Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH3:15])[C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([N:5]([CH3:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCCCN(C)Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
In a manner analogous to Example 1 a solution of N-butyl-N-methyl-4-chlorobenzamide (4.49 g; 0.02 mol) in dry THF (50 ml) was reacted with an ice-cooled solution of 1.0M diborane-THF complex (90 ml); 0.09 mol) to give the title compound which was converted to the hydrochloride salt and crystallised from ethyl acetate (1.51 g; 65.7%), mp 136°-138°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: CNCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 80.5 %

Procedure:
N1,N1,N2-Trimethylethane-1,2-diamine (83 mg, 0.82 mmol) was added to a mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 409 mg, 0.74 mmol), DIPEA (0.259 mL, 1.48 mmol) and DMA (3 mL). The resulting mixture was heated in a microwave at 140° C. for 0.5 h. Part-purification was achieved by ion exchange chromatography, using an SCX column (20 g) and eluting with 0.35 M methanolic ammonia. Appropriate fractions were concentrated in vacuo to provide an orange/brown gum. This gum was triturated with ethanol (15 mL) to give a solid which was collected by filtration and dried under vacuum to give the title compound (275 mg, 80%) as an orange solid; 1H NMR: 2.18 (6H, s), 2.45-2.55 (2H, m), 2.87 (3H, s), 3.25-3.30 (2H, m), 3.97 (3H, s), 6.87 (1H, s), 7.08 (1H, t), 7.18 (1H, t), 7.29 (1H, d), 7.46 (1H, d), 8.03 (1H, s), 8.33 (3H, dd), 8.66 (1H, s), 11.80 (1H, s); m/z: ES+ MH+ 462.34.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:30])[C@@H:5](/[CH:6]=[CH:7]\[C:8](=[O:10])[OH:9])[C@H:4]1[C:11]([O:13][CH:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12].C(O)(=O)C.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl>[CH3:2][C:3]1([CH3:30])[C@@H:5](/[CH:6]=[CH:7]\[C:8](=[O:9])[O:10][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)[C@H:4]1[C:11]([O:13][CH:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12]
Reactant: C1=COCCC1
Reactant: CC1(C)[C@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)[C@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A methanolic N hydrochloric acid solution was added dropwise at 15° C. with stirring to a mixture of 1.5 g of α-cyano-3-phenoxy-benzyl (IR,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy -1-propenyl]-cyclopropane-carboxylate solvated with one mole of acetic acid, 4.5 ml of dihydropyran and 10 ml of methylene chloride and the mixture was stirred at room temperature for 30 minutes. Calcium carbonate was added to the mixture which was then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 hexane-ether mixture yielded 1.07 g of α-cyano-3-phenoxy-benzyl (IR,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(tetrahydropyran-2-yloxy) -1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+47° (c=0.5% in benzene).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCOCC1>ClCCl>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:7]
Reactant: Brc1ccccc1
Reactant: O=C1NCC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1[C@@H](O)CCN1c1ccccc1
Temperature: 25 °C

Procedure:
A Schlenk flask is initially charged with 0.123 g of 3(S)-hydroxy-pyrrolidin-2-one, 0.453 g of caesium carbonate, 0.032 g of dipalladiumtris(dibenzylidenacetone)-chloroform complex and 0.052 g of 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthane under argon. 0.110 ml of bromobenzene and 2 ml dioxane are added and the reaction mixture is heated to reflux over 14 hours. The reaction mixture is subsequently cooled to room temperature, diluted with dichloromethane and filtered through Hyflo, and the filtrate is concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F). Rf=024 (4:1 EtOAc-heptane); Rt=2.50.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH:27]([NH:30][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:3])([CH3:29])[CH3:28]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC(C)C)nn1
Yield: 53 %

Procedure:
As described for example 81, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) was converted, using isopropylamine instead of aminomethylcyclopropane, to the title compound (49 mg, 53%) which was obtained as a white foam. MS: m/e=370.3 [M+H]+.
Reaction SMILES: C1(CN2CCC([S:18]([N:21]3[CH2:26][CH2:25][CH:24](OC4C=CC(OC(F)(F)F)=CC=4)[CH2:23][CH2:22]3)(=[O:20])=[O:19])(C(OC)=O)CC2)C=CC=CC=1.C=NS(=O)=O.C(=O)([O-])[O-].[K+].[K+].ClCC[N:53](CCCl)[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:54]([NH:53][S:18]([N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)(=[O:19])=[O:20])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: COC(=O)C1(S(=O)(=O)N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)CCN(Cc2ccccc2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C=N[SH](=O)=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=S(=O)(NCc1ccccc1)N1CCCCC1
Temperature: 60 °C
Yield: 52 %

Procedure:
Part G: Preparation of methyl 1-(phenylmethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxylate. To a solution of the methylene sulfonamide from part F (20.46 g, 51.5 mmol) in dimethylformamide (90 mL) was added potassium carbonate (21.3 g, 154.7 mmol), bis-(2-chloroethyl)benzyl amine (12.0 g, 51.5 mmol; and 18-Crown-6 (700 mg). The slurry was stirred at 60° C. After twenty four hr the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water three times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was recrystallized (methanol) to give the N-benzyl piperidine sulfonamide as a white solid (15 g, 52%).
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[CH:7]=[C:8]3[N:13]([C:5]=2[CH:4]=[N:3][NH:2]1)[CH2:12][CH2:11][CH2:10][CH2:9]3.Br[C:16]1[N:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:17]=1[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>[Cu]I.O1CCOCC1>[Cl:24][C:20]1[C:17]([CH:18]=[O:19])=[C:16]([N:2]2[C:1](=[O:14])[C:6]3[CH:7]=[C:8]4[N:13]([C:5]=3[CH:4]=[N:3]2)[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:23]=[CH:22][CH:21]=1
Reactant: O=c1[nH]ncc2c1cc1n2CCCC1
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1-n1ncc2c(cc3n2CCCC3)c1=O
Temperature: 90 °C
Yield: 43.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 1,4-dioxane (40 mL), 193e (800 mg, 3.6 mmol), 2-bromo-4-chloronicotinaldehyde (2.8 g, 12.6 mmol), and potassium carbonate (1.2 g, 8.4 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, copper(I) iodide (800 mg, 4.2 mmol) and 4,7-dimethoxy-1,10-phenanthroline (1.0 g, 4.2 mmol) were added, and the reaction mixture was heated at 90° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between methylene chloride (60 mL) and water (40 mL). The aqueous layer was separated and extracted with methylene chloride (3×40 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:1 ethyl acetate/petroleum ether to afford 193f as a brown solid (513 mg, yield 37%). MS-ESI: [M+H]+ 329.1.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][CH:54]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]3[C:55]2=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:51])[CH2:46][CH2:45]1>CN(C)C=O>[CH:65]1[C:66]2[CH:54]([CH2:53][O:52][C:50]([N:47]3[CH2:48][CH2:49][CH:44]([NH:43][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][C:22]([NH:21][C:19]5[N:18]=[CH:17][C:8]6[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]7[CH2:5][CH2:4][CH2:3][CH2:2]7)[C:7]=6[N:20]=5)=[C:23]([O:31][CH3:32])[CH:24]=4)[CH2:45][CH2:46]3)=[O:51])[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:61]=2[CH:62]=[CH:63][CH:64]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a mixture of 0.15 g (0.34 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.24 mL (1.3 mmole) of ethyldiisopropyl amine and 0.13 g (0.37 mmole) of 4-amino-1-Fmoc-piperidine hydrochloride in 5.0 mL of dimethylformamide was added 0.16 g (0.37 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum to give 0.25 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (I-70) as a white solid.
Reaction SMILES: BrC1C=C2CCC3C=C(Cl)C=CC=3C([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[C@@H:20]([C:31]([N:33]4[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH2:41][N:42]5[CH:46]=[CH:45][N:44]=[CH:43]5)[CH2:35][CH2:34]4)=[O:32])[CH2:19]3)C2=NC=1>ClCCl>[N:42]1([CH2:41][CH2:40][CH2:39][CH:36]2[CH2:37][CH2:38][N:33]([C:31]([C@H:20]3[CH2:19][NH:18][CH2:23][CH2:22][NH:21]3)=[O:32])[CH2:34][CH2:35]2)[CH:46]=[CH:45][N:44]=[CH:43]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)C[C@@H]1C(=O)N1CCC(CCCn2ccnc2)CC1
Solvent: ClCCl
Product: O=C([C@H]1CNCCN1)N1CCC(CCCn2ccnc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-peroxybenzoic acid (25 g, 102.59 mmol, 2.5 eq.) in anhydrous dichloromethane (250 mL) was added dropwise over a period of one hour to a stirred solution of 8-chloro-4-aza-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one 1 (10 g, 41.04 mmol, 1.0 eq.) in anhydrous dichloromethane (100 mL) at 0° C. under a nitrogen atmosphere. The solution was slowly (3 h) warmed to room temperature and stirred for another 12 h. The solution was extracted with 1 M aqueous sodium hydroxide solution (5×100 mL), washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated under house vacuum at 30° C. to give 2 as a canary-yellow solid. The title compound 2 was used directly without further attempts at purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Cn1cc(C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)c2ccccc21
Yield: 28 %

Procedure:
The title compound is prepared from 1-methyl-1H-indole-3-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 28% of theory; LC (method 4): tR=2.05 min; Mass spectrum (ESI+): m/z=345 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)=C>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:10])=[CH:14][CH:15]=1
Reactant: C=COc1ccc(OC)cc1
Reactant: C=CCCCCCCBr
Product: COc1ccc(O/C=C\CCCCCCBr)cc1
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Following the general procedure, 8-bromooct-1-ene (50.0 mg, 0.262 mmol) was treated with p-methoxyphenyl vinyl ether (79.0 mg, 0.5 23 mmol) and 1.2 mol % of in situ-generated complex 1a (31.0 μL, 0.10 M, 3.14 μmol; final substrate concentration=8.45 M) and allowed to stir for 16 h. The unpurified product is >98% Z (as determined by 400 MHz 1H NMR analysis). Excess p-methoxyphenyl vinyl ether was removed by vacuum distillation (1.0 torr, 80° C.). The resulting oil was purified by neutral alumina chromatography (100% hexanes to 100:1 hexanes:Et2O) to afford 10b (56.9 mg, 0.182 mmol, 69.0% yield, >98% Z isomer) as a colorless oil. IR (neat): 2924 (s), 2854 (m), 1665 (m), 1503 (s), 1463 (m), 1441 (m), 1389 (w), 1214 (s), 1180 (m), 1102 (m), 1040 (s); 1H NMR (400 MHz, CDCl3): δ 6.95-6.90 (2H, m), 6.86-6.82 (2H, m), 6.28 (1H, dt, J=6.0, 1.5 Hz), 4.73 (1H, td, J=7.4, 6.0 Hz), 3.78 (3H, s), 3.40 (2H, t, J=7.0 Hz), 2.24-2.17 (2H, m), 1.90-1.81 (2H, m), 1.49-1.32 (6H, m); 13C NMR (100 MHz, CDCl3): δ 155.2, 151.8, 141.4, 117.5, 114.8, 112.0, 55.8, 34.1, 33.0, 29.4, 28.4, 28.1, 23.9; HRMS (ESI+) [M+H]+ calcd for C15H22BrO2: 313.0803, found: 313.0800
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:16][CH:12]([CH2:13][C:14]=2[CH:15]=1)[CH2:11][NH:10][CH2:9]3.[NH4+].[OH-]>Br>[ClH:1].[CH:8]12[CH2:16][CH:12]([CH2:11][NH:10][CH2:9]1)[CH2:13][C:14]1[CH:15]=[C:4]([OH:3])[CH:5]=[CH:6][C:7]2=1
Reactant: COc1ccc2c(c1)CC1CNCC2C1
Agent: Br
Agent: Cl
Agent: [NH4+]
Product: Oc1ccc2c(c1)CC1CNCC2C1
Yield: 39.8 %

Procedure:
5-Methoxy-11-aza-tricyclo[7.3.1.02.7]trideca-2(7),3,5-triene hydrochloride (187 mg, 0.78 mmol) was brought to reflux in 48% HBr (5 mL). After 1 hour the solution was cooled and poured into aq. NH4OH soin., the pH was adjusted to ˜9 and the product was extracted with EtOAc (3×40 mL). The organic player was washed with brine (50 mL), dried (MgSO4) and concentrated to a solid. (TLC 10%MeOH/CH2Cl2 (NH3) Rf 0.13). This material was dissolved in excess 1N HCl MeOH and concentrated. Recrystallization from MeOH/Et2O provided a solid (70 mg, 40%). 1H NMR (CD3OD) δ 6.99 (d, J=8.0 Hz, 1H), 6.83 (m, 2H). 3.48-3.11 (6H), 2.83 (d, J=18.0 Hz, 1H), 2.42 (br s, 1H), 2.08 (AB d, J=12.5 Hz, 1H), 1.93 (AB d, J=12.5 Hz, 1H). mp295-298° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:4][CH:3]=1.[CH3:36][C@@H:37]1[O:39][C@H:38]1[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[OH:39][C@@H:38]([CH3:40])[C@H:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:6][CH:7]=1)[CH3:36]
Reactant: C[C@@H]1O[C@H]1C
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ccnn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O[C@H](C)[C@H](C)O)cc2)c2ccnn12
Yield: 54 %

Procedure:
To a solution of 4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.92 g) in N,N-dimethylformamide (10 mL) were added trans-2,3-epoxybutane (1.8 mL) and then cesium carbonate (2.0 g), and the mixture was stirred at 100° C. for 15 hr. The mixture was allowed to cool, to the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.57 g, 54%).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O>C(Cl)(Cl)Cl>[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=1
Reactant: Cc1cccc(C(=O)CCC(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)CCC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a mixture of 24.5 g. 3-(m-toluoyl)propionic acid (0.10 mole) and 10.1 g. triethylamine (0.10 mole) in 250 ml. of chloroform cooled to 0°C., there is added dropwise 10.8 g. (0.10 mole) of ethyl chloroformate at such a rate that the critical temperature does not exceed 10°C. The reaction is stirred for 2 1/2 hours to obtain the mixed anhydride of 3-benzoylpropionic acid which is then treated with 3.1 g. of methylamine (0.10 mole) in 100 ml. of chloroform. The cooling apparatus is removed and the reaction is stirred for about 20 hours. The chloroform layer is then washed with 50 ml. of water, 100 ml. 1N hydrochloric acid, 100 ml. saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-tolyl) pyrrolidone; m.p. 128°-130°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32](O)[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.P([N:62]=[N+:63]=[N-:64])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CCOC(C)=O>[N:62]([CH:32]([C:18]1[CH:17]=[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:44]=[CH:45][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:35][C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)[N:10]=2)[C:21]([NH:22][C:23]2[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=2)=[N:20][CH:19]=1)[CH3:33])=[N+:63]=[N-:64]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N=[N+]=[N-])cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 16 h
Yield: 105.7 %

Procedure:
A glass microwave reaction vessel was charged with 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (0.9 g, 1.635 mmol) in toluene (15 mL). The tube was sealed under inert atmosphere. To this suspension, diphenyl azidophosphate (0.9 mL, 4.2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.64 mL, 4.3 mmol) were mixed, the solution was stirred for 16 h. The mixture was diluted with EtOAc, washed by saturated NH4Cl and brine, concentrated under a vacuum to provide 4-(5-(1-azidoethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.1 g, 92% purity, 100% yield) as a yellow solid, which was used in next step without further purification. MS (ESI positive ion) m/z: 637 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:30][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCC1CCCCC1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3-Cyclohexyl-1-propanol (5.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (10.2 g) and N-bromosuccinimide (6.90 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (7.17 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:18]=[CH:17]3)[C@@H:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[F:30][CH2:31][C:32](Cl)=[O:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[C@@H:10]([NH:12][C:32](=[O:33])[CH2:31][F:30])[CH3:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Reactant: O=C(Cl)CF
Product: CCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CF)cc1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-(4-ethylphenyl)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}propan-2-amine (7a, 20 mg, 50 μmol) and fluoroacetyl chloride (14 mg, 150 μmol). Yield 15 mg (65%).