Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH2:19]([O:21][C:22]([C:24]1[N:25]=[CH:26][NH:27][C:28]=1[NH2:29])=[O:23])[CH3:20]>C(O)(=O)C>[CH2:19]([O:21][C:22]([C:24]1[N:25]=[CH:26][N:27]2[C:3]([CH:2]([F:18])[F:1])=[CH:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[N:29][C:28]=12)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1nc[nH]c1N
Reactant: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 49.5 %

Procedure:
A mixture of 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (8.87 g, 33.3 mmol) and 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (5.17 g, 33.3 mmol) in acetic acid (100 ml) was refluxed for 27 h and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/heptane 7:3) and crystallization (diethyl ether/hexane) to yield 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (6.35 g, 49%) as a yellow solid. MS (EI) 385.1 [(M)+]; mp 219° C.
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:5]=1[CH:6]=[O:7].Cl>CS(C)=O.O>[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:1])[C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1c(O)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium hydroxide (10 g) was added slowly to a stirred solution of 2-chloro-6-fluoro-benzaldehyde (14.0 g, 88.3 mmol) in dimethylsulfoxide (20 mL) at 0° C., the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with water (100 mL) and acidified to pH 2 with concentrated HCl. The precipitates were filtered, washed with water (2×100 mL) and dried over anhydrous sodium sulfate, to give a residue which was used directly in the next step. Yield: 8.5 g (62%). 1H NMR (400 MHz, CDCl3) δ ppm 6.85-7.02 (m, 2H) 7.39-7.47 (m, 1H) 10.41 (s, 1H) 11.95 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH3:53])=[CH:45]1>>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[C:23]([CH2:22][O:21][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:40][CH2:41][CH2:42][CH2:43][N:44]5[C:52]6[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=6)[C:46]([CH3:53])=[CH:45]5)=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]3)[CH:32]=2)[CH2:27][CH2:28][C:29]1=[O:38]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: Cc1cn(CCCCBr)c2ccccc12
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCn4cc(C)c5ccccc54)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.149 g of 1-(4-bromobutyl)-3-methyl-1H-indole are reacted. The title compound is obtained as a colourless oil. Rf=0.21 (2:1 EtOAc-heptane); Rt=6.27.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:43]3[C:38](=[CH:39][C:40]([S:44](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:46])=[O:45])=[CH:41][CH:42]=3)[CH:37]=[N:36][N:35]=2)=[C:30]([O:59][CH3:60])[CH:29]=1>C1COCC1.[Cl-].[NH4+].O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:43]3[C:38](=[CH:39][C:40]([S:44]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=4)[C:9]4[CH:14]=[CH:13][N:12]=[CH:11][N:10]=4)(=[O:45])=[O:46])=[CH:41][CH:42]=3)[CH:37]=[N:36][N:35]=2)=[C:30]([O:59][CH3:60])[CH:29]=1
Reactant: COc1ccc(CNc2ccncn2)cc1
Reactant: COc1cc(Cl)ccc1-c1nncc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OC)nncc3c2)cc1
Reaction time: 0.08 h
Yield: 36.7 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)pyrimidin-4-amine (80 mg, 0.371 mmol) and THF (1238 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (371 μl, 0.371 mmol) was added drop wise. The flask was removed from the cooling bath for 3 min, and then re-cooled in the bath. A solution of perfluorophenyl 1-(4-chloro-2-methoxyphenyl)phthalazine-6-sulfonate (128 mg, 0.248 mmol) in THF (1 mL with a 0.5 mL-flask wash) was added drop wise. After another minute, the flask was transferred to an ice-water bath. After 5 min, the mixture was diluted with saturated aq. ammonium chloride and water, then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 50-100% EtOAc/Heptane) to give 1-(4-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)phthalazine-6-sulfonamide (50 mg, 0.091 mmol, 36.8% yield) as an off-white solid. m/z (ESI) 548.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:12]1([C:10]2[O:9][C:8]3[C:3]([CH:2]=[O:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1cccc2cc(-c3ccccc3)oc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc2cc(-c3ccccc3)oc12

Procedure:
12 g of manganese dioxide are added to 2 g of 7-hydroxymethyl-2-phenylbenzo [b]furan (prepared according to Example 1 from EP 306 226) in 100 ml of methylene chloride and the mixture is heated under reflux for 1 hour. It is cooled end filtered with suction over a filtering auxiliary, and the filtrate is concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A mixture of the sulfone from Step 7C (3.09 g, 7.8 mmol), MeOH (21 mL), and 5N HCl (4.5 mL) was heated to reflux for 1.5 h. The mixture was cooled to room temperature and sat. Na2CO3 solution (80 mL) was added. The mixture was extracted with CH2Cl2 (2×100 mL). The organic phase washed with H2O and brine, dried (MgSO4) and concentrated to afford the amine (1.82 g), a white foam, in 79% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[S:24]([NH2:27])(=[O:26])=[O:25])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.Cl>[NH2:21][C:19]1[CH:18]=[CH:17][C:16]([S:24]([NH2:27])(=[O:26])=[O:25])=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH:20]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCCCCNc1nc(Cl)ncc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(S(N)(=O)=O)c(OCCCCNc2nc(Cl)ncc2Br)c1
Reaction time: 4 h

Procedure:
A solution of 160 mg (0.33 mmol) of 2-[4-(5-bromo-2-chloro-pyrimidin-4-ylamino)-butoxy]-4-nitro-benzenesulfonamide in 10 ml of THF is mixed under argon at room temperature with 1.4 ml of a 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid. After 4 hours, the reaction solution is again mixed with 0.2 ml of the Ti(III)Cl solution and stirred for another 14 hours. The batch is made basic with 2N NaOH solution and then filtered. The filter cake is rewashed 2× with 50 ml of ethyl acetate/MeOH (30 ml/20 ml) in each case. The filtrate is concentrated by evaporation in a rotary evaporator and then extracted with ethyl acetate (2×). The combined organic phases are washed with NaCl solution, dried (MgSO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (dichloromethane/methanol 9:1; Flashmaster II). 70 mg (0.81 mmol, corresponding to 47% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C(COC3C=C(C(O)=O)N(C)N=3)=C(CO)O[N:34]=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([NH2:34])=[O:23])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)O
Reactant: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)O
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(N)=O
Yield: 25 %

Procedure:
As described for example 93b, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.28 mmol), instead of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid, was converted to the title compound (25 mg, 25%) which was obtained as a white solid. MS: m/e=363.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:25])[C@H:9](OS(C2C=CC(C)=CC=2)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[O:25][C@H:9]2[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1O[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
In dimethylformamide (75 ml) was dissolved methyl (2S,3R)-3-(4-fluorophenyl)-3-hydroxy-2-p-toluenesulfonyloxypropionate (5.48 g, 14.9 mmol), and water (1.4 ml, 74.5 mmol) was added to the solution. The reaction mixture was cooled by an ice bath, potassium carbonate (6.16 g, 44.6 mmol) was added thereto, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was cooled again by an ice bath, water (100 ml) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the solvent was removed, the residue obtained was purified by silica gel column chromatography (diethyl ether/hexane=1/3) to obtain methyl (2R,3R)-3-(4-fluorophenyl)-2,3-epoxypropionate (2.69 g, yield: 92%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:25]=[C:26]([CH3:39])[C:27]([OH:31])=[C:28]([CH3:30])[CH:29]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:48]3[CH:49]=[CH:50][C:45]([C:44]([F:55])([F:54])[F:43])=[CH:46][CH:47]=3)[C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3ccc(C(F)(F)F)cc3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.561 g, 0.932 mmol), 4-(trifluoromethyl)phenylboronic acid (0.354 g, 1.86 mmol), copper (II) acetate (0.169 g, 0.932 mmol), triethylamine (0.26 mL, 1.86 mmol), 4 angstrom molecular sieves, and dichloromethane (15 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.498 g, 0.667 mmol), in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (1.80 mL). Stir for 1 h. Add 1N aqueous HCl(10 mL), water (40 mL), and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.283 g (59%) of the title compound: mass spectrum (FAB): m/z=518(M+1); 1H NMR(DMSO-d6): δ8.32 (s, 2H), 7.98 (d, 2H), 7.79 (d, 2H), 7.40 (d, 1H), 7.32 (td, 1H), 7.21 (td, 1H), 6.99 (d, 1H), 6.80 (s, 4H), 2.13 (s, 12H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:14]1[S:15][C:16]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=2)=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[N:18]=1)[CH3:13].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[C:12]([C:14]1[S:15][C:16]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=2)=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[N:18]=1)(=[O:11])[CH3:13]
Reactant: CCC(=O)Nc1cc(-c2sc(C(C)O)nc2-c2cccc(C)c2)ccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(-c2sc(C(C)=O)nc2-c2cccc(C)c2)ccn1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
A solution of dimethylsulfoxide (0.30 mL, 4.2 mmol) in dichloromethane (1.0 mL) was added to a solution of oxalyl chloride (0.11 mL, 1.26 mmol) at −78° C. and the resulting mixture was stirred for 15 minutes. A solution of N-[4-[2-(1-hydroxyethyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide (0.38 g, 1.0 mmol) in dichloromethane (1.5 mL) was added to the mixture and the resulting mixture was stirred for 45 minutes. The reaction mixture was allowed to warm up to −50° C. and triethylamine (0.72 mL, 5.17 mmol) was added dropwise to the mixture. The resulting mixture was stirred for 30 minutes and poured into aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the extracts were washed with aqueous sodium hydrogen carbonate solution and brine. The resulting solution was dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to obtain a crude crystal. The obtained crude crystal was recrystallized from isopropyl ether to give a title compound (0.22 g, yield 58%).
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CO[CH2:32][CH2:33]OC.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1.C(B1OB(C=C)OB(C=C)O1)=C>O>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([CH:32]=[CH2:33])[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=1
Reactant: COCCOC
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1Br
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1c(F)c(Cl)cc(C(C)Nc2ncnc3c2ncn3C2CCCCO2)c1OC
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of N-[1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (50 mg, 0.10 mmol, from Example 187, Step 7) in water (0.21 mL) was added 1,2-dimethoxyethane (0.7 mL), potassium carbonate (14 mg, 0.10 mmol), pyridine:trivinylboroxin (1:1) (26 mg, 0.10 mmol) and tetrakis(triphenylphosphine)Pd(0) (5.2 mg, 0.0045 mmol). The mixture was bubbled with nitrogen for five min and heated at 80° C. overnight. The reaction was diluted with water and EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification on silica gel using 0-100% EtOAc in hexane gave the desired compound (29 mg, 60%). LCMS calculated for C21H24ClFN5O2 (M+H)+: m/z=432.2. found: 432.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:20]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(CCc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(CCc2ccccn2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To an acetic acid (30 mL) solution of 4-(2-pyridin-2-yl-ethyl)benzaldehyde (2.57 g, 12.2 mmol) described in Manufacturing Example 93-1-5 were added nitromethane (7.45 g, 122 mmol) and ammonium acetate (1.88 g, 24.4 mmol) under nitrogen atmosphere at room temperature, which was stirred for 3 hours at 120° C. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporation under a reduced pressure to obtain the title compound (2.83 g, 91%) as a raw product.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH2:9][OH:10])([CH3:6])([CH3:5])[CH3:4].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1>C1(C)C=CC=CC=1.O>[C:3]([O:7][CH2:8][CH2:9][O:10][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([Br:11])[N:13]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OCCOc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (6.8 g, 60% dispersion in mineral oil, 0.169 mol) was added portionwise to an ice-cold solution of 2-(tert-butoxy)ethanol (20.0 g, 0.169 mol) in toluene (500 ml) under nitrogen, and the solution stirred for 30 minutes whilst warming to ambient temperature. 2,6-Dibromopyridine (40.0, 0.169 mol) was added, and the reaction heated under reflux for 3 hours. The mixture was allowed to cool to ambient temperature and was diluted with water (100 ml), and extracted with ethyl acetate (2×400 ml). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow oil (quantitative). 1H nmr (CDCl3, 400 MHz) δ: 1.21 (s, 9H), 3.67 (t, 2H), 4.40 (t, 2H), 6.68 (d, 1H), 7.05 (d, 1H), 7.38 (t, 1H). LRMS: m/z 296/298 (M+23)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClCCCl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[S:17][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCCCc2sc(-c3ccncc3)cc21
Solvent: ClCCCl
Product: Clc1ccc(C2=CCCCc3sc(-c4ccncc4)cc32)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-pyridin-4-yl-5,6,7,8-tetrahydro-4H-cyclohepta thiophene-4-ol (500.0 mg, 1.405 mmol) in 1,2-dichloroethane (6.0 mL, 76 mmol) trifluoroacetic acid (1.082 mL, 14.05 mmol) was added at 0° C., and the resulting brownish solution was heated at 60° C. for 16 hr. The reaction mixture was allowed to cool to rt, the solvent was evaporated, saturated NaHCO3 (5 mL) and ethyl acetate (5 mL) were added, and the mixture was stirred for 30 min, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (3×5 mL), the combined organic layers were dried over MgSO4, filtered, concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 0-100% EA/DCM) to give the title compound as a yellow solid (428.7 mg, 91.2% yield). LCMS: (FA) ES+ , 338/340. 1H NMR (300 MHz, DMSO) E. 8.64 (d, J=6.7 Hz, 2H), 7.92 (d, J=6.6 Hz, 2H), 7.63 (s, 1H), 7.47-7.37 (m, 2H), 7.37-7.21 (m, 2H), 6.49 (t, J=6.5 Hz, 1H), 2.91 (t, J=6.4 Hz, 2H), 2.31-2.07 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:34])[C@@H:5]1[CH2:12][N:11]2[C:13]3[CH:14]=[C:15]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=[CH:17][C:18]=3[C:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:10]2[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[O:7][CH2:6]1.[CH:35](OCC(F)(F)F)=O>C1COCC1>[CH:20]1([C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:26]([O:28][CH3:29])=[O:27])=[CH:14][C:13]=3[N:11]3[C:10]=2[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[O:7][CH2:6][C@H:5]([N:4]([CH3:34])[CH2:3][CH2:2][NH:1][CH3:35])[CH2:12]3)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN)COc1ccccc1-3
Reactant: O=COCC(F)(F)F
Solvent: C1CCOC1
Product: CNCCN(C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution (0.1 M) of methyl(7R)-7-[(2-aminoethyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in THF was treated dropwise with 2,2,2-trifluoroethyl formate (1.5 eq.) and stirred overnight at RT. The volatiles were removed in vacuo and the residue dissolved (0.1 M) in THF and treated dropwise with BH3-DMS complex (2M in THF; 5 eq.). The resulting solution was stirred at RT for 3 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution heated to dryness. The residue was then partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by FC (EtOAc/MeOH 99.5:0.5+1% NEt3) to afford the product (40%). (ES+) m/z 476 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:5]1([CH2:19][OH:20])[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6]1)[CH2:3]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.O>ClCCl.C([Sn](=O)CCCC)CCC>[OH:1][CH:2]1[C:5]2([CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:8]2)[CH2:19][O:20][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC(CO)(C(O)CO)C1
Agent: CCCC[Sn](=O)CCCC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2(COCC2O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
Benzyl 3-(1,2-dihydroxyethyl)-3-(hydroxymethyl)azetidine-1-carboxylate (from step (iii); 956 mg, 3.4 mmol) was dissolved in dichloromethane (150 mL) and dibutyltin oxide (17 mg) was added. p-Toluenesulfonyl chloride (686 mg, 3.6 mmol) was added and the solution was cooled to 0° C. Triethylamine (520 μL, 3.75 mmol) was added dropwise and the solution was then allowed to stir at ambient temperature for 16 hrs. Further triethylamine (260 μL, 1.9 mmol) was added and after stirring for 2 hrs, water (250 mL) was added. The mixture was extracted with dichloromethane (2×250 mL), and the extracts dried (MgSO4) then concentrated. The residue was purified by silica chromatography to give the title compound as an oil (456 mg, 1.7 mmol, 51%).