Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:18]([C:19](O)=[O:20])=[CH:17][C:16]([O:22][CH3:23])=[CH:15][C:13]=3[CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:25][NH:26][O:27][CH3:28].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:28][O:27][N:26]([CH3:25])[C:19]([C:18]1[C:12]2[O:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[CH:14][C:13]=2[CH:15]=[C:16]([O:22][CH3:23])[CH:17]=1)=[O:20]
Reactant: COc1cc(C(=O)O)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)OC)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Yield: 63.5 %

Procedure:
A solution of 44 (0.400 g, 1.27 mmole), N,O dimethylhydroxylamine hydrochloride (0.247 g, 2.53 mmole), DMAP (0.309 g, 2.53 mmole), and EDCI (0.364 g, 1.90 mmole), in 40 mL dimethylformamide was stirred at rt for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 7:3) to afford 0.290 g (63%) of amide 45 as a tan solid: Mp=100-102° C.; 1H NMR (DMSO-d6) δ 7.74 (dd, 1H, J=2.0 Hz), 7.66 (d, 1 H, J=8.6 Hz), 7.37 (s, 1 H), 7.31 (t, 1 H, J=8.7 Hz), 7.24 (d, 1 H, J=2.6 Hz), 6.93 (d, 1 H, J=2.6 Hz), 3.90 (s, 3 H), 3.82 (s, 3 H), 3.59 (br s, 3 H), 3.30 (s, 3H); MS 360 (M+H)+
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[CH2:3][C:4](=[O:11])[CH2:5]1.[BH4-].[Na+]>C(O)C>[CH:7]12[CH2:10][CH:1]([CH2:9][CH2:8]1)[CH:2]1[CH:6]2[CH2:5][CH:4]([OH:11])[CH2:3]1
Reactant: O=C1CC2C3CCC(C3)C2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CC2C3CCC(C3)C2C1
Reaction time: 24 h
Yield: 96.6 %

Procedure:
Tricyclo[5.2.1.02.6 ]decan-4-one (1.5 g, 10 mmol) is dissolved in 25 ml of absolute ethanol and treated with sodium borohydride (0.189 g, 5.0 mmol). The reaction is stirred 24 hours, concentrated in vacuo and the resulting crude is redissolved in ether. The organics are washed 2×H2O, 2×brine, dried, filtered and concentrated in vacuo to afford 1.47 g (96.79%) of the alcohol as a clear oil.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].CO.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH:1]([C:4]1[NH:5][C:6]2[C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2nc(C(C)C)[nH]c2c1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nc(C(C)C)[nH]c2c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Isopropyl-5-methoxybenzimidazole (50 g) was dissolved in 150 mL TFA and to the mixture was added 5 mL 90% nitric acid. The reaction was stirred overnight, and the solvents removed in vacuo and the residue neutralized to pH 7 with saturated aqueous sodium bicarbonate. The residue was extracted with ethyl acetate (4×100 mL). The combined ethyl acetate fractions were dried over sodium sulfate and concentrated to give a dark residue. Chromatography (3% methanol/methylene chloride) gave 2-isopropyl-4-nitro-5-methoxybenzimidazole as a yellow solid, 24 g. Also obtained was 25 g of 2-isopropyl-5-nitro-6-methoxybenzimidazole.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH2:10][C@@:9]1([C:13](=[O:30])[N:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH3:12])=O)(C)(C)C.Cl>O1CCOCC1>[ClH:29].[CH3:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[C:13]([C@@:9]1([CH3:12])[CH2:10][CH2:11][NH:8]1)=[O:30]
Reactant: COC(=O)CCCN(Cc1cccc(Cl)c1)C(=O)[C@@]1(C)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCCN(Cc1cccc(Cl)c1)C(=O)[C@@]1(C)CCN1
Temperature: 20 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of (R)-2-[(3-chloro-benzyl)-(3-methoxycarbonyl-propyl)-carbamoyl]-2-methyl-azetidine-1-carboxylic acid tert-butyl ester, Intermediate 175 (17.6 g, 1 eq.) in 200 mL of dioxane under nitrogen was added a solution of HCl (4N) in dioxane (50 mL, 5 eq.). The reaction was stirred for 16 h at 20° C., then concentrated under reduced pressure. The crude was solubilised in DCM, poured into Et2O and the resulting solid was filtered, washed with Et2O and pentane and dried to afford 4-[(3-chloro-benzyl)-((R)-2-methyl-azetidine-2-carbonyl)-amino]-butyric acid methyl ester hydrochloride (12.5 g, yield=81%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH:26]=O)[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2].[CH2:29]([NH2:31])[CH3:30]>>[CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][C:17]=2[CH2:26][NH:31][CH2:29][CH3:30])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)C(C)(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)(C)C(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: 2-(2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-2-methyl-propionic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30](=[O:46])[N:31]([CH:43]([CH3:45])[CH3:44])[CH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])[CH:27]=[C:26]([Cl:47])[CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:47][C:26]1[CH:27]=[C:28]([CH:29]=[C:24]([O:23][CH2:22][CH2:21][NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:25]=1)[C:30]([N:31]([CH:43]([CH3:44])[CH3:45])[CH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]([F:40])([F:42])[F:41])(=[O:37])=[O:38])=[O:46]
Reactant: CC(C)N(CCCNS(=O)(=O)C(F)(F)F)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCCNS(=O)(=O)C(F)(F)F)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
A solution of (2-{3-chloro-5-[isopropyl-(3-trifluoromethanesulfonylamino-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate (0.038 g) in dichloromethane (1 ml) was treated with dichloromethane:trifluoroacetic acid (1:1 v/v) (1 ml) stirred for 3 h at room temperature and concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.024 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:4]=1.[Mn]([O-])(=O)(=O)=[O:28].[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([C:14]([OH:28])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[N:4]=1
Reactant: COc1ccc(CCNc2cc(-c3ccc(C=O)s3)nc(OC)n2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CCNc2cc(-c3ccc(C(=O)O)s3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
To a solution of 5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbaldehyde [700 mg, 1.895 mmol, Example 8(b)] in acetone (20 mL) is added a solution of potassium permanganate (898 mg, 5.684 mmol) and NaH2PO4.H2O (79 mg, 0.568 mmol) in water (20 mL) followed by the addition of silica gel (4 g). The mixture is allowed to stir at ambient temperature for 6 hours, allowed to stand overnight, evaporated to remove the acetone and extracted several times with ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated. The residual crude product is dissolved in refluxing acetonitrile and the solids that formed upon cooling are collected by filtration to afford 5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid [362 mg, 50%, Example 61].
Reaction SMILES: [CH3:1][Mg]Br.[N:4]1([C:10]2[N:11]=[C:12]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][CH:33]=3)[C:13]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15][C:14]=3[N:30]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CCOCC.C1COCC1>[N:4]1([C:10]2[N:11]=[C:12]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:40])([CH3:1])[CH3:39])=[CH:36][CH:37]=3)[C:13]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15][C:14]=3[N:30]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Nc2nc(N3CCCCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Nc2nc(N3CCCCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
To a solution of methylmagnesium bromide (170 mL of a 3.0 M solution in Et2O, 0.51 mmol) in THF at 0° C. was added a solution of 1-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone (Example 156; 59.8 mg, 0.117 mmol) in THF. The solution was allowed to warm to rt over 1 h, and stirred at rt for an additional 5 min. The reaction mixture was then quenched with satd. aq. NH4Cl and extracted with EtOAc. The organic layers were combined, dried, and concentrated. The crude residue was purified (FCC) to give the title compound (51 mg, 83%). MS (ESI): mass calcd. for C28H33F3N6O, 526.27; m/z found, 527.3 [M+H]+. 1H NMR (CDCl3): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.46-7.41 (m, 2H), 6.94-6.90 (m, 1H), 6.35 (s, 1H), 3.77-3.69 (m, 4H), 3.63-3.53 (m, 4H), 3.10-3.03 (m, 2H), 2.87-2.80 (m, 2H), 1.70 (s, 1H), 1.66-1.60 (m, 6H), 1.54 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CC[N:25](C(C)C)[CH:26]([CH3:28])[CH3:27].CC(N)C>CS(C)=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Solvent: CC(C)N
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)C)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol) in DMSO (10 mL) was added DIEA (489 mg, 3.79 mmol) and propan-2-amine (149.4 mg, 2.53 mmol) under nitrogen atmosphere. After stirring overnight at 70° C., the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3×80 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue. Purification via silica gel column chromatography (2% ethyl acetate in petroleum ether) afforded methyl 2-(4-fluorophenyl)-3-(isopropylamino)quinoxaline-6-carboxylate as a light yellow solid (100 mg, 44%).
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[C:19]1[N:23]([CH:24]2[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]2)[N:22]=[CH:21][CH:20]=1.N.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>ClCCl.O>[NH:26]1[CH2:25][CH:24]([N:23]2[C:19]([C:10]3[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:9]=3[OH:8])=[CH:20][CH:21]=[N:22]2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: N
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(C(F)(F)F)cc1-c1ccnn1C1CNC1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a stirred solution of tert-butyl 3-{5-[2-hydroxy-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate, (Preparation 857, 375 mg, 0.001 mol) in dichloromethane (10 mL) under nitrogen and the solution was stirred for 3 hours. The pink solution was evaporated and the residue dissolved in methanol and then the solvents were removed in vacuo. This was repeated a further two times. The residue was then suspended in diethyl ether and the solvents removed in vacuo to give an off-white foam. The foam was dissolved in water and treated with aqueous ammonia solution (7.5 molar) until pH10 to give a white precipitate. The mixture was extracted with ethyl acetate (6×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2×20 mL), dried over anhydrous sodium sulphate, filtered and the solvents removed in vacuo to give a solid. The solid was triturated with diethyl ether to give the title compound as a white solid (200 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3([NH:18]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=2)O1.[Cl:27][CH:28]([Cl:47])[C:29]([N:31]1[C@H:35]([CH2:36][F:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=2)[O:33]C1(C)C)=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:15]1([C:11]2[CH:10]=[C:9]([C:41]3[CH:42]=[CH:43][C:38]([C@@H:34]([OH:33])[C@H:35]([NH:31][C:29](=[O:30])[CH:28]([Cl:27])[Cl:47])[CH2:36][F:37])=[CH:39][CH:40]=3)[CH:14]=[CH:13][CH:12]=2)[CH2:16][CH2:17]1
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: NC1(c2cccc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc3)c2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
A mixture of tert-butyl (1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (241 mg, 0.672 mmol), 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone (250 mg, 0.56 mmol), Cs2CO3 (365 mg, 1.12 mmol) in dioxane (4 mL) and water (1 mL) is bubbled with nitrogen gas for 2 minutes. Pd(PPh3)4 (64 mg, 0.056 mmol) is added and the resulting reaction mixture heated at 80° C. for 4 hours. Reaction is diluted with water (10 ml) and extracted with ethyl acetate (3×10 mL). Combined organic solution is dried over Na2SO4 and concentrated. Crude compound dissolved in DCM (3 mL) and stirred with TFA (0.6 mL) at room temperature for 1 hour. Reaction is diluted with toluene (10 mL) and concentrated. Crude compound is basified slowly using saturated aq. NaHCO3, extracted with ethyl acetate (3×30 mL) and combined extracts dried over Na2SO4 and concentrated. Solid dissolved in DMF (2 mL) and purified using HPLC eluting from 5 to 95% water/acetonitrile to give the title compound (50 mg): 1 HNMR (400 MHz, MeOH-d4) δ: 1.33-1.39 (m, 2H), 1.40-1.47 (m, 2H), 4.33-4.42 (m, 1.5H), 4.44-4.51 (m, 0.5H) 4.56-4.63 (m, 0.5H), 4.68-4.75 (m, 0.5H), 5.03 (d, 1H, J=4 Hz), 6.31 (s, 1H), 7.44-7.48 (m, 1H), 7.50-5.55 9 m, 3H), 7.63-7.68 (m, 3H), 7.75-7.78 (m, 1H), m/z (Cl) 411 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([OH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:28]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([O:20][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([C:27]#[N:28])=[CH:30][CH:31]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(O)c2CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(OCc3ccc(C#N)cc3)c2CC1
Temperature: 25 °C

Procedure:
Combine 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.67 mmol), potassium carbonate (111 mg, 0.8 mmol), and 4-cyanobenzyl bromide (263 mg, 1.34 mmol) in DMSO (5 mL) and heat the stirred mixture to 100° C. for 24 h. Cool to ambient temperature and partition the mixture between water and EtOAc/hexane (1:1). Wash the organic layer with brine and dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-cyanobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[N:29][S:30][N:31]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].[CH3:32][NH2:33]>>[CH3:32][NH:33][C:7]([C:6]1[C:11]([NH:10][C:9]([C:12]2[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:16]=2)=[O:8])=[C:2]([Cl:1])[C:3]2[C:4]([CH:5]=1)=[N:29][S:30][N:31]=2)=[O:28]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nsnc3cc12
Reactant: CN
Product: CNC(=O)c1cc2nsnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
See step f) of Example H2 using 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-7-oxa-2-thia-1,3,5-triaza-cyclopenta[b]naphthalen-8-one as starting material and methylamine (40% in H2O). After overnight reaction and chromatography column purification, a slightly brown solid is obtained (75%). LC/MS: 538/539 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:5][N:6]=1.[C:13]([C:20](OCC)=[O:21])#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[N:7]1([C:4]2[S:3][C:2]3=[N:1][C:20](=[O:21])[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Nc1nnc(N2CCCCC2)s1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(N3CCCCC3)nn12

Procedure:
The procedure used was as described in Example 5. However, there were used 9.2 g of 2-amino-5-piperidino-1,3,4-thiadiazole, 8.5 g of diethyl acetylenedicarboxylate and 200 ml of ethanol. Thus 9.8 g (63.7% of the theoretical yield) of ethyl 2-piperidino-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylate, melting at 125° to 127° C., were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[N:12]\OS(C)(=O)=O)=[CH:5][CH:4]=1.B(F)(F)F.CO.CS(Cl)(=O)=[O:26]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:12][C:9]2=[O:26])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)/C(=N/OS(C)(=O)=O)CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: FB(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 117.1 %

Procedure:
To a stirred suspension of (1E)-6-methoxy-N-[(methylsulfonyl)oxy]-2,3-dihydro-1H-inden-1-imine (1b, 27 g, 106 mmol), BF3/MeOH (14% in MeOH, 16.8 g, 170 mmol) and TiCl4 (32.3 g, 170 mmol) in dry DCM (200 mL) was added MsCl (20.9 g, 183 mmol) dropwise at 0° C. After the addition, the resulting solution was stirred at room temperature for 14 hours. To the reaction mixture was added DCM (200 mL) and the solution was washed with saturated NaHCO3 to pH ˜7. The organic layer was washed with brine (150 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (DCM/MeOH) to give 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1c, 22 g, 100%) as a gray solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:20]([CH3:34])[CH2:21][CH2:22][N:23]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:23][CH2:22][CH2:21][CH:20]([N:16]1[CH2:17][CH2:18][CH:13]([N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]2=[O:12])[CH2:14][CH2:15]1)[CH3:34]
Reactant: O=C1OC[C@@H](c2ccccc2)N1C1CCNCC1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(N2C(=O)OC[C@H]2c2ccccc2)CC1
Yield: 62.2 %

Procedure:
Using general procedure B with the above amine (101 mg, 0.41 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (179 mg, 0.82 mmol) followed by general procedure D gave (R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-phenyl-oxazolidin-2-one (81 mg, 62% over 2 steps).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([O:18]C)=[C:11]([O:20]C)[CH:10]=1)=[O:8].[BrH:22]>>[BrH:22].[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([OH:18])=[C:11]([OH:20])[CH:10]=1)=[O:8]
Reactant: COc1cc(C(=O)c2nccn2C)cc([N+](=O)[O-])c1OC
Agent: Br
Product: Cn1ccnc1C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
5.0 g of 3,4-dimethoxy-5-nitrophenyl (1-methylimidazol-2-yl) ketone are treated with 50 ml of hydrobromic acid (48%), whereupon the mixture is stirred under reflux temperature for 2 hours. After cooling the separated precipitate is filtered under suction, washed with ice-water and recrystallized from ethanol. There is obtained 3,4-dihydroxy-5-nitrophenyl (1-methyl-imidazol-2-yl) ketone hydrobromide in the form of yellow crystals of decomposition point >240°.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)O1.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1>>[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[N:22]=1
Reactant: CC1(C)OB(c2cccc(C(F)(F)F)c2)OC1(C)C
Reactant: Brc1cccc(Br)n1
Product: FC(F)(F)c1cccc(-c2cccc(Br)n2)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 4,4,5,5-tetramethyl-2-(3-trifluoromethyl-phenyl)-[1,3,2]dioxaborolane and 2,6-dibromo-pyridine.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:34]1[CH:35]=[C:36]([CH:45]=[CH:46][CH:47]=1)[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:19]=[CH:20][C:21]([C:43]5[CH:42]=[CH:41][CH:40]=[C:39]([C:37]([C:36]6[CH:45]=[CH:46][CH:47]=[CH:34][CH:35]=6)=[O:38])[CH:44]=5)=[CH:22][CH:23]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1cccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
In a sealed tube, a mixture of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (179 mg, 0.265 mmol), 3-bromobenzophenone (66 mg, 0.253 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.012 mmol) in 2M aq potassium carbonate (0.5 mL, 1.00 mmol) and 1,4-dioxane (1.5 mL) was stirred at 100° C. for 1 h. The reaction was cooled to room temperature and the reaction mixture was diluted with ethyl acetate (10 mL). The layers were separated and the aqueous layer was acidified to pH˜5 using 1N aq HCl. The aqueous layer was then extracted with ethyl acetate (20 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-3% methanol/ethyl acetate) provided the title compound as an ivory solid (68 mg, 55%) after drying in the vacuum oven (70° C.) for 4 days. MS(ES)+ m/e 493.2 [M+H]+.