Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].Cl.[N:13]1([CH2:19][CH:20]([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:21][C:22]#[N:23])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.FC(F)(F)C(O)=O.C(N)CN>C(#N)C.CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([N:16]1[CH2:15][CH2:14][N:13]([CH2:19][CH:20]([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:21][C:22]#[N:23])[CH2:18][CH2:17]1)=[O:6]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Agent: Cl
Solvent: CO
Solvent: NCCN
Solvent: ClCCl
Product: N#CCC(CN1CCN(C(=O)c2cc(F)cc(F)c2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,5-Difluorobenzoyl chloride (8.44 mg, 0.0478 mmol), 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (from example 1, step 4; 0.02 g, 0.0398 mmol) and triethylamine (16.6 μL, 0.119 mmol) were mixed in acetonitrile (0.2 mL). The mixture was stirred at RT for 1 h. Solvents were evaporated. The crude product was treated with DCM (0.2 mL) and trifluoroacetic acid (0.2 mL, 0.002 mol) for 30 min. The reaction mixture was evaporated under reduced pressure. To the resultant residue was added methanol (1 mL) and ethylenediamine (0.1 mL, 0.001 mol). The reaction mixture was stirred at RT for 30 min and concentrated under reduced pressure. The residue was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 30 mL/min) to give the desired product. LCMS calculated for C24H23F2N8O(M+H)+: m/z=477.2; Found: 477.0.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=1)[CH2:10][NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS([C:30]1[S:34][C:33]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH:41]=[N:40][CH:39]=[CH:38]3)=[N:32][N:31]=1)(=O)=O.CS(C1SC(C2C=C3C(=CC=2)C=NC=C3)=NN=1)=O>CC(N(C)C)=O>[Si:1]([O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH:13]=1)[CH2:10][NH:11][C:30]1[S:34][C:33]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH:41]=[N:40][CH:39]=[CH:38]3)=[N:32][N:31]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(CN)O[Si](C)(C)C(C)(C)C)c1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3cnccc3c2)s1
Agent: CS(=O)c1nnc(-c2ccc3cnccc3c2)s1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(CNc2nnc(-c3ccc4cnccc4c3)s2)O[Si](C)(C)C(C)(C)C)c1

Procedure:
(±)-2-(tert-Butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)phenyl)ethanamine and 6-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)isoquinoline and 6-(5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl)isoquinoline (prepared as in Scheme 7) was heated at 80-100° C. for 3 hours in DMA (0.3 M) to provide (±)-N-(2-(tert-butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)phenyl)ethyl)-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amine. This intermediate was dissolved in THF and TBAF (1M in THF, 1.24 mmol) was added. After 16 hours, the mixture was concentrated in vacuo and the residue purified by flash chromatography on silica (eluting with DCM/MeOH gradients) to provide (±)-3-(1-hydroxy-2-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-ylamino)ethyl)phenol (20 mg, 8%). LCMS (M+H) 365 calc. for C19H17N4O2S 365.1. 1H NMR (300 MHz, DMSO-d6): δ ppm 9.33 (s, 1H+OH), 8.56 (d, J=5.8 Hz, 1H), 8.27 (m, 2H), 8.18 (m, 2H), 7.92 (d, J=5.8 Hz, 1H), 7.14 (t, J=7.6, 1H), 6.84 (m, 2H), 6.65 (m, 1H), 5.58 (d, J=4.0 Hz, OH), 4.80 (m, 1H), 3.60 (m, 1H). 1H missing, covered by water signal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][Si:12]([CH2:15][CH2:16][O:17][CH2:18]Cl)([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.00 g, 5.08 mmol), SEMCl (0.898 mL, 5.08 mmol) and DIPEA (1.768 mL, 10.15 mmol) in DCM (20.0 mL) was stirred at RT. After 3 nights the mixture was evaporated to dryness. The residues were purified on silica eluting with isohexane and ethyl acetate (0-100%). The appropriate fractions were combined and evaporated to dryness producing the title compound (1.65 g). LCMS (A): m/z (M+H)+ 327/329, C13H19BrN2OSi requires 326/328 (basic).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2[CH:15]=[C:16]([O:21][CH2:22]C3C=CC=CC=3)[C:17]([O:19]C)=[CH:18][C:10]=2[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:33]CC1>CO.[Pd]>[CH2:1]([N:8]1[C:14](=[O:33])[CH2:13][CH2:12][CH2:11][C:10]2[CH:18]=[C:17]([OH:19])[C:16]([O:21][CH3:22])=[CH:15][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCCN(Cc1ccccc1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1O)CCCC(=O)N2Cc1ccccc1

Procedure:
A solution of 2-benzyl-7-(benzyloxy)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (1 mmol) in THF (20 mL) and methanol (20 mL) was treated with 10% Pd/C (40 mg) and stirred under an atmosphere of hydrogen. The reaction was monitored by TLC. Upon completion, the resultant suspension was filtered through celite, washed with ethyl acetate and then evaporated under reduced pressure. The resulting solid was stirred in diethyl ether, filtered and dried under vacuum or purified by flash chromatography (hexane/ethyl acetate) then stirred in diethyl ether, filtered and dried under vacuum.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[N:3]=1.C(O)C.O.[NH2:26][NH2:27]>O>[NH:26]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[N:3]=1)[NH2:27]
Reactant: NN
Reactant: Fc1cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n1
Solvent: CCO
Solvent: O
Product: NNc1cccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)n1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Next, a reaction flask was loaded with 2-fluoro-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)pyridine (10 g) and ethanol (8 ml), followed by dropwise addition of a mixture of hydrazine monohydrate (7.7 g) and ethanol (8 ml) to the flask in 30 minutes with stirring. After the dropwise addition was ended, stirring was continued at 55 to 65° C. for one hour. The heating was stopped, and water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was condensed to give 2-hydrazino-6-(2,2,3,3,4,4,5,5-octafluoropentyloxy)pyridine (10 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCC3CCCCC3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: BrCCC1CCCCC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(CCC3CCCCC3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(CCC3CCCCC3)c3c2CCNCC3)cc1

Procedure:
The title compound (0.056 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 1-bromo-2-cyclohexylethane (0.053 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-cyclohexyl-ethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H28ClN3, 357.20. found, m/z 358.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.46-7.34 (m, 4H), 4.08 (t, J=7.6 Hz, 2H), 3.37-3.35 (m, 2H), 3.27-3.25 (m, 2H), 3.13-3.11 (m, 2H), 2.94-2.92 (m, 2H), 1.68-1.20 (m, 7H), 1.18-1.05 (m, 4H), 0.93-0.86 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:19]([Mg]Br)[CH2:20][CH3:21]>C1COCC1>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12]([CH:15]([OH:16])[CH2:19][CH2:20][CH3:21])=[CH:13][N:14]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a −78° C. solution of 2-(4-(trifluoromethyl)phenyl)pyrimidine-5-carbaldehyde (1.0 g, 3.96 mmol) in THF (20 mL) was added n-propylmagnesium bromide (2.97 mL of a 2.0M solution in THF, 5.95 mmol). The solution was stirred at 0° C. for two hours. The mixture was quenched with saturated aqueous NH4Cl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give (+/−)-1-(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)butan-1-ol (1.1 g) as a red oil. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 2H), 8.50 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 4.79-4.68 (m, 1H), 1.98-1.91 (m, 1H), 1.85-1.63 (m, 2H), 1.47-1.29 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[S:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:16][CH2:17][CH2:18]Br.Cl.[OH-].[Na+]>C(O)C.CN(C=O)C>[S:12]1[C:10]2[N:11]([C:7]3[C:8]([N:9]=2)=[CH:13][CH:14]=[C:5]([CH2:3][OH:4])[CH:6]=3)[CH2:18][CH2:17][CH2:16]1
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc2[nH]c(=S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: OCc1ccc2nc3n(c2c1)CCCS3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
To a round bottomed flask was added 4.06 grams of 2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester, 4.04 grams of 1,3-dibromopropane and 50 ml DMF and 50 ml ethanol. The mixture was refluxed for 10 hours. Then it was concentrated to dry on a rotary evaporator. The solid was next dissolved in 100 ml THF and 20 ml of 1M LiAlH4 (in THF) was next injected within five minutes. The reaction media was stirred at room temperature for one hour. Ethanol was next added (˜10 ml), followed by 50 ml 2N HCl. The aqueous layer was adjusted to basic Ph=14 with 10N sodium hydroxide. The aqueous was extracted with 2×500 ml ethyl acetate. The combined organic layers was dried over magnesium sulfate. Filter off the drying agent and cocentrate yielded 3 grams (68%) product. NMR(DMSO): δ 7.91 (m, 3H), 4.13 (m, 2H), 3.93 (s, 1H), 3.23 (m, 2H, CH2), 2.48 (m, 2H, CH2). MS: 221.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:15][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: O=CCCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCNCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the crude 3-(4-fluorophenyl)propanal and propylamine (3.0 g, 51 mmol) in CH2Cl2 and was treated with NaBH(OAc)3 and stirred at room temperature overnight. The reaction was quenched with 1 N NaOH, and washed successively with water and brine. The solvent was evaporated under vacuum to give 4.3 g of 3-(4-fluorophenyl)-N-propylpropan-1-amine.
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.Cl.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[C:34]([CH2:35][NH2:36])=[CH:33][C:32]([C:37]([F:40])([F:39])[F:38])=[N:31]2)[CH:27]=[CH:28][CH:29]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[C:34]([CH2:35][NH:36][C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([C:2]4([OH:1])[CH2:3][O:4][CH2:5]4)=[CH:11][CH:10]=3)=[O:21])=[CH:33][C:32]([C:37]([F:38])([F:39])[F:40])=[N:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(C2(O)COC2)cc1)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C2(O)COC2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred solution of phenyl 4-(3-hydroxyoxetan-3-yl)phenylcarbamate (100 mg, 0.35 mmol, 1.0 eq) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (119.3 mg, 0.35 mmol, 1.0 eq) in DCM (10 mL) was added TEA (106 mg, 1.049 mmol, 3.0 eq) at RT and stirred at 40° C. overnight. The mixture was diluted with DCM (30 mL) and washed with water (10 mL), brine (10 mL) and dried over anhydrous Na2SO4 and concentrated. Crude product was purified by CC using MeOH/CHCl3 (1:9) to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(3-hydroxyoxetan-3-yl)phenyl)urea (100 mg; 61%) as a white solid (TLC system: MeOH/CHCl3 (1:9); Rf: 0.45).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1cccc(-c2cccn3nc(N)nc23)c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5cccc(S(C)(=O)=O)c5)cccn4n3)c2)CC1

Procedure:
[8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow foam (0.050 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.59 (s, 1H), 8.49-8.43 (m, 2H), 8.00 (d, J=7.5 Hz, 1H), 7.75-7.65 (m, 2H), 7.30-7.20 (m, 2H), 7.06 (d, J=7.7 Hz, 1H), 7.00 (t, J=6.6 Hz, 1H), 6.85 (s, 1H), 6.60 (d, J=8.0 Hz, 1H), 3.30-3.25 (m, 4H), 3.13 (s, 3H), 2.62-2.57 (m, 4H), 2.37 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([C:30]1[N:35]=[CH:34][C:33](Br)=[CH:32][N:31]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].CS(C)=[O:48]>>[F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:30]1[N:35]=[CH:34][C:33]([OH:48])=[CH:32][N:31]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CS(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (1.06 g) is dissolved in dimethylsulfoxide (5 ml), and the mixture is degassed and thereto are added [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (61 mg), potassium acetate (442 mg) and bis(pinacolato)diboron (571 mg). The mixture is degassed and heated to 80° C. under nitrogen flow and stirred for 45 minutes. The reaction solution is allowed to cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (5 ml), and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (1.5 ml) under ice-cooling and stirred at the same temperature for 1 hour and a half. To the reaction mixture is added dropwise saturated aqueous sodium thiosulfate solution under ice-cooling, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:1) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ol (866 mg). MS (m/z): 644 [M+H]+
Reaction SMILES: FC(F)(F)C([O-])=O.[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:28]1[NH:29][C:30]([I:33])=[CH:31][NH+:32]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[I:33][C:30]1[NH:29][C:28]([C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:37][CH3:36])=[O:27])=[N:32][CH:31]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1[nH]c(I)c[nH+]1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(I)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of D5 in DMF (0.3 M) was added methylamine (2.0 M solution in THF, 5.0 eq.) followed by HBTU (2.0 eq.). Solution pH was adjusted to basic value by addition of methylamine (2.0 M solution in THF, 2.5 eq.). Reaction mixture was stirred at room temperature for 1 h, then two more addition of HBTU (4.47 g, 28.5 mmol, 1.0 eq.) and methylamine (2.0 M solution in THF, 2.5 eq.) every 30 min were performed to reach completion of reaction. Solvent was concentrated under reduced pressure and the resulting residue was diluted with EtOAc, washed with sat. aq. NaHCO3, Brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (eluent: petroleum ether/EtOAc from 4:1 to EtOAc) to give the title compound as a white solid. 1H-NMR (400 MHz, 300K, CDCl3) δ 12.11 (br s, 1H), 7.69-7.59 (m, 2H), 7.41-7.27 (m, 4H), 7.19 (s, 1H), 5.06 (d, 1H, J 12.8 Hz), 5.00 (d, 1H, J 12.8 Hz), 4.57 (m, 1H), 2.54 (d, 3H, J 4.8 Hz), 2.01 (t, 2H, J 7.4 Hz), 1.85-1.60 (m, 2H), 1.50-1.38 (m, 2H), 1.32-1.12 (m, 4H). MS (ES+) C19H25IN4O3: 485 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19](I)[C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([Cu])#[N:33].O>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([C:32]#[N:33])[C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1I)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CC2
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1C#N)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CC2
Temperature: 190 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-iodo-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (53c, 300 mg, 0.568 mmol) in NMP (8 mL, dry) was added CuCN (152 mg, 1.705 mmol) at room temperature. The resulting mixture was stirred at 190° C. for 3 hours. The mixture was cooled to room temperature and H2O (20 mL) was added to the mixture. The mixture was diluted with EtOAc (5×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over Na2SO4, and concentrated under vacuum to give a residue, which was purified by column chromatography (petroleum ether/EtOAc, 3:1) to obtain 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile (53d, ˜0.568 mmol, 100%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[CH2:27]([C:31]1[CH:32]=[CH:33][C:34](CCl)=[N:35][CH:36]=1)[CH2:28][CH2:29][CH3:30]>>[ClH:19].[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([CH2:21][S:20][C:15]2[C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[N:35][CH:36]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CCCCc1ccc(CCl)nc1
Agent: Cl
Product: CCCCc1ccc(CSc2c(Cl)ccc3c2CCNCC3)nc1

Procedure:
Use a method similar to the Example 315, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 5-butyl-2-chloromethylpyridine hydrochloride to give the title compound as a white solid. MS (APCI+) m/z: 330 (M+H)+.
Reaction SMILES: [CH3:1][C:2]12[C:11]([CH3:13])([CH3:12])[CH:8]([CH2:9][CH2:10]1)[C:4]1([CH2:7][CH2:6][CH2:5]1)[CH:3]2[NH:14][CH:15]=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:15][NH:14][C@@H:3]1[C:4]2([CH2:5][CH2:6][CH2:7]2)[C@@H:8]2[C:11]([CH3:13])([CH3:12])[C@@:2]1([CH3:1])[CH2:10][CH2:9]2
Reactant: CC1(C)C2CCC1(C)C(NC=O)C21CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@@H]1C2(CCC2)[C@H]2CC[C@]1(C)C2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
To a solution of N-(4,7,7-trimethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-yl)formamide (1.50 g, 6.78 mmol) in THF (40 mL) at 0° C. was slowly added lithium aluminum hydride (27.1 mmol, 27.1 mL of 1.0 M solution in THF). After complete addition, the reaction was refluxed for 48 h. The reaction mixture was cooled to 0° C. and quenched by addition, in portions, of solid sodium sulfate decahydrate (10 g). After stirring for 1 h, this mixture was filtered, and the filtrate was concentrated. The residue was purified on a 40 g silica gel column, using 0-100% CMA (chloroform:methanol:30% aqueous ammonia; 9:1:0.1) in chloroform as the eluent, to obtain an exo amine product, (1S,3R,4R)—N,4,7,7-tetramethylspiro[bicyclo[2.2.1]heptane-2.1′-cyclobutan]-3-amine (0.49 g; 35% yield), and an endo-amine product, (1S,3S,4R)—N,4,7,7-tetramethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-amine (0.30 g; 21% yield), both as oils. The two products were converted to their hydrochloride salts by dissolving each in 1 mL of concentrated hydrochloric acid and concentrating and vacuum drying the samples. 1H NMR of exo-(1S,3R,4R)—N,4,7,7-tetramethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-amine hydrochloride (D2O 400 MHz): δ 2.80 (s, 3H), 2.72 (brs, 1H), 2.22-1.91 (m, 4H), 1.84-1.72 (m, 3H), 1.54-1.45 (m, 2H), 1.38-1.31 (m, 1H), 1.10-1.01 (m, 1H), 0.87 (s, 3H), 075 (s, 3H), 0.72 (s. 3H); LCMS (m/z): 208 (M+1). 1H NMR of endo-(1S,3S,4R)—N4,7,7-tetramethylspiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-amine hydrochloride (D2O, 400 MHz); δ 3.12 (brs, 1H), 2.79 (s, 3H), 2.26-2.16 (m, 1H), 2.01-1.85 (m, 3H), 1.78-1.69 (m, 3H), 1.60-1.51 (m, 1H), 1.36-1.24 (m, 2H), 1.08-1.00 (m, 1H), 0.85 (s, 3H), 0.78 (s, 3H) 0.75 (s, 3H); LCMS (m/z): 208 (M+1).