH2:55])[CH2:53][CH3:54])=[CH:48][CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[F:56][C:45]([F:44])([F:57])[C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH:55][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:53][CH3:54])=[CH:48][CH:47]=1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1ccc(C(F)(F)F)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (50 mg, 0.180 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (27 mg, 0.197 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.197 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(6-trifluoromethyl-pyridin-3-yl)-propylamine hydrochloride (48 mg, 0.20 mmol) and triethylamine (55 mg, 0.54 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 45 mg (54%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide as white solid. LC/MS (method 5): Rt=4.12 min; m/z=465.35 (M+H+). 1H-NMR (400 MHz): δ (ppm)=8.76 (1H, s), 8.26 (1H, d), 8.01 (1H, d), 7.89 (1H, d), 7.24 (1H, s), 4.93-4.98 (2H, m), 4.84 (1H, d), 4.20-4.29 (2H, m), 3.92-3.99 (2H, m), 3.79-3.84 (1H, m), 3.69 (2H, bs), 2.07 (1H, m), 1.96 (1H, m), 1.77-1.89 (3H, m), 1.56 (1H, m), 1.19 (3H, d), 0.92 (3H, t).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.O>CC(=O)CC>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)=[CH:23][CH:24]=1)#[N:27]
Reactant: CNC(=O)COc1ccc(O)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CNC(=O)COc1ccc(OCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91 %

Procedure:
A solution of 500 mg of 2-(4-hydroxy-phenoxy)-N-methyl-acetamide in 25 ml of 2-butanone was treated with 762 mg of potassium carbonate and 595 mg of 4-bromomethyl-benzonitrile. The reaction mixture was stirred at room temperature for 60 h. For the working-up, the reaction mixture was treated with water, then extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residue was triturated in ether and the crystals obtained were collected on a filter funnel. After drying there were obtained 744 mg (95% of theory) of 2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-acetamide as white crystals; MS: m/e=297 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)[CH:11]=[N:10][C:9]=2[O:15][C@@H:16]([CH3:21])[C:17]([F:18])([F:20])[F:19])=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1ncc(N)nc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@H](Oc1ncc(NC(=O)c2cccnc2)nc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
6-(4-Chloro-phenyl)-5-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyrazin-2-ylamine (0.100 g, 315 μmol) was dissolved in dried pyridine (1.0 mL), nicotinoyl chloride hydrochloride (61.6 mg, 346 μmol) was added and the suspension was stirred at 140° C. for 10 minutes in the microwave. The solvent was evaporated and the crude material was purified by flash chromatography (silica gel, 10 g, 0% to 50% CH2Cl2/MeOH/NH3 9/1/0.1) to give 0.121 g (91%) of the title compound as white solid; LC-MS (UV peak area/ESI) 100%, 423.0821 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]([Cl:21])([Cl:20])[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:21][C:12]([Cl:11])([Cl:20])[C:13]([C:15]1[NH:16][CH:17]=[C:18]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=1)=[O:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h
Yield: 60 %

Procedure:
In a dry flask, phenylacetyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM). To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 1 in 60% yield. 1H NMR (CDCl3) δ 4.0 (s, 2H), 7.1-7.35 (m, 7H), 9.7 (br s, NH). HPLC using method B (as described below for Example 5) provided retention time of 4.9 minutes. LC/MS (M+1) 330.2, (M−1) 328.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][O:12][C:13]1[CH:37]=[C:36](F)[CH:35]=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][O:12][C:13]1[CH:37]=[C:36]([N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH:35]=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)COc1cc(F)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Product: CC(C)(CNC(=O)OC(C)(C)C)COc1cc(N2CCCC2)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 80 °C
Yield: 43 %

Procedure:
Using methods substantially equivalent to those described in Example 4-F, except that the reaction was heated to 80° C., 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethyl-propoxy)-4-(pyrrolidin-1-yl)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (453 mg, 0.73 mmol, 43%) was prepared from 2-[2-(3-tert-butoxycarbonylamino-2,2-dimethyl-propoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)benzamide and pyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:20])C(=O)C1.O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([Br:20])=[CH:4][N:3]=1
Reactant: Nc1nccc2cc(F)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1ncc(Br)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
To a solution of 1-amino-6-fluoro-isoquinoline (0.41 g, 2.53 mmol) in CHCl3 (25 mL) is added NBS (0.45 g, 2.53 mmol), and the reaction mixture is stirred RT for 1.5 h. The reaction mixture is treated with water (10 mL). The aqueous phase is extracted with CH2Cl2 (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum. Purification of the crude material using a Biotage column (10-40% MeOH/CH2Cl2) afforded 0.395 g (65%) of 1-amino-4-bromo-6-fluoro-isoquinoline. LC/MS m/z=242 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[NH:5][C:6]=1[Cl:7].CC(C)([O-])C.[K+].[CH2:24]([O:26][CH:27](Cl)[CH3:28])[CH3:25]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]([CH:24]([O:26][CH2:27][CH3:28])[CH3:25])[C:6]=1[Cl:7]
Reactant: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Cl)c1Cl
Reactant: CCOC(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(C)n1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To 4,5-dichloro-2-(3,4-dichlorophenyl)-pyrrole-3-carbonitrile (5.0 g, 0.016 mol) dissolved in 300 mL of tetrahydrofuran is added, portionwise, potassium t-butoxide (2.75 g, 0.025 mol) with ice cooling and stirring. The cooled mixture is treated with a solution of 1-chloroethyl ethyl ether (2.31 g, 0.021 mol) in 15 mL of tetrahydrofuran at 10° C. over a 5 minute period. The mixture is stirred for 1/2 hour at ambient temperatures, evaporated to a volume of 50 mL and poured into a mixture of 200 mL of ethyl acetate and 100 mL of water. The organic layer is separated, washed with water (2×100 mL), saturated NaCl solution (1×100 mL), dried over anhydrous magnesium sulfate and evaporated to give the title product 5.9 g, mp 124°-126° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:10]([O-])=O.[Na+]>S(=O)(=O)(O)O>[N:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:8])[NH:9][N:10]=1
Reactant: NC(=O)c1ccsc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]nnc2sccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
To an ice cold solution (0° C.) of 2-aminothiophene-3-carboxamide (5 g, 35.21 mmol) in concentrated sulfuric acid (40 mL) was added a cold (0° C.) solution of sodium nitrite (2.5 g, 35.21 mmol) in concentrated sulfuric acid (30 mL) for 30 min (while adding, the temperature should keep between −5-0° C.). After addition, the mixture was stirred at the same temperature (0° C.) for 3 h. The mixture was poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solution was extracted with ethyl acetate (4×200 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a pale red color solid (1.0 g, 18%), mp 175-176° C. 1H NMR (400 MHz, DMSO-d6): δ 15.18 (1H, s), 8.16 (1H, d, J=5.6 Hz), 7.64 (1H, d, J=5.6 Hz); 13C NMR (100 MHz, DMSO-d6): δ 159.1, 153.8, 132.0, 126.1, 121.2; LC-MS (negative ion mode): m/z 152 (M−H)−.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[N:11][CH:12]=1.[B:20](OC)([O:23]C)[O:21]C.Cl>O.C(OCC)C>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([B:20]([OH:23])[OH:21])=[CH:12][N:11]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COB(OC)OC
Reactant: CCCCCCOc1ccc(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCCCCOc1ccc(B(O)O)cn1
Reaction time: 1 h

Procedure:
250 mmol of n-butyllithium (1.6M solution in n-hexane) are added dropwise at 0° C. with exclusion of moisture and under a protective-gas atmosphere to a solution of 250 mmol of 5bromo-2-hexyloxypyridine in 500 ml of abs. diethyl ether. The mixture is stirred at this temperature for a further 1 hour, and 275 mmol of trimethyl borate are subsequently added slowly. After the mixture has been stirred at 0° C. for a further hour, a solution of 175 ml of water and 25 ml of 37 percent hydrochloric acid is added dropwise. The mixture is stirred at room temperature for 1 hour, the phases are then separated, the aqueous phase is extracted a number of times with dichloromethane, and the combined organic extracts are dried using magnesium sulfate. The solvents are removed in vacuo. After drying in a high vacuum, the red-brown, high-viscosity crude product is reacted further without additional purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:17]([O:18][CH3:19])[CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[CH3:13])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccccc1C
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccccc1C)C(=O)C=C1OC(C)(C)OC1=O
Yield: 100 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-methylbenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (100% yield): mp 96–97° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.78 (6H, s, CH3), 2.4 (3H, s, CH3), 3.59 (3H, s, OCH3), 4.89 (2H, s, NCH2), 6.44 (1H, s, CH), 7.2–7.28 (4H, m, aromatics). Anal. calcd. for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C, 62.90; H, 6.21; N, 4.52.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH:9]=[O:10].C[Si](C)(C)[C:13]([F:16])([F:15])[F:14]>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:13]([F:16])([F:15])[CH:9]([OH:10])[CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=CCCc1ccccn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(CCc1ccccn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
A solution of 760 mg (5.6 mmol) of 3-pyridin-2-ylpropionaldehyde in 3 mL of THF was treated with 13.6 mL (6.8 mmol, 1.2 eq.) of trimethyl(trifluoromethyl)silane (0.5 M solution in THF) and 0.06 mL (0.06 mmol) of tetrabutylammonium fluoride (1.0 M solution in THF) at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes, and quenched with 1 N HCl solution. After stirring for 5 minutes, the pH of the reaction mixture was adjusted to 9 with saturated NaHCO3 solution, and the product was extracted into ether. The ethereal layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give 706 mg (61%) of 1,1,1-trifluoro-4-pyridin-2-ylbutan-2-ol as a colorless oil.
Reaction SMILES: [H-].[Na+].C([N:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[CH:8]=[N:7]1)(=O)C.Br[CH2:15][CH2:16][CH2:17][CH3:18]>CN(C=O)C>[CH2:15]([N:10]1[C:9](=[O:13])[CH:8]=[N:7][NH:6][C:11]1=[O:12])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCBr
Reactant: CC(=O)n1ncc(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)cn[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a 50% sodium hydride suspension (4.8 g) in DMF (100 ml), compound 11a (15.5 g) dissolved in DMF (200 ml) is added drop by drop, maintaining the temperature at room temperature. After agitation for 2 hours, bromobutane (20 g) is added and the agitation continued for 12 hours. The reaction mixture is concentrated to dryness under vacuum at 60° C., taken up in water, and then extracted with methylene chloride. After concentration to dryness under vacuum, the oil is taken up in ethanol (100 ml), whereupon p-toluene-sulfonic acid (2 g) is added. After heating under reflux for 2 hours and leaving at room temperature for 12 hours, the reaction mixture is filtered. The precipitate is washed with an aqueous solution of sodium bicarbonate and water, and then dried in an oven under vacuum in order to give the compound 11b (8.7 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1>CN(C)C=O>[Cl:27][C:25]1[CH:24]=[CH:23][C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:3]3[C:4](=[O:15])[C:5]4[C@@H:6]5[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]5)[C:10]=4[N:2]3[CH3:1])[C:19]=2[CH:26]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1csc3ccc(Cl)cc13)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 73.8 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3-(bromomethyl)-5-chlorobenzo[b]thiophene (Maybridge plc, Tintagel, Cornwall, UK; 164 mg, 0.63 mmol) in dimethylformamide (5 mL) was heated at 100° C. for 2 days. The solvent was evaporated and ethyl acetate (50 mL) was added. The solution was washed with water (twice) and brine, dried (magnesium sulfate), filtered, evaporated and purified by chromatography, eluting with 1-3% methanol/dichloromethane to give (4S,7R)-2-(5-chloro-benzo[b]thiophen-3-ylmethyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (140 mg, 74%) as an off-white foam. APCI(+)-MS (M+H) 387.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[CH3:44][C:45](OC(C)=O)=[O:46].[ClH:51]>C(Cl)Cl>[ClH:51].[Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:45](=[O:46])[CH3:44])[CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: COc1cccc(Sc2cnc(Nc3nc(C4CCNCC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(C)=O)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A 20 mL vial was charged with 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine (40 mg, 0.068 mmol), triethylamine (0.0190 mL, 0.14 mmol), and CH2Cl2 (2 mL). Ac2O (0.008 mL, 0.082 mmol) was added and the reaction was stirred at room temperature for 10 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated to afford the title compound (38.2 mg, 84.2% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.20 (bs, 1H), 8.17 (d, 1H), 7.74 (m, 1H), 7.31 (m, 2H), 7.21 (t, 1H), 6.93 (d, 1H), 6.78 (m, 1H), 6.74 (s, 1H), 6.71 (m, 2H), 4.43 (d, 1H), 3.87 (d, 1H), 3.69 (s, 3H), 3.14 (m, 1H), 2.86 (m, 1H), 2.64 (m, 1H), 2.01 (s, 3H), 1.95 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci) m/z=631.4 (M+H—HCl).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH:54]([CH3:56])[CH3:55])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([O:59][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:67])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH:54]([CH3:56])[CH3:55])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([OH:59])[CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 67.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tertbutyldimethylsiloxy)-12-[2'-(4"-azido-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (38 mg) in acetonitrile (1 ml) was added a solution of 2% HF in aqueous acetonitrile (150 μl), and the mixture stirred at room temperature. After 4.5 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (22.5 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.[O-]CC.[Na+].CS(C)=O.Br[CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:1]([C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Cc1ccc2c(c1)=NC(=O)N=2
Reactant: CCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CCCCCc1ccc2c(c1)=NC(=O)N=2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-methylbenzimidazol-2-one (50 mg, 3.378×10−4 mol) in dry ethanol (5 ml), the freshly made sodium ethoxide in ethanol (1M, 1.01×10−3 mol equivalents) was added dropwise under a nitrogen atmosphere. At room temperature the mixture was stirred for 3 hrs under an atmosphere of nitrogen and the ethanol was then removed under reduced pressure. To this a solution of dry DMSO (3 ml) and 1-bromobutane (54 μl, 5.1×10−4 mol) was added and stirred at room temperature under an atmosphere of nitrogen overnight. The reaction mixture was then quenched with ice and neutralised using 1M hydrochloric acid solution, forming a white solid product. The solid was collected by filtration and purified using preparative thin liquid chromatography with 10% MeOH/CHCl3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(#N)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:12]#[C:11][CH2:10][CH2:9][OH:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCO
Reactant: Brc1cccc(I)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCCC#Cc1cccc(Br)c1
Reaction time: 18 h

Procedure:
A stirred, cooled solution of 1-bromo-3-iodobenzene (31 g) and 3-butyn-ol (7 ml) in acetonitrile (100 ml) and triethylamine (100 ml) was purged with nitrogen for 20 min under nitrogen. Dichlorobis(triphenylphosphine)palladium (500 mg) and cuprous iodide (800 mg) were added. The mixture was stirred for 18 h and then the solvent was removed in-vacuo. The residual oil was triturated with ethyl acetate (200 ml) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on Biotage (90 g) eluting with light petroleum 40-60°-diethyl ether (3:2) to give the title compound (21 g). LCMS RT=3.26 min.