Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:31])([CH2:27][CH2:28][C:29]#[N:30])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:31])([CH2:27][CH2:28][C:29]4[NH:36][N:35]=[N:34][N:30]=4)[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(CCC#N)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CCc1nnn[nH]1)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 110 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (83 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1 mL) containing ammonium chloride (128 mg, 2.41 mmol), sodium azide (156 mg, 2.40 mmol), and a magnetic stir bar. The reaction mixture was heated at 110° C. for 40 minutes in a microwave reactor. The crude product was filtered and then purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(2-methyl-4-(1H-tetrazol-5-yl)butan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 458.2. found 459.2 (M+1)+. Retention time of 1.53 minutes. 1H NMR (400 MHz, CD3CN) 9.23 (s, 1H), 7.51-7.48 (m, 2H), 7.19 (d, J=8.6 Hz, 1H), 7.06-7.03 (m, 2H), 6.95-6.89 (m, 2H), 6.17 (dd, J=0.7, 2.2 Hz, 1H), 6.02 (s, 2H), 2.61-2.57 (m, 2H), 2.07-2.03 (m, 2H), 1.55-1.51 (m, 2H), 1.39 (s, 6H), 1.12-1.09 (m, 2H).
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.[C:21]([O-:24])(=[O:23])C.[K+].CN(C)C=O>O>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([CH:3]([CH3:2])[C:21]([OH:24])=[O:23])[CH:13]=[CH:12]2
Reactant: CC(=O)[O-]
Reactant: COc1ccc2cc(C(OC)(OC)C(C)Br)ccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Reaction time: 48 h
Yield: 97 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propane (3.39 g; 10 mmol), potassium acetate (1.2 g; 12 mmol), N,N-dimethylformamide (14 ml) and of water (8 ml) is heated at 100° C. under stirring for 48 h. The reaction mixture is worked up as described in example 1a to provide 2-(6-methoxy-2-naphthyl)-propionic acid (2.23 g; 9.7 mmol; yield 97%), m.p. 155°-157° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CN(C=O)C.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and p-anisidine (0.42 gm, 0.003 mole) was taken in dry DMF (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(4-methoxyphenyl)-[3-(naphthalen-2-yloxy) propyl]amine as yellow solid, m.p. 110° C., (yield 0.64 gm, 92.5%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>ClCCl>[C:34]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1)(=[O:37])[CH:35]=[CH2:36]
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(\C)c1cc(C)oc1C
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3cc(C)oc3C)C2=O)cc1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution obtained by dissolving 211 mg of N-(4-hydroxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 5 in 5 ml of dichloromethane, 72 mg of triethylamine was added, followed by dropwise addition of 66 mg of acryloyl chloride in 10 minutes. The reaction was carried out at room temperature for 30 minutes with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, and subjected to removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give pale red crystals of N-(4-acryloyloxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethylidene]-3-isopropylidenesuccinimide in yield of 44.0%.
Reaction SMILES: C1(C)C=CC(S(OCC[C@:13]2([OH:27])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18](F)[CH:19]=3)[C@H:14]2C(C)C)(=O)=O)=CC=1.C(N(C(C)C)C(C)C)C>CS(C)=O>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[OH:27]
Reactant: Cc1ccc(S(=O)(=O)OCC[C@]2(O)CCc3cc(F)ccc3[C@H]2C(C)C)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc2ccccc2c1

Procedure:
A solution of 12.6 g (0.031 mol) of [1R,2R]-(-)-2-[6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl]ethyl p-toluenesulphonate, 6.1 g (0.031 mol) of 3,4-(methylenedioxy)-N-methyl-β-phenethylamine and 5.3 ml (0.031 mol) of ethyldiisopropylamine in 50 ml of dimethyl sulfoxide was stirred under a nitrogen atmosphere for 3 hours at 80° and thereafter concentrated in a high vacuum. The residue was dissolved in methylene chloride and the solution obtained was washed with a saturated sodium carbonate solution and extracted three times with 3N hydrochloric acid. The aqueous extracts were made alkaline with a 28% sodium hydroxide solution. The oily suspension was extracted three times with methylene chloride. The organic extracts were dried and evaporated under reduced pressure. The residual oil was chromatographed on silica gel with ethyl acetate/methanol (9:1), yielding 9.3 g (73%) of [1R,2R]-(-)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-[[3,4-(methylenedioxy)phenethyl]methylamino]ethyl]-2-naphthalenol as a yellowish oil; [α]D20 =-22.1°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[S:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][CH:22]=[CH:21]2)(=[O:17])=[O:16].NC1C=C2C(=CC=1)C=NC=C2.Cl.Cl.N1(S(C2C=C3C(=CC=2)C=NC=C3)(=O)=O)CCNCC1>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)(=[O:16])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: Nc1ccc2cnccc2c1
Agent: O=S(=O)(c1ccc2cnccc2c1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cnccc3c2)CC1

Procedure:
0.5 mL of triethylamine and 0.5 g of tert-butoxycarbonylpiperazine were added with stirring at room temperature to a dichloromethane solution (100 mL) of 6-chlorosulfonylisoquinoline (Reference Compound 2) synthesized according to Reference Example 2 from 500 mg of 6-aminoisoquinoline (Reference Compound 1), and reacted for 6 hours. After the completion of reaction, the reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 150 mg of the compound of interest as a white crystal (23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:31]1([CH3:40])[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:38]([NH:37][C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)=[O:39])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)Nc2nc3nc(NCCCN4CCN(C)CC4)ncc3cc2-c2c(Cl)cccc2Cl)cc1

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 36 was reacted with 0.29 g of 4-tolyl isocyanate according to the general procedure of Example 37 to give 0.9492 g of the title compound. ESMS (20/80 MeOH/CH3CN+0.1% ACOH): M+ +H=579;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15])[CH3:2].[Br:18]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:16])[CH2:15][Br:18])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a cooled (0° C.) solution of (2-acetyl-4-bromophenoxy)acetic acid ethyl ester (2.5 g, 8.3 mmol) in CHCl3 (25 mL) was slowly added bromine (425 uL, 8.3 mmol). After completion the reaction mixture was allowed to stir at room temperature for 1 hour. The mixture was partitioned between CH2Cl2 and brine. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (2.97 g, 7.8 mmol, 94%): 1H NMR (CDCl3): δ 1.35 (t, 3H), 4.32 (q, 2H), 4.75 (s, 2H), 4.76 (s, 2H), 6.77 (d, 1H), 7.60 (dd, 1H), 7.97 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22](=[N:42]O)[C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][N:29]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[CH:25][CH:24]=1>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:16][N:21]=[C:22]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][N:29]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)=[CH:25][CH:24]=3)[N:42]=2)=[CH:10][C:9]=1[C:17]([F:20])([F:18])[F:19]
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc4c(c3)CN(CCC(=O)OC(C)(C)C)CC4)no2)cc1C(F)(F)F

Procedure:
Title compound was prepared following general procedure 3 starting from Intermediate 24 (168 mg; 0.6 mmol) and Intermediate 25 (182 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum. Purification by silica column chromatography (c-Hex/(DCM/EtOAc 1:1), 90/10 to 50/50) afforded the title compound as a yellow oil. LC/MS (method B): 565.2 (M+H)+. HPLC (Method A) Rt 5.00 min (Purity: 95.4%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9](/[CH:13]=[N:14]/[C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:23]=[C:24]([CH3:26])[CH3:25].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:23][C:24]1([CH3:26])[C:20]2[N:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[NH:14][CH:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:25]1
Reactant: C=C(C)C
Reactant: N#Cc1ccc(/N=C/c2cccc(N3CCOCC3)c2)cn1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C#N)nc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
To a stirred solution of 5-{[1-(3-morpholin-4-yl-phenyl)-meth-(E)-ylidene]amino}-pyridine-2-carbonitrile (22.9 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 90° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonitrile (3.3 g, 12.1%) as a light yellow solid: MS (ESI) M+1=349.1.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([C:23](Cl)=[O:24])[O:20][C:19]2=[O:26])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCCC1.O>[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([C:23]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:24])[O:20][C:19]2=[O:26])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C=CCN
Reactant: O=C(Cl)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
To a flame-dried flask under nitrogen is added allylamine (0.60 mL, 8.05 mmol). The flask is cooled in an ice bath, and a solution of (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarbonyl chloride (EXAMPLE 1, Step 2, 0.805 mmol theory) in anhydrous tetrahydrofuran (8.0 mL) is added. The resulting mixture is stirred under nitrogen for 2 h, allowing the cooling bath to slowly expire, and is then diluted with water (10 mL) and extracted with methylene chloride (20 mL). The organic phase is washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (0.5/99.5-2/98). Pooling and concentration of those fractions with an Rf=0.44 by TLC (methanol/chloroform, 5/95) provides the title compound, mp 167-169° C.; MS (ESI+) for C17H20FN3O4 m/z 350 (M+H)+; [α]25D=−44° (c 0.94, DMSO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:28](CO)[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[CH2:10]3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39]([O:42]S(C)(=O)=O)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:28]([O:42][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][C@H:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:24])[CH3:25])[CH2:10]3)=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(C#N)cc1C1CO[C@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)C1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(C#N)cc1[C@H]1CO[C@]2(CC[C@H](OS(C)(=O)=O)[C@@H]2c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,6S,7S)-6-(4-fluorophenyl)-3-(5-cyano-2-isopropoxy-phenyl)-1-oxaspiro[4.4]nonane-7-methanol (35 mg, 0.085 mmol) in methylene chloride (1 mL) were added triethylamine (24 μL, 0.172 mmol) and methanesulfonic anhydride (22 mg, 0.126 mmol). The reaction mixture was stirred for 2 hours at room temperature, diluted with methylene chloride, washed with water, 2N hydrochloric acid, saturated sodium hydrogencarbonate solution, saturated brine solution, dried (Na2SO4), and evaporated. The product was used without further purification in Step C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].O[C:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=2[N:17]=[N:18][N:19]=1>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=2[N:17]=[N:18][N:19]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: NCc1cccc(C(F)(F)F)c1
Product: NC(=O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)nnnc12

Procedure:
Compound 1 was prepared following general synthetic scheme 7 wherein 3-trifluoromethyl-benzylamine was reacted with 4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide to give the title compound. LC-MS [348 (M+1)], 1HNMR (400 MHz, DMSO-d6): δ 9.36-9.33 (m, 2H), 8.55-8.49 (m, 2H), 8.04 (s, 1H), 8.02-7.98 (m, 1H), 7.80 (s, 1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.59-7.56 (m, 1H), 5.00 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59])=[O:6]
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)c(F)c1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)cc2F)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
The 2-fluoro-4-(1-phenoxyethyl)benzoic acid (150 mg, 0.514 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (353 mg, 0.84 mmol) was dissolved in 20 mL dichloromethane, and then added triethylamine (2 mL). After the mixture was stirred at room temperature for 10 minute, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.514 mmol, 96 mg) was added. The mixture was stirred at room temperature for 12 hours then washed with water (10 mL), extracted with dichloromethane (20 mL). The organic layer were concentrated and s purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 2-fluoro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide (70 mg, 47%). LCMS (M+H+) m/z: calcd 394.17. found 394. 1H NMR (300 MHz, CD3OD) δ 7.69 (t, J=6.1 Hz, 1H), 7.28-7.13 (m, 4H), 6.86-6.81 (m, 3H), 6.06 (s, 1H), 5.43-5.41 (m, 1H), 4.47 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H). 1.57 (d, J=6.6 Hz, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a cold solution (ice water bath) of the compound (346 g, 1.48 mol) prepared in Example 6 in 4.2 L CH2Cl2, was added AlCl3 (984.6 g, 7.38 mol) portionwise under argon such that the reaction temperature was maintained below 10° C. The light brown suspension was stirred 10 minutes, then EtSH (546 mL, 7.38 mol) was added dropwise at such a rate that the reaction temperature was maintained below 5° C. After 2.5 h of stirring below 10° C., the reaction mixture was slowly poured into 6 L of ice water with strong agitation. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3×1 L). The combined CH2Cl2 layers were washed with water (2×1 L), then dried over Na2SO4. The solvent was removed under reduced pressure, giving a brown oil, which was filtered through a pad of silica gel (eluted with 0-10% EtOAc/Hexanes). Fractions were collected and the title compound (314 g, 96%) was obtained as a thick yellow oil after solvent removal and vacuum drying. 1H NMR (CDCl3) δ 6.92 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.10 (q, 2H), 3.43 (q, 1H), 2.75 (m, 2H), 2.64 (dd, 1H), 2.31 (dd, 1H), 2.29 (m, 1H), 1.67 (m, 1H), 1.20 (t, 3H). MS (CI) m/z 221 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH2:15])([CH2:13][CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:16](OC1C=CC=CC=1)=[O:17]>>[CH3:1][C:2]([NH:15][CH:16]=[O:17])([CH2:13][CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CCC(C)(N)Cc1c[nH]c2ccccc12
Reactant: O=COc1ccccc1
Product: CCC(C)(Cc1c[nH]c2ccccc12)NC=O

Procedure:
The 3-(2'-methyl-2'-aminobutyl)-indole obtained as reduction product in accordance with Example 1 or 3 was reacted with phenyl formate to yield 3-(2'-methyl-2'-formylaminobutyl)-indole; melting point 121.5°-124.5°C. (from ether). Reduction thereof with LiAlH4 yielded 3-(2'-methyl-2'-methylaminobutyl)-indole having a melting point of 100°-103°C. (from cyclohexane).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][C@@H:29]([CH3:45])[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([Cl:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:29]([NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[CH3:45])[N:32]=2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cnn(C)c2)on1
Reaction time: 24 h
Yield: 13.8 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (51 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 12 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.31 (m, 1H), 4.42-4.48 (m, 1H), 4.55-4.66 (m, 1H), 6.63 (d, 1H), 6.66 (s, 1H), 7.50 (d, 1H), 7.69 (d, 1H), 7.79-7.94 (m, 4H), 8.07 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[Cl:20][C:17]([F:19])([F:18])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)[C:3]([N:24]3[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1)([F:22])[F:21]
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using (R)-5-bromo-N-(4-(2-chloro-1,1,2,2-tetrafluoroethyl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 278.1) and pyrimidin-5-ylboronic acid to afford an amorphous white powder. HPLC (Condition 4) tR=5.21 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=496.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.77 (m, 1H) 1.78-1.89 (m, 1H) 2.82-2.92 (m, 1H) 3.14-3.26 (m, 2H) 3.32-3.42 (m, 1H) 4.15-4.26 (m, 1H) 4.87 (d, J=3.13 Hz, 1H) 7.63 (d, J=8.99 Hz, 2H) 7.97 (d, J=8.60 Hz, 2H) 8.10 (dd, J=2.35, 0.78 Hz, 1H) 8.79 (dd, J=2.35, 0.78 Hz, 1H) 8.88 (d, J=0.78 Hz, 2H) 9.18 (d, J=0.78 Hz, 1H) 10.31 (s, 1H).