Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][OH:14]>>[Cl:1][C:2]1[C:7]([NH:8][CH2:11][CH2:12][CH2:13][OH:14])=[C:6]([CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Cc1cccc(Cl)c1N
Product: Cc1cccc(Cl)c1NCCCO
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A mixture of the 6-chloro-2-methyl aniline (70.8 g) and 3-bromo-1-propanol (27.8 g) was heated under nitrogen to 100° C. for 2 hours. The mixture was cooled and partitioned between dichloromethane and 1N sodium hydroxide. The organic layer was washed with 20% aqueous sodium chloride, dried over anhydrous potassium carbonate and evaporated to dryness. The residue was flash chromatographed on Merck-60 flash silica gel. Elution with a hexane-ethyl acetate gradient (from 8:1 to 3:1) provided the title compound (30.86 g, 77.5%) as a pale yellow oil, which was used as such in the next step.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][C@H:7]2[CH2:9][C@@H:4]1[C:5](=[O:10])[O:6]2)[CH3:2].[NH:11]([C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=1)[NH2:12].C[Al](C)C.Cl>O1CCOCC1>[CH2:1]([C@@H:3]1[CH2:8][C@H:7]([OH:6])[CH2:9][C@@H:4]1[C:5]([NH:12][NH:11][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=1)=[O:10])[CH3:2]
Reactant: CC[C@@H]1C[C@H]2C[C@@H]1C(=O)O2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one (0.835 g, 5.96 mmol, Preparation #GG.1) in 1,4-dioxane (12 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Example #1, Step D, 1.81 g, 5.96 mmol). The reaction mixture was heated at about 80° C. for about 16 h then cooled to ambient temperature. 1,4-Dioxane (25 mL) and trimethylaluminum (2 N in toluene, 9 mL, 18 mmol) were added sequentially. The reaction mixture was stirred at ambient temperature for about 30 min. Aqueous HCl (1 N, 50 mL) was added dropwise and the reaction mixture was stirred for about 30 min. The layers were separated. The aqueous portion was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (10 mL), saturated aqueous NaHCO3 (15 mL), brine (15 mL) and dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified using silica gel chromatography (40 g) eluting with 100% EtOAc to give (1S,2R,4S)-2-ethyl-4-hydroxy-N′-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)cyclopentane-carbohydrazide (1.887 g, 53%): LC/MS (Table 1, Method b) Rt=2.05 min; MS m/z: 444 (M+H)+.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@:4]([OH:12])([CH3:1])[CH2:8][CH2:7][N:6]1[C:20]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[CH:21]=1)[CH3:11]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4-difluorobenzonitrile (240 mg) and lithium carbonate (187 mg), the title compound was obtained as pale-yellow oil (yield: 188.6 mg, yield: 66%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:36])([F:1])[F:35])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[C:9]=2[C:8]1=[O:27]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C1c2c(-c3ccc(Cl)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccc(Cl)cc3)cc(N3CCC(N4CCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 55.5 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (67.4 mg, 56%).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[O:18][CH2:19][C:20]([O:22]CC)=[O:21].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>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.O.C(OCC)(=O)C.CO>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:15]1[CH:27]=[CH:26][CH:25]=[C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])[CH:16]=1
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)COc1cccc(Br)c1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cccc(OCC(=O)O)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 58.2 %

Procedure:
Under an Ar atmosphere, 12 mL of toluene, 3 mL of methanol, and 3 mL of 2M aqueous sodium carbonate solution were added to 500 mg (1.93 mmol) of ethyl (3-bromophenoxy)acetate and 352 mg (2.32 mmol) of (2-methoxyphenyl)boronic acid, and the mixture was degassed. Further, 112 mg (0.097 mmol) of tetrakis(triphenylphosphine)palladium(0) was added thereto, and the mixture was heated under stirring at 80° C. for 6 hours. After the mixture was cooled to room temperature, ethyl acetate and water were added thereto to separate the mixture. The water layer was separated, and filtration was performed. Thereafter, acidification was performed with 1N hydrochloric acid, and extraction with ethyl acetate was performed. The organic layer was washed with saturated saline and dried over anhydride magnesium sulfate, followed by filtration and condensation, thereby giving 290 mg of [(2′-methoxybiphenyl-3-yl)oxy]acetic acid (yield: 58%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][Br:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:29]I.[Cl-].[NH4+]>C1COCC1>[CH3:29][N:17]([CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][Br:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(NC(Cc1ccccc1)c1ccccc1)c1ccc(CBr)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C(Cc1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium hydride (60% dispersion in oil: 190 mg, 4.7 mmol) was added to a stirred solution of N-1,2-diphenylethyl 4-bromomethylbenzenesulphonamide (2.00 g, 4.7 mmol) in dry THF (50 ml) at 0° C. under argon. Methyl iodide (0.6 ml, 9.3 mmol) was added immediately to the reaction mixture. The mixture was stirred for 48 h at ambient temperature. Saturated aqueous ammonium chloride (50 mi) was added and the mixture extracted with ethyl acetate (2×80 ml). The combined organics were washed with brine (50 ml), dried over anhydrous sodium sulphate, filtered and concentrated to give N-methyl-N-1,2-diphenylethyl 4-bromomethylbenzenesulphonamide as an orange oil which was used directly in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1.O>CS(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:20][C:21](=[O:23])[CH3:22])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C=Cc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of quinoline-6-carboxaldehyde (5.29 g) and 1-triphenylphosphoranylidene-2-propanone (1.5 equiv) in dimethyl sulfoxide (100 ml) was stirred at room temperature for 24 hr. The solution was poured into water (600 ml) which was subsequently extracted with ethyl acetate. The dried (MgSO4) organic fraction was evaporated under reduced pressure and the residue was purified by column chromatography over silica with dichloromethane/ethyl acetate (4:1 v/v) elution to give 1-(quinolin-6-yl)but-1-ene-3-one as a white solid. Pmr spectrum (CDCl3 ; δ in ppm): 2.41 (3H,s); 6.83 (1H,d); 7.3-9.0 (7H,m).
Reaction SMILES: N#N.[F:3][C:4]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[C:38]2[C:33](=[CH:34][N:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N:31]([CH3:40])[CH:30]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:4]=2[F:3])=[C:8]([C:29]2[C:38]3[C:33](=[CH:34][N:35]=[CH:36][CH:37]=3)[C:32](=[O:39])[N:31]([CH3:40])[CH:30]=2)[CH:9]=1
Reactant: CC1(C)OB(c2cc(N)ccc2Oc2ccc(F)cc2F)OC1(C)C
Reactant: Cn1cc(Br)c2ccncc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)c2ccncc2c1=O
Reaction time: 0.08 h
Yield: 53.1 %

Procedure:
For 5 min, N2 was bubbled through a mixture of 4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (64.8 mg, 0.187 mmol), the title compound of Example 51, step 2 (30.0 mg, 0.124 mmol), K2CO3 (51.6 mg, 0.374 mmol) and Pd(dppf)Cl2 (18.3 mg, 0.025 mmol) in dioxane (2.0 mL) and water (0.2 mL) which was then microwaved at 100° C. for 1 h. Purification by preparative TLC (DCM:MeOH=20:1, Rf=0.5) gave the title compound (25.0 mg, 53%) as yellow gum. LCMS: 380.0 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18]([O-:20])=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[NH:29][C:25]=2[CH:24]=1>>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]2[NH:27][C:26]3[CH:39]=[CH:40][C:23]([NH:22][C:18]([C:16]4[CH:15]=[CH:14][C:12]5[NH:13][C:9]([C:6]6[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:8][CH:7]=6)=[N:10][C:11]=5[CH:17]=4)=[O:20])=[CH:24][C:25]=3[N:29]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cccc(Nc2nc3ccc(N)cc3[nH]2)c1
Reactant: CN(C)c1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Product: COc1cccc(Nc2nc3cc(NC(=O)c4ccc5[nH]c(-c6ccc(N(C)C)cc6)nc5c4)ccc3[nH]2)c1

Procedure:
Compound 439 was prepared from 2-(4-dimethylaminophenyl)benzimidazole-5-carboxylate and 5-amino-2-(3-methoxyphenyl)aminobenzimidazole by standard conditions. [M+H]+ calcd for C30H27N7O2: 518.22; found: 518.03.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>CC#N>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CN(C)CCNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
N-(2-(dimethylamino)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine was prepared by heating 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (0.219 g, 1 mmol), potassium iodide (0.006 g, 0.03 mmol), potassium carbonate (0.060 g, 0.4 mmol) and 2-dimethylaminoethyl chloride hydrochloride (0.043 g, 0.3 mmol) in MeCN (2 ml) to 110° C. by microwave irradiation for 10 minutes. The crude reaction was purified by preparative HPLC to give the desired compound as a white solid, (0.025 g, 0.086 mmol). LCMS (3) 2.12 min; m/z (ES+) 291
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:12][C:13]([CH3:15])=[CH2:14])[S:8]([CH3:11])(=[O:10])=[O:9].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:12][C:13]1([CH3:15])[CH2:14][O:24]1)[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: C=C(C)CN(Cc1ccco1)S(C)(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(CN(Cc2ccco2)S(C)(=O)=O)CO1
Temperature: 40 °C
Reaction time: 18 h
Yield: 26.4 %

Procedure:
To a stirring solution of N-(furan-2-ylmethyl)-N-(2-methylallyl)methanesulfonamide (1.0 g, 4.3 mmol) in anhydrous methylene chloride (20 mL) was added 3-chloroperbenzoic acid (70%, 2.1 g, 8.6 mmol). The mixture was stirred at ambient temperature for 2 hours and at 40° C. for 18 hours. The mixture was diluted with methylene chloride and successively washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The crude residue was purified by silica gel column chromatography (10-60% ethyl acetate in hexanes) to give a clear oil (0.278 g, 26%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.35 (dd, 1H, J=0.9, 1.8 Hz), 6.33-6.30 (m, 2H), 4.52-4.51 (m, 2H), 3.48-3.43 (d, 1H, J=15 Hz), 3.13-3.09 (d, 1H, J=15 Hz), 2.73-2.72 (d, 1H, J=4.5 Hz), 2.70 (s, 3H), 2.62-2.61 (d, 1H, J=4.5 Hz), 1.35 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][N:15]=2)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH3:38][C:39]1([CH3:53])[C:43]([CH3:45])([CH3:44])[O:42][B:41]([C:46]2[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=2)[O:40]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[NH:50][C:49]3[CH:48]=[CH:47][C:46]([B:41]4[O:42][C:43]([CH3:45])([CH3:44])[C:39]([CH3:53])([CH3:38])[O:40]4)=[CH:52][CH:51]=3)=[CH:16][N:15]=2)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)O)cn1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cn1
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A solution of (R)-4-(5-carboxy-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.6 mmol) and EDC (140 mg, 0.75 mmol) and HOAt (100 mg, 0.75 mmol) dissolved in DMF (4.6 mL) was stirred for 30 min and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (140 mg, 0.62 mmol) and N,N-diisopropylethylamine (130 μL, 0.75 mmol) were added. The reaction mixture was stirred at RT overnight and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 0-70% ethyl acetate:hexanes) to provide the title intermediate (250 mg, 80% yield). (m/z): [M+H]+ calcd for C28H39BN4O5 523.30. found 523.5.
Reaction SMILES: BrCCBr.[Mg].[CH3:6][N:7]1[CH2:12][CH2:11][CH:10](Cl)[CH2:9][CH2:8]1.[Br:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]=[N:23][C:17]=2[CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[Br:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]([CH:10]3[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]3)[NH:23][C:17]=2[CH:16]=1
Reactant: CN1CCC(Cl)CC1
Reactant: Brc1ccc2c(c1)N=Cc1cccc3c1N2CC3
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CN1CCC(C2Nc3cc(Br)ccc3N3CCc4cccc2c43)CC1
Reaction time: 1 h

Procedure:
1,2-Dibromoethane (0.5 ml) was added to a refluxing slurry of magnesium chips (12 gm) in tetrahydrofuran (60 ml) to initiate a Grignard reaction. N-Methyl-4-chloropiperidine (55 ml) in tetrahydrofuran (100 ml) was added rapidly. The mixture was refluxed for 1 hour, during which a white precipitate formed. A solution of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (30 gm) in tetrahydrofuran (150 ml) was added at 0° C. After one hour of stirring, the mixture was poured into cold saturated ammonium chloride solution (750 ml) and extracted with ethyl acetate (2×400 ml). The ammonium chloride solution was basified with ammonium hydroxide and extracted once with ethyl acetate (400 ml). The combined ethyl acetate solutions were washed with brine (2×500 ml), dried over anhydrous magnesium sulfate and concentrated to a solid (38 gm). The crude solid was purified by flash chromatography (700 gm silica, eluted with 4% methanol/dichloromethane, 6 L; 4 % methanol/0.5% ammonium hydroxide/dichloromethane, 4 L). The fractions containing the desired product were pooled and concentrated to give 23 gm of a solid. Recrystallization from dichloromethane/ethanol (200 ml:1 L) yielded 17.0 gm of crystals, m.p. 206°-208° C.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:13]OC(OC)N(C)C>C1C=CC=CC=1>[N:1]12[CH:13]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:3][CH2:2]2
Reactant: C1CNCCNCCNCCN1
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: C1CN2CCN3CCN(CCN1)C23

Procedure:
In a manner similar to that of Example 2 (A), 5.00 g (29.1 mmol) of 1,4,7,10-tetraazacyclododecane, 3.46 g of dimethylformamide dimethyl acetal and 50 ml of dry benzene gave 5.00 g of colorless liquid, bp 88.5°-90° (0.30 mm). Analytically pure 1,4,7,10-tetraazatricyclo[5.5.1.04,13 ]tridecane was obtained by distillation of this material through a spinning band column, bp 82°-83° (two fractions) (0.25 mm) One fraction had nD25 = 1.5331. The other fraction was analyzed.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].O[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][O:5][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CCCCCCO
Reactant: OCCC(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCCCCCOCCC(F)(F)F
Reaction time: 0.25 h

Procedure:
3,3,3-Trifluoropropanol (10 ml, 110 mmol), methyl 7-hydroxyheptanoate (133 mmol, 1.2 eq), triphenylphosphine (35 g, 133 mmol, 1.2 eq) are initially introduced in 37 ml of THF in a round-bottomed flask and introduced into an ultrasound bath for a few minutes in order to mix the substances. During the exposure to ultrasound, DIAD (26.5 ml, 133 mmol, 1.2 eq) is very slowly added dropwise (temperature rises), and the reaction mixture is left under ultrasound for 15 min. A TLC sample is taken and subsequently left in the ultrasound bath for a further 2 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][N:13]2C(=O)C3C(=CC=CC=3)C2)=O)=[CH:6][C:5]=1[Br:23].CNN>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:12][NH2:13])=[CH:6][C:5]=1[Br:23]
Reactant: COC(=O)c1ccc(C(=O)ON2Cc3ccccc3C2=O)cc1Br
Agent: CNN
Solvent: ClCCl
Product: COC(=O)c1ccc(CON)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 2-bromo-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxymethyl)-benzoic acid methyl ester (0.40 g, 1.02 mmol) in methylene chloride (15 mL) cooled to 0° C. was added methyl hydrazine (0.087 g, 1.88 mmol). After a few minutes the ice bath was removed and the mixture was allowed to stir at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/methylene chloride (0/100 gradient to 6/94) to give 4-aminooxymethyl-2-bromo-benzoic acid methyl ester (0.25 g, 94%) as a colorless oil. 1H NMR (400 MHz, CDCl3); δ 7.79 (d, 1H), 7.66 (s, 1H), 7.32 (d, 1H), 4.67 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=[C:10]([CH3:18])[CH:9]=2)=[C:4]([F:19])[CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]([CH3:18])[CH:9]=2)=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(-c2ccc(Cl)cc2F)c(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a solution of Methyl 4-(4-chloro-2-fluorophenyl)-6-methylnicotinate (700 mg, 2.50 mmol) in MeOH (5 mL) was added NaOH (200 mg, 7.51 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 2 h. Then it was evaporated under reduced pressure and the residue obtained was adjusted to pH ˜3 by adding 1.5N HCl solution. The product was extracted with dichloromethane. The organic phase was dried over Na2SO4, and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-6-methylnicotinic acid (500 mg, 1.730 mmol, 69% crude yield) as white solid. The material was carried forward without further purification. LC/MS (ESI) m/e 266.0 [(M+H)+, calcd for C13H10ClFNO2 266.0]; LC/MS retention time (Method I): tR=1.51 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](OC)=[O:11])=[C:7]([CH2:14][O:15][CH3:16])[C:6]=2[CH:17]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[Cl-].[NH4+].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C.O1CCCC1.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH2:14][O:15][CH3:16])[C:6]=2[CH:17]=1
Reactant: COCc1c(C(=O)OC)oc2ccc(F)cc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCO
Product: COCc1c(C=O)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a mixture of methyl 5-fluoro-3-(methoxymethyl)-1-benzofuran-2-carboxylate (5.01 g) synthesized above, calcium chloride (4.66 g), ethanol (50 mL) and tetrahydrofuran (50 mL) was added at 0° C. sodium borohydride (3.18 g), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, the organic solvent was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a colorless oil. To a mixture of the obtained oil, 4-methylmorpholine N-oxide (3.69 g) and acetonitrile (50 mL) was added tetrapropylammonium perruthenate (738 mg) at 0° C., and the mixture was stirred for 1.5 hr and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate/hexane) to give the title object compound (2.33 g, 53%) as a pale-yellow solid.