Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:9]3[CH:10]=[C:11]([I:15])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl.O>CN(C=O)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:16]3[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])[C:9]3[CH:10]=[C:11]([I:15])[CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1cccc(F)c1-c1nc2c(Br)n[nH]c2c2ccc(I)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3cc(I)ccc3c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 150 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 1.2 g of 3-bromo-5-(2,6-difluorophenyl)-7-iodo-1H-pyrazolo[4,3-c]isoquinoline, prepared in step 1 of example 6, in 24 ml of DMF, 3 ml of diisopropylethylamine and 0.92 ml of 2-(trimethylsilyl)ethoxymethyl chloride. The mixture is stirred at RT for 24 h and then poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. This gives 1.52 g of crude product, which is purified by chromatography on silica gel (20-45 μm), eluting with a DCM/methanol mixture (99.5/0.5 by vol.), to give on one hand 832 mg of 3-bromo-5-(2,6-difluorophenyl)-1-(2-trimethylsilanyl ethoxymethyl)-7-iodo-1H-pyrazolo[4,3-c]isoquinoline in the form of a white solid. MS (E/I): m/z=616 (M+), and on the other hand 526 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanyl-ethoxymethyl)-7-iodo-2H-pyrazolo[4,3-c]isoquinoline (ochre oil), which is used as it is in the following step. MS (E/I): m/z=616 (M+).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH3:5].[C:7]([CH2:9][C:10]([NH2:12])=[S:11])#[N:8].C(N(CC)CC)C>CCO>[CH2:4]([C:3]1[N:12]=[C:10]([CH2:9][C:7]#[N:8])[S:11][CH:2]=1)[CH3:5]
Reactant: N#CCC(N)=S
Reactant: CCC(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1csc(CC#N)n1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
To a solution of 1-bromo-2-butanone (10.3 g, 57.98 mmol) in EtOH (200 mL) were added 2-cyanothioacetamide (5.8 g, 57.98 mmol) and triethylamine (1.59 mL, 11.6 mmol) and the solution was stirred under reflux for 1 h. After cooling down to r.t., the solvent was removed. The orange solid obtained was washed with AcOEt then cyclohexane, and recrystallized from EtOH to afford 7.2 g of the title compound as orange needles (Y=81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:7]([CH2:19][O:20][CH3:21])=[CH:6]2.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[H-].[Na+].[I-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:14][CH:13]=1)[C:7]([CH2:19][O:20][CH3:21])=[CH:6]2
Reactant: COCc1cc2cc(OC)ccc2n1-c1ccc(O)cc1
Reactant: ClCCCN1CCCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc2cc(OC)ccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Yield: 40 %

Procedure:
4-(5-Methoxy-2-methoxymethylindol-1-yl)phenol (0.43 mmol) was dissolved in N,N-dimethylformamide under N2. 1-(3-Chloropropyl)pyrrolidine (74 mg, 0.5 mmol), sodium hydride (20 mg, 60% wt dispersion in mineral oil, 0.5 mmol) and sodium iodide (75 mg, 0.5 mmol) were added, and the mixture was heated at 70° C. for 2 hours. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. Purification by semi-prep LC-MS gave the desired product, 67.4 mg (40% yield, 2 steps). LC-MS (C24H30N2O3 calc'd 394) m/z 395 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.34-7.29 (m, 2H), 7.09 (d, J=2.4 Hz, 1H), 7.04-6.98 (m, 3H), 6.82 (d, J=2.4 Hz, 1H), 6.58 (s, 1H), 4.37 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 2H), 3.86 (s, 3H), 3.28 (s, 3H), 2.69-2.64 (m, 2H), 2.58-2.54 (m, 4H), 2.11-2.01 (m, 2H), 1.83-1.79 (m, 4H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:23])[CH:10]([NH:22][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([CH3:24])=[CH:26][CH:27]=2)=[O:36])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(=O)c2ccc(F)cc2)c2ccccc12
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (600 mg, 1.73 mmol) and 4-methyl-1-naphthalenecarboxylic acid (354 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg, 2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixture was stirred overnight. To the reaction solution were added 1N aqueous hydrochloric acid solution (10 ml) and water (100 ml), and the mixture was extracted with ethyl acetate (50 ml×2): The extract was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 and recrystallized from ethyl acetate-hexane to give N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-methyl-1-naphthalenecarboxamide (665 mg, 80%).
Reaction SMILES: C(N(CC)[C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH3:18])C.[OH-:33].[K+]>O.C(O)C>[OH:29][C@H:21]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[CH2:20][NH:19][C@H:17]([CH3:18])[CH2:16][C:12]1[C:11]2[C:15](=[C:7]([O:6][CH2:5][C:4]([OH:33])=[O:30])[CH:8]=[CH:9][CH:10]=2)[NH:14][CH:13]=1
Reactant: [OH-]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3ccc(O)cc3)c[nH]c12
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC[C@H](O)c1ccc(O)cc1
Yield: 67.4 %

Procedure:
A solution of N,N-diethyl-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxyphenyl)ethylamino]propyl}-1H-indol-7-yloxy) acetamide (12 mg, 0.027 mmol) and potassium hydroxide (60 mg, 1.1 mmol) in water (0.5 mL) and ethanol (0.5 mL) is stirred at 60° C. for 6 hours. After cooling, the mixture is concentrated and acidified by addition of water (30 mL) and acetic acid. The resultant is purified by reversed phase column chromatography (COSMOSIL 75C18-OPN (Nacalai Tesque) (octadecyl-silica gel, particle diameter: 75 μm, hereinafter, the same), water→water/methanol=10/ 1) to give the desired (3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxyphenyl)ethylamino]propyl}-1H-indol-7-yloxy)acetic acid (7 mg, yield: 68%).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH:10]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(OCC1CCCCC1)c1ccc(Br)o1
Reaction time: 8 h

Procedure:
A mixture of 5-bromofuran-2-carboxylic acid (2.64 g, 13.8 mmol), (cyclohexylmethyl)bromide (2.62 g, 14.8 mmol), K2CO3 (2.30 g, 16.64 mmol) in anhydrous NMP was stirred under Ar at +70° C. for 8 hrs after which additional (cyclohexylmethyl)bromide (1.55 g, 8.75 mmol) was added. Stirring continued overnight then the reaction mixture was concentrated under reduced pressure. The residue was partitioned between aqueous NaHCO3 (10%) and hexanes, and then aqueous layer was extracted with hexanes. Combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure to give cyclohexylmethyl 5-bromofuran-2-carboxylate as a light yellow oil. Yield (2.22 g, 56%); 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J=3.9 Hz, 1H), 6.44 (d, J=3.4 Hz, 1H), 4.10 (d, J=6.4 Hz, 2H), 1.64-1.84 (m, 6H), 1.12-1.34 (m, 3H), 0.95-1.09 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([CH3:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[O:9])=[C:6]([C:22]([F:25])([F:24])[F:23])[N:5]=[CH:4][CH:3]=1.[CH2:26]([O:33][C:34]1[C:35]([CH:40]=O)=[N:36][CH:37]=[CH:38][CH:39]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:26]([O:33][C:34]1[C:35]([CH:40]2[NH:1][C:2]3[CH:3]=[CH:4][N:5]=[C:6]([C:22]([F:25])([F:24])[F:23])[C:7]=3[C:8](=[O:9])[N:10]2[CH:11]([CH3:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[N:36][CH:37]=[CH:38][CH:39]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1ncccc1OCc1ccccc1
Reactant: CC(Cc1ccc(F)c(F)c1)NC(=O)c1c(N)ccnc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(Cc1ccc(F)c(F)c1)N1C(=O)c2c(ccnc2C(F)(F)F)NC1c1ncccc1OCc1ccccc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
4-amino-N-(1-(3,4-difluorophenyl)propan-2-yl)-2-(trifluoromethyl)nicotinamide (3.61 g, 10.05 mmol) and 3-(benzyloxy)picolinaldehyde (2.57 g, 12.1 mmol) were combined along with a catalytic amount of 4-toluenesulfonic acid (0.03 g, 0.20 mmol) in anhydrous toluene (150 mL). This was heated at reflux overnight in a round bottom flask fitted with a Dean-Stark trap. The resultant dark solution was cooled to room temperature, concentrated in vacuo to a dark brown oil. This oil was purified by silica gel column chromatography using 30% acetone/hexanes as eluant to provide the product diastereomers as an oil (4.61 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 8.2 (m, 1H), 8.0 (m, 1H), 7.3-7.6 (m, 7H), 5.15 (d, 2H), 3.0 (dd, 1H), 2.8 (m, 1H), 1.25 (d, 3H). MS m/z 555.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.Cl>COCCOC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:26]([C:21]2[C:20]([C:17]3[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][CH:18]=3)=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:28])=[O:27])=[N:5][CH:6]=1
Reactant: COc1nc(Br)cnc1N
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
Sodium hydride (oil free; 0.053 g) was added to a solution of 2-amino-5-bromo-3-methoxypyrazine (0.151 g) in DME (5 ml). The solution was stirred for 10 minutes and then a solution of 4'-methyl-2-biphenylsulphonyl chloride (0.198 g) in DME (2 ml) was added. The solution was allowed to stand for 1 hour and then water (25 ml) was added. 2M Hydrochloric acid (2 ml) was added and the mixture was extracted eith ethyl acetate (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was recrystallised from ethyl acetate to give N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.12 g) m.p. 204°-206° C.; 1H NMR (d6 -DMSO): 2.4 (s,3H), 3.85(s,3H), 7.05-7.2(m,4H), 7.3(dd,1H), 7.55-7.7(m,2H), 7.8(s,1H), 8.1(dd,1H); mass spectrum (+ve FAB, methanol/NBA): 436 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Zn]CC)C.CC1(C)[C@@H]2CC[C@@]1(CSSCC13C(C)(C)C(CC1)CC3N1CCOCC1)[C@H](N1CCOCC1)C2.[C:49]1([CH3:57])[CH:54]=[CH:53][C:52]([CH:55]=[O:56])=[CH:51][CH:50]=1>[Zn].C1(C)C=CC=CC=1>[C:1]1([C@H:55]([C:52]2[CH:53]=[CH:54][C:49]([CH3:57])=[CH:50][CH:51]=2)[OH:56])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: CC1(C)C2CCC1(CSSC[C@]13CC[C@H](C[C@H]1N1CCOCC1)C3(C)C)C(N1CCOCC1)C2
Agent: CC[Zn]CC
Agent: [Zn]
Solvent: Cc1ccccc1
Product: Cc1ccc([C@H](O)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a toluene (4.0 mL) solution of phenylboronic acid (0.24 g, 2 mmol) was added diethylzinc (6.0 mL, 6 mmol 1.0 M in hexanes). The mixture was heated at 60° C. overnight and was then cooled to ambient temperature. The mixed zinc solution was transferred to another flask containing (1S,2R,4R)-1,2-bis((7,7-dimethyl-2-morpholinobicyclo[2.2.1]heptan-1-yl)methyl)disulfane (IIIa) (51 mg, 0.1 mmol) via syringe. After 10 minutes at ambient temperature, the mixture was cooled to 0° C. and neat p-tolualdehyde (108 μL, 1 mmol) was added dropwise. The reaction was stirred at 0° C. for 24 hours and was quenched by slow addition of sat. aq. NH4Cl (3 mL) and subsequent dilution with DCM (25 mL) and 1 N aq. HCl (30 mL). After layer separation, the aqueous solution was washed twice with DCM (20 mL). The DCM layers were combined, dried over Na2SO4, and concentrated to give a yellow oil which was purified by silica gel column chromatography (1:6 ethyl acetate:n-heptane) to give (R)-phenyl-p-tolyl-methanol as a white solid (0.147 g; 74% yield; 95.9% e.e.). The optical purity was determined by normal phase HPLC using a Chiralcel OD-H chiral column (eluted with isocratic 10:90 IPA/hexane, with 0.5 mL/minute flow rate; monitoring at 254 nm).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C:10]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:35]=[N:36][N:37]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:38]=3)=[CH:24][CH:23]=2)[C:17]2[CH2:16][NH:15][CH2:14][CH2:13][C:12]=2[N:11]=1)[CH3:9].C(N(CC)CC)C>ClCCl>[C:1]([N:15]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([CH2:8][CH3:9])[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[N:35]=[N:36][N:37]([C:39]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[N:38]=4)=[CH:26][CH:27]=3)[C:17]=2[CH2:16]1)(=[O:3])[CH3:2]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCNC2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCN(C(C)=O)C2
Reaction time: 20 h
Yield: 65.8 %

Procedure:
Acetic anhydride (78 mg) was added to a stirred solution of 2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl)methoxy]-1,6-naphthyridine (500 mg) and triethylamine (150 mg) in dichloromethane (10 ml) under an atmosphere of argon. The solution was left to stand for 20 hours and then volatile material was removed by evaporation. The residue was purified by flash chromatography, eluting with a mixture of methanol/ethyl acetate (1:9 v/v), to give 6-acetyl-2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,6-naphthyridine (350 mg), m.p. 97°-98° C.; NMR (d6 -DMSO, d4 -acetic acid): 1.25(t,3H), 2.15(s,3H), 2.75(q,2H), 2.9-3.0(m,3H), 3.7(m,2H), 4.5(d,2H), 5.2(s,2H), 6.8-7.7 (complex m,23H), 7.75-7.85(m,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.[N+](C1C=CC([O:37][C:38](=O)[O:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=2)=CC=1)([O-])=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][N:16]([C:38]([O:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=3)=[O:37])[CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: COc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: Cn1c(C(=O)Nc2ccccc2N)cc2c1CNCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)N2CCc3cc(C(=O)Nc4ccccc4N)n(C)c3C2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1.0 eq) obtained in step IX of example 228, in DMF was added Et3N (3.0 eq.) followed by carbonic acid 3,4-dimethoxy-phenyl ester 4-nitro-phenyl ester (1.0 eq) and stirred at room temperature overnight. Reaction mixture was then quenched with water and extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 71.6 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (281 mg, 1.1 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (170 mg, 1.1 mmol) and DIPEA (1 mL, 5.5 mmol) in IPA (2 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-20% DCM in EtOAc) to afford 275 as a white solid (295 mg, 72%). LCMS (Method K): RT 3.37 min [M+H]+ 375.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.60 (1H, ddd, J=4.88, 1.91, 0.81 Hz), 8.06 (1H, td, J=7.75, 1.94 Hz), 7.86 (1H, s), 7.78-7.68 (3H, m), 7.50 (1H, ddd, J=7.52, 4.87, 0.98 Hz), 7.21-7.11 (4H, m), 5.87-5.78 (1H, m), 1.53 (3H, d, J=6.83 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39](O)=[O:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39]([C:31]4[S:30][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=5[N:32]=4)=[O:40])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc2ccccc2s1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nc3ccccc3s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and benzo[d]thiazole-2-carboxylic acid (27 mg, 0.15 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][C:25]([CH2:30][CH2:31][NH:32][CH3:33])=[CH:24][C:23]=1[Br:34]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:32]([CH3:33])[CH2:31][CH2:30][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[C:22]([NH2:21])=[C:23]([Br:34])[CH:24]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCc1cc(Br)c(N)c(C#N)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Br)c(N)c(C#N)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloro-propane and 2-(4-amino-3-bromo-5-cyano-phenyl)-N-methyl-ethylamine.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2.CO>CC(N(C)C)=O>[CH3:3][NH:4][CH2:5][CH2:6][O:7][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2
Reactant: O=c1[nH]cnc2cccc(F)c12
Reactant: CNCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CNCCOc1cccc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 732 mg, 18.3 mmol) was suspended in DMA (50 ml) and N-methylethanolamine (734 μl, 9.15 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature, and 5-fluoroquinazolin-4(3H)-one (1.0 g, 6.10 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 85° C. for 90 minutes. The mixture was cooled to ambient temperature, and the resulting slurry poured into methanol (100 ml). Dowex resin (50WX4-400, 25 g) was added, and the mixture stirred for 1 hour at ambient temperature. The resin was collected by filtration, and washed with methanol (100 ml). The resin was suspended in a solution of ammonia in methanol (2.3 N, 150 ml), and the mixture stirred for 30 minutes. The mixture was filtered and the residue washed with ammonia in methanol (2.3 N, 100 ml). The combined filtrates were concentrated in vacuo, and dried in vacuo (1 mbar, 60° C.) for 16 hours to give 5-[2-(methylamino)ethoxy]quinazolin-4(3H)-one as an off white solid (1.09 g, 82%); NMR Spectrum (DMSO-d6, 400) 2.36 (s, 3H), 2.85 (t, 2H), 5.11 (t, 2H), 6.97 (d, 1H), 7.14 (d, 1H), 7.61 (dd, 1H), 7.97 (s, 1H); Mass spectrum MH+ 220.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[C:25]2[N:29]=[CH:28][NH:27][N:26]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:27]1[CH:28]=[N:29][C:25]([C@@H:20]2[CH2:21][CH2:22][CH2:23][CH2:24][N:19]2[S:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)(=[O:17])=[O:18])=[N:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCCC[C@H]1c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC[C@H]1c1ncn(Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
Benzyl bromide (40 μl) was added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(1H-1,2,4-triazol-3-yl)piperidine (95 mg) [see Preparation 42] and potassium carbonate (47 mg) in dimethylformamide (5 ml). The reaction mixture was stirred at 50° C. for 7 hours, after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate. The organic solution was washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 100:0 changing to 50:50, by volume, hexane:ethyl acetate (in 10% increments), to afford (2S)-2-(1-benzyl-1H-1,2,4-triazol-3-yl)-1-[(4-fluorophenyl)sulfonyl]piperidine (35 mg) as a white solid.